Qualification: 
Ph.D
manzoork@aims.amrita.edu

Manzoor Koyakutty is a Professor at the Amrita Centre for Nanosciences and Molecular Medicine, Cochin, India. He specializes in the area of Cancer nanomedicine & Immunotherapeutics. Dr. Manzoor joined ACNS during June 2007 after 9 years of service as Staff-Scientist at the Defence Research and Development Organization (DRDO), Government of India. During this tenure, he completed Ph. D. in Physics (Nanoscience) from DRDO (JNVU, Jodhpur) under the guidance of Dr. S. R. Vadera, Director, DRDO and Prof. T. R. N. Kutty, Indian Institute of Science, Bangalore. After shifting to Amrita, Dr. Manzoor’s team focused on the area of cancer-nanomedicine and developed many novel nano-systems to interfere with the complex biology of cancer. With the emergence of cancer-immunotherapy, his team also work on activating the immune system against cancer using novel nano-immunomedicines. Specific areas of research include: nanomedicines for drug -radiation resistant cancer and cancer stem cells, brain implantable nanomedicine for prolonged drug-delivery, nanoparticle-based image guided radio-wave therapy and photodynamic therapy, cancer immunotherapy using dendritic cells (DC), neo-mRNA nano-vaccines, Raman spectral imaging of cancer, application of artificial intelligence (IA) in nanomedicine and immunotherapy. He has 32 international patents (10 issued in USA/ Japan/China/Europe) and published more than 65 peer reviewed research papers in nanomedicine. Three IPs are licenced to pharma companies for commercial development. He serves as Associate Editor of the Journal: Precision Nanomedicine (European Foundation for Clinical Nanomedicine-CLINAM). He also served in the editorial board member of the journal Nanomedicine: NBM (Elsevier). He is an expert member in ‘Translational Nano-Biotechnology’ Task force, Dept. of Biotechnology, Govt of India. He is a co-founder of the bio-pharma start-up company M/s LuxMatra Innovations Pvt. Ltd, C-Camp, Bangalore.

Awards / Recognitions

  • 2003 DRDO Laboratory Scientist of the Year
  • 2004 DRDO Young Scientist Award
  • 2006 DRDO Technology Developer Award
  • 2003 National Science Day Award for best scientific publication, DRDO
  • 2004 National Science Day Award for best scientific publication, DRDO
  • 2005 National Science Day Award for best scientific publication, DRDO
  • 2006 National Science Day Award for best scientific publication, DRDO
  • 2007 Marie Curie International Incoming Fellowship (IIF), FP-7
  • 2013 Best Reviewer award, Journal Nanomedicine: NBM
  • 2014 Taskforce Member: RNAi Program, Govt of India
  • 2014 Taskforce Member: NanoBiotechnology Program, Govt of India
  • 2017 Fellow of National Academy of Sciences, FNASc (Biological Sciences)
  • 2018 Taskforce Member: Translational Nanomedicine Program, DBT, Govt of India
  • 2018 Assoc. Editor, Journal Precision nanomedicine (Eur. Found. for Clinical Nanomedicine)

Research Projects

  • Nano-fiber brain implant for prolonged and localized delivery of anti-glioma drugs: Funding by TPF-Nanomission, Dept of Sci & Tech (DST), India
  • Nanoparticle based gene editing using CRISPR-Cas 9, TPF-Nanomission, DST, India; Collaborator: Dr Lekshmi Sumitra, ACNS
  • Translational Development of Protein-Sorafenib nanomedicine, Dept of Biotechnology (DBT)
  • Translational development of nCP nanotheranostic agent, Dept of Biotechnology (DBT)
  • Nano-Photomedicine for Glioblastoma, M/s Lead Invent Pharma, USA,
  • Indo-Singapore Grant on stem cell tracking using nCP:Fe contrast agent (DBT), with Prof. Kishore Bhakoo, SBIC, Singapore
  • Portable Cancer Raman Device (DBT) : Dept of Biotechnology (DBT) with Dr Girish C M
  • Gamma Delta T Cell cancer immunotherapy, as Co-PI with Dr Anusha, SERB-DST
  • Nanoengineered autoantigens for the prevention and treatment of autoimmunity, Indo-Australian project with Dr K Menon and Claud Bernard, Monash University:
  • Controlled release of human hormones, M/S Function Promoting Technologies (FPT), Cambridge, USA

Publications

Publication Type: Journal Article

Year of Publication Title

2019

K. Meethaleve Sajesh, Anusha Ashokan, Gowd, G. Siddaraman, Dr. Manzoor K., Unni, A. K. K., and Shantikumar V Nair, “Magnetic 3D scaffold: A theranostic tool for tissue regeneration and non-invasive imaging in vivo.”, Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 18, pp. 179-188, 2019.[Abstract]


We report an osteoconducting magnetic 3D scaffold using Fe doped nano-hydroxyapatite-Alginate-Gelatin (AGHFe1) for Magnetic Resonance Imaging based non-invasive monitoring of bone tissue regeneration. In rat cranial defect model, the scaffold facilitated non-invasive monitoring of cell migration, inflammatory response and matrix deposition by unique changes in transverse relaxation time (T2). Cell infiltration resulted in a considerable increase in T2 from ~37 to ~62 ms, which gradually returned to that of native bone (~23 ms) by 90 days. We used this method to compare in vivo performance of scaffold with bone-morphogenic protein-2 (AGHFe2) or faster degrading (AGHFe3). MRI and histological analysis over 90 days showed non-uniform bone formation in AGHFe1 with ∆T2 (T2 - T2 ) ~13 ms, whereas, AGHFe2 and AGHFe3 showed ∆T2 ~ 09 and 05 ms respectively, suggesting better bone formation in AGHFe3. Thus, we show that MR-contrast enabled scaffold can help better assessment of bone-regeneration non-invasively.

More »»

2019

Girish C. M., Dr. Subramania Iyer K., Dr. Krishnakumar T., GS, G., Dr. Manzoor K., and Shantikumar V Nair, “A Novel Surface Enhanced Raman Catheter for Rapid Detection, Classification, and Grading of Oral Cancer”, Advanced Healthcare Materials, vol. 8, no. 13:e1801557, 2019.[Abstract]


Fabrication and testing of a novel nanostructured surface-enhanced Raman catheter device is reported for rapid detection, classification, and grading of normal, premalignant, and malignant tissues with high sensitivity and accuracy. The sensor part of catheter is formed by a surface-enhanced Raman scattering (SERS) substrate made up of leaf-like TiO2 nanostructures decorated with 30 nm sized Ag nanoparticles. The device is tested using a total of 37 patient samples wherein SERS signatures of oral tissues consisting of malignant oral squamous cell carcinoma (OSCC), verrucous carcinoma, premalignant leukoplakia, and disease-free conditions are detected and classified with an accuracy of 97.24% within a short detection-cum-processing time of nearly 25-30 min per patient. Neoplastic grade changes detected using this device correlate strongly with conventional pathological data, enabling correct classification of tumors into three grades with an accuracy of 97.84% in OSCC. Thus, the potential of a SERS catheter device as a point-of-care pathological tool is shown for the rapid and accurate detection, classification, and grading of solid tumors.

More »»

2018

A. R. Melge, Kumar, L. G., Pavithran, K., Shantikumar V Nair, Dr. Manzoor K., and Dr. Gopi Mohan C., “Predictive Models for Designing Potent Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia for Understanding its Molecular Mechanism of Resistance by Molecular Docking and Dynamics Simulations”, Journal of Biomolecular Structure and Dynamics, 2018.[Abstract]


BCR-ABL fusion protein drives chronic myeloid leukemia (CML) which constitutively activates tyrosine kinase involved in the initiation and maintenance of CML phenotype. Ponatinib, an oral drug, was discovered as an efficient BCR-ABL inhibitor by addressing imatinib drug resistance arising due to the point mutations at its active sites. In this study, 44 BCR-ABL kinase inhibitors, which are derivatives of ponatinib, were used to develop a robust two-dimensional quantitative structure–activity relationship (2D-QSAR) and 3D-Pharmacophore models by dividing dataset into 32 training sets and 12 test set molecules. 2D-QSAR model was developed using Genetic Function Approximation (GFA) algorithm consisting of four types of information-rich molecular descriptors, electrotopological (ES_Count_aasN and ES_Sum_aaaC), electronic (Dipole_X), spatial (PMI_Y) and thermodynamic (LogD), primarily contributing to BCR-ABL kinase inhibitory activity. For the best 2D-QSAR model, the statistics were R 2 = 0.8707, R 2 pred = 0.8142 and N = 32 for the training set molecules. Phase module of Schrödinger suit was employed for 3D-Pharmacophore model development showing five different pharmacophoric features–ADHHPRR with good R 2 of 0.9629, F of 175.3, Q 2 of 0.645 and root-mean-square error (RMSE) of 0.214 that are essential for an effective BCR-ABL kinase inhibition. These two models were further validated by cross-validation, test set predictions, enrichment factor calculations and predictions based on the external dataset. The molecular mechanism of resistance arising due to gate keeper mutation T315I of ABL kinase in complex with its inhibitors was also studied using molecular docking and molecular dynamics simulations. Our developed models predicted key chemical features for designing potent inhibitors against BCR-ABL kinase activity and its resistance mechanism to CML disease therapy. Communicated by Ramaswamy H. Sarma. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.

More »»

2018

F. Basheer, Melge, A. R., Sasidharan, A., Shantikumar V Nair, Dr. Manzoor K., and Dr. Gopi Mohan C., “Computational Simulations and Experimental Validation of Structure- Physicochemical Properties of Pristine and Functionalized Graphene: Implications for Adverse Effects on p53 Mediated DNA Damage Response”, International Journal of Biological Macromolecules, vol. 110, pp. 540-549, 2018.[Abstract]


<p>Recent reports indicated DNA damaging potential of few-layer graphene in human cell systems. Here, we used computational technique to understand the interaction of both pristine (pG) or carboxyl functionalized graphene (fG) of different sizes (1, 6, and 10nm) with an important DNA repair protein p53. The molecular docking study revealed strong interaction between pG and DNA binding domains (DBD) of p53 with binding free energies (BE) varying from -12.0 (1nm) to -34 (6nm)kcal/mol, while fG showed relatively less interaction with BE varying from -6.7 (1nm) to -11.1 (6nm)kcal/mol. Most importantly, pG or fG bound p53-DBDs could not bind to DNA. Further, microarray analysis of human primary endothelial cells revealed graphene intervention on DNA damage and its structure-properties effect using comet assay studies. Thus, computational and experimental results revealed the structure-physicochemical property dependent adverse effects of graphene in DNA repair protein p53.</p>

More »»

2017

A. Anitha, Menon, D., Sivanarayanan, T. B., Dr. Manzoor K., Mohan, C. C., Shantikumar V Nair, and Nair, M. B., “Bioinspired Composite Matrix Containing Hydroxyapatite-Silica Core-Shell Nanorods for Bone Tissue Engineering”, ACS Applied Materials and Interfaces, vol. 9, no. 32, pp. 26707-26718, 2017.

2017

A. Ashokan, Somasundaram, V. Harish, Gowd, G. Siddaraman, Anna, I. M., Malarvizhi, G. L., Sridharan, B., Jobanputra, R. B., Peethambaran, R., Unni, A. K. K., Shantikumar V Nair, and Dr. Manzoor K., “Biomineral Nano-Theranostic Agent for Magnetic Resonance Image Guided, Augmented Radiofrequency Ablation of Liver Tumor.”, Scientific Reports, vol. 7, no. 1, p. 14481, 2017.[Abstract]


<p>Theranostic nanoparticles based on biocompatible mineral compositions can significantly improve the translational potential of image guided cancer nano-therapy. Here, we report development of a single-phase calcium phosphate biomineral nanoparticle (nCP) with dual-mode magnetic resonance contrast (T1-T2) together with radiofrequency (RF) mediated thermal response suitable for image-guided RF ablation of cancer. The nanoparticles (NP) are engineered to provide dual MR contrast by an optimized doping concentration (4.1 at%) of paramagnetic ion, Fe, which also renders lossy dielectric character for nCP leading to thermal response under RF exposure. In vivo compatibility and dual-mode MR contrast are demonstrated in healthy rat models. MRI and T2 mapping suggest hepatobiliary clearance by ~96 hours. MRI guided intratumoral injection in subcutaneous rat glioma and orthotopic liver tumor models provide clear visualization of NP in MRI which also helps in quantifying NP distribution within tumor. Furthermore, by utilising RF mediated thermal response, NP treated tumor could be ablated using clinically approved RF ablation system (10 W,13.3 GHz). Real-time in vivo thermal imaging exhibits 119 ± 10% increase in temperature change (ΔT) for NP treated orthotopic liver tumor (ΔT = 51.5 ± 2 °C), compared to untreated healthy liver control (ΔT = 21.5 ± 2 °C). In effect, we demonstrate a promising nano-biomineral theranostic agent for dual-mode MRI combined with radiofrequency ablation of solid tumors.</p>

More »»

2017

R. Ramachandran, Junnuthula, V. Reddy, G Gowd, S., Ashokan, A., Thomas, J., Peethambaran, R., Thomas, A., Unni, A. Kodakara K., Panikar, D., Shantikumar V Nair, and Dr. Manzoor K., “Theranostic 3-Dimensional Nano Brain-Implant for Prolonged and Localized Treatment of Recurrent Glioma”, Scientific Reports, vol. 7, p. 43271, 2017.[Abstract]


Localized and controlled delivery of chemotherapeutics directly in brain-tumor for prolonged periods may radically improve the prognosis of recurrent glioblastoma. Here, we report a unique method of nanofiber by fiber controlled delivery of anti-cancer drug, Temozolomide, in orthotopic brain-tumor for one month using flexible polymeric nano-implant. A library of drug loaded (20 wt%) electrospun nanofiber of PLGA-PLA-PCL blends with distinct in vivo brain-release kinetics (hours to months) were numerically selected and a single nano-implant was formed by co-electrospinning of nano-fiber such that different set of fibres releases the drug for a specific periods from days to months by fiber-by-fiber switching. Orthotopic rat glioma implanted wafers showed constant drug release (116.6 μg/day) with negligible leakage into the peripheral blood (<100 ng) rendering ~1000 fold differential drug dosage in tumor versus peripheral blood. Most importantly, implant with one month release profile resulted in long-term (>4 month) survival of 85.7% animals whereas 07 day releasing implant showed tumor recurrence in 54.6% animals, rendering a median survival of only 74 days. In effect, we show that highly controlled drug delivery is possible for prolonged periods in orthotopic brain-tumor using combinatorial nanofibre libraries of bulk-eroding polymers, thereby controlling glioma recurrence.

More »»
PDF icontheranostic-3-dimensional-nano-brain-implant-for-prolonged-and-localized-treatment-of-recurrent-glioma.pdf

2016

V. H. Somasundaram, Pillai, R., Malarvizhi, G., Anusha Ashokan, Gowd, S., Peethambaran, R., Palaniswamy, S., Unni, A. K. K., Shantikumar V Nair, and Dr. Manzoor K., “Biodegradable Radiofrequency Responsive Nanoparticles for Augmented Thermal Ablation Combined with Triggered Drug Release in Liver Tumors”, ACS Biomaterials Science and Engineering, vol. 2, pp. 768-779, 2016.[Abstract]


Radiofrequency ablation (RFA) and doxorubicin (Dox) chemotherapy are separately approved for liver cancer therapy; however, both have limited success in the clinic due to suboptimal/nonuniform heating and systemic side effects, respectively. Here, we report a biodegradable nanoparticle (NP) system showing excellent RF hyperthermic response together with the ability to locally deliver Dox in the liver under RF trigger and control. The nanosystem was prepared by doping a clinically permissible dose (∼4.3 wt %, 0.03 ppm) of stannous ions in alginate nanoparticles (∼100 nm) coloaded with Dox at ∼13.4 wt % concentration and surface conjugated with galactose for targeting asialo-glycoprotein receptors in liver tumors. Targeted NP-uptake and increased cytotoxicity when combined with RF exposure was demonstrated in HEPG2 liver cancer cells. Following in vitro (chicken liver phantom) demonstration of locally augmented RF thermal response, in vivo scintigraphic imaging of 99Tc-labeled NPs was performed to optimize liver localization in Sprague-Dawley (SD) rats. RF ablation was performed in vivo using a cooled-tip probe, and uniformly enhanced (∼44%) thermal ablation was demonstrated with magnetic resonance imaging along with RF-controlled Dox release. In orthotopic rat liver tumor models, real-time infrared imaging revealed significantly higher (∼20 °C) RF thermal response at the tumor site, resulting in uniform augmented ablation (∼80%) even at a low RF power exposure of 15 W for just 1 min duration. Being a clinically acceptable, biodegradable material, alginate nanoparticles hold strong translational potential for augmented RF hyperthermia combined with triggered drug release.

More »»

2016

A. Sasidharan, Swaroop, S., Chandran, P., Shantikumar V Nair, and Dr. Manzoor K., “Cellular and molecular mechanistic insight into the DNA-damaging potential of few-layer graphene in human primary endothelial cells”, Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 12, pp. 1347-1355, 2016.[Abstract]


Despite graphene being proposed for a multitude of biomedical applications, there is a dearth in the fundamental cellular and molecular level understanding of how few-layer graphene (FLG) interacts with human primary cells. Herein, using human primary umbilical vein endothelial cells as model of vascular transport, we investigated the basic mechanism underlying the biological behavior of graphene. Mechanistic toxicity studies using a battery of cell based assays revealed an organized oxidative stress paradigm involving cytosolic reactive oxygen stress, mitochondrial superoxide generation, lipid peroxidation, glutathione oxidation, mitochondrial membrane depolarization, enhanced calcium efflux, all leading to cell death by apoptosis/necrosis. We further investigated the effect of graphene interactions using cDNA microarray analysis and identified potential adverse effects by down regulating key genes involved in DNA damage response and repair mechanisms. Single cell gel electrophoresis assay/Comet assay confirmed the DNA damaging potential of graphene towards human primary cells. © 2016 Elsevier Inc.

More »»

2015

P. Chandran, Pavithran, K., Sidharthan, N., Sasidharan, A., Shantikumar V Nair, and Dr. Manzoor K., “Protein Nanomedicine Exerts Cytotoxicity toward CD34+ CD38– CD123+ Leukemic Stem Cells”, ACS Biomaterials Science & Engineering, vol. 1, pp. 1194-1199, 2015.[Abstract]


The efficacy of protein-vorinostat nanomedicine (NV) is demonstrated in leukemic stem cells (LSC) isolated from refractory acute myeloid leukemia (AML) patient samples, where it successfully ablated both CD34+ CD38– CD123+ LSC and non-LSC “leukemic blast” compartments, without inducing myelosuppression or hemotoxicity. Besides, NV also exerted excellent synergistic lethality against leukemic bone marrow cells (BMC) at lower concentrations (0.1 μM) in combination with DNA methyltransferase (DNMT) inhibitor, decitabine. Considering the extermination of resilient LSC and synergism with decitabine, NV shows promise for clinical translation in the setting of a more tolerable and effective epigenetic targeted therapy for leukemia

More »»

2015

A. Sasidharan, Sivaram, A. J., Retnakumari, A. P., Chandran, P., Malarvizhi, G. Loghanatha, Shantikumar V Nair, and Dr. Manzoor K., “Radiofrequency Ablation of Drug-Resistant Cancer Cells Using Molecularly Targeted Carboxyl-Functionalized Biodegradable Graphene”, Advanced Healthcare Materials, vol. 4, pp. 679-684, 2015.[Abstract]


Under ultralow radiofrequency (RF) power, transferrin-conjugated graphene nanoparticles can thermally ablate drug- or radiation-resistant cancer cells very effectively. The results suggest that graphene-based RF hyperthermia can be an efficient method to manage drug-/radiation-resistant cancers.

More »»

2015

Abhilash Sasidharan, Siddharth Swaroop, Chaitanya K. Koduri, Girish C. M., Parwathy Chandran, L.S. Panchakarla, Vijay H. Somasundaram, Genekehal S. Gowd, Shantikumar V Nair, and Dr. Manzoor K., “Comparative in Vivo Toxicity, Organ Biodistribution and Immune Response of Pristine, Carboxylated and PEGylated Few-layer Graphene Sheets in Swiss Albino Mice: A three month study”, Carbon, vol. 95, pp. 511 - 524, 2015.[Abstract]


We present a comprehensive 3 month report on the acute and chronic toxicity of intravenously administered (20&nbsp;mg&nbsp;kg−1) few-layer graphene (FLG) and, its carboxylated (FLG-COOH) and PEGylated (FLG-PEG) derivatives in Swiss albino mice. Whole-animal in&nbsp;vivo tracking studies revealed that irrespective of surface modifications, graphene predominantly accumulated in lungs over a period of 24&nbsp;h. Histological assessment and ex&nbsp;vivo confocal Raman spectral mapping revealed highest uptake and retention in lung tissue, followed by spleen, liver and kidney, with no accumulation in brain, heart or testis. FLG and FLG-COOH accumulated within organs induced significant cellular and structural damages to lungs, liver, spleen, and kidney, ranging from mild congestion to necrosis, fibrosis and glomerular filtration dysfunction, without appreciable clearance. Serum biochemistry analysis revealed that both FLG and FLG-COOH induced elevated levels of hepatic and renal injury markers. Quantitative RT-PCR studies conducted on 23 critical inflammation and immune response markers showed major alterations in gene expression profile by FLG, FLG-COOH and FLG-PEG treated animals. FLG-PEG in spite of its persistance within liver and spleen tissue for 3 months, did not induce any noticeable toxicity or organ damage, and displayed significant changes in Raman spectra, indicative of their biodegradation potential.

More »»

2015

Dr. Manzoor K., D, B., Girish C. M., A, S., and S, N., “Transferrin-Conjugated Biodegradable Graphene for Targeted Radiofrequency Ablation of Hepatocellular Carcinoma”, ACS Biomaterials Science and Engineering, vol. 1, no. 12, pp. 1211-9, 2015.[Abstract]


Radiofrequency ablation (RFA) is a clinically established therapy for hepatocellular carcinoma (HCC). However, because of poor radio-thermal conductivity of liver tissues, RFA is less efficient against relatively larger (>5 cm) liver tumors. Recently, nanoparticle-enabled RFA has emerged as a better strategy. On the basis of our recent understanding on biodegradability and novel electrothermal properties of graphene, herein, we report development of transferrin conjugated, biodegradable graphene (TfG) for RFA therapy. Cellular uptake studies using confocal microscopy and Raman imaging revealed significantly higher TfG uptake by HCC cells compared to bare graphene. TfG-treated cancer cells upon 5 min exposure to 100 W, 13.5 MHz RF showed >85% cell death, which was 4 times greater than bare graphene. Further evaluation in 3D (3 Dimensional) HCC culture system as well as in vivo rat models demonstrated uniform destruction of tumor cells throughout the 3D microenvironment. This study reveals the potential of molecularly targeted graphene for augmented RFA therapy of liver tumor.

More »»

2015

N. Vadera, Anusha Ashokan, Genekehal S. Gowd, Sajesh, K. M., Chauhan, R. P., Dr. Jayakumar Rangasamy, Shantikumar V Nair, and Dr. Manzoor K., “Manganese doped Nano-bioactive Glass for Magnetic Resonance Imaging”, Materials Letters, vol. 160, pp. 335 - 338, 2015.[Abstract]


Magnetic resonance imaging (MRI) is an attractive method to image biomaterial implants owing to its high spatial resolution and absence of ionizing radiation. However, most of the biomaterials lack magnetic contrast sufficient enough to be imaged in MRI. Here, we report synthesis of manganese doped nano-bioactive glass (Mn-nBG) giving bright contrast for MRI. We have optimized a room temperature method of doping nBG for efficient T1 weighted magnetic contrast. In vitro study using primary mesenchymal stem cells showed no toxicity for Mn-nBG up to a tested concentration of 100µg/ml, suggesting potential applications in cell labeling and tissue engineering.

More »»

2015

M. G. Sangeet Nair, Dr. Ullas Mony, Dr. Deepthy Menon, Dr. Manzoor K., Sidharthan, N., Pavithran, K., Shantikumar V Nair, and Krishnakumar N. Menon, “Development and molecular characterization of polymeric micro-nanofibrous scaffold of a defined 3-D niche for in vitro chemosensitivity analysis against acute myeloid leukemia cells”, International journal of nanomedicine, 2015.[Abstract]


Standard in vitro drug testing employs 2-D tissue culture plate systems to test anti-leukemic drugs against cell adhesion-mediated drug-resistant leukemic cells that harbor in 3-D bone marrow microenvironments. This drawback necessitates the fabrication of 3-D scaffolds that have cell adhesion-mediated drug-resistant properties similar to in vivo niches. We therefore aimed at exploiting the known property of polyurethane (PU)/poly-L-lactic acid (PLLA) in forming a micro-nanofibrous structure to fabricate unique, not presented before, as far as we are aware, 3-D micro-nanofibrous scaffold composites using a thermally induced phase separation technique. Among the different combinations of PU/PLLA composites generated, the unique PU/PLLA 60:40 composite displayed micro-nanofibrous morphology similar to decellularized bone marrow with increased protein and fibronectin adsorption. Culturing of acute myeloid leukemia (AML) KG1a cells in FN-coated PU/PLLA 60:40 shows increased cell adhesion and cell adhesion-mediated drug resistance to the drugs cytarabine and daunorubicin without changing the original CD34(+)/CD38(-)/CD33(-) phenotype for 168 hours compared to fibronectin tissue culture plate systems. Molecularly, as seen in vivo, increased chemoresistance is associated with the upregulation of anti-apoptotic Bcl2 and the cell cycle regulatory protein p27(Kip1) leading to cell growth arrest. Abrogation of Bcl2 activity by the Bcl2-specific inhibitor ABT 737 led to cell death in the presence of both cytarabine and daunorubicin, demonstrating that the cell adhesion-mediated drug resistance induced by Bcl2 and p27(Kip1) in the scaffold was similar to that seen in vivo. These results thus show the utility of a platform technology, wherein drug testing can be performed before administering to patients without the necessity for stromal cells.

More »»

2015

S. Narayanan, Dr. Ullas Mony, Vijaykumar, D. K., Dr. Manzoor K., Dr. Bindhu Paul, and Dr. Deepthy Menon, “Sequential release of epigallocatechin gallate and paclitaxel from PLGA-casein core/shell nanoparticles sensitizes drug-resistant breast cancer cells”, Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 11, pp. 1399-1406, 2015.[Abstract]


Nanomedicines consisting of combinations of cytotoxic drugs and molecular targeted therapeutics which inhibit specific downstream signals are evolving as a novel paradigm for breast cancer therapy. This research addresses one such combination of Paclitaxel (Ptx), having several adversities related to the activation of NF-κB pathway, with Epigallocatechin gallate (EGCG), a multiple signaling inhibitor, encapsulated within a targeted core/shell PLGA-Casein nanoparticle. The sequential release of EGCG followed by Ptx from this core/shell nanocarrier sensitized Ptx resistant MDA-MB-231 cells to Ptx, induced their apoptosis, inhibited NF-κB activation and downregulated the key genes associated with angiogenesis, tumor metastasis and survival. More importantly, Ptx-induced expression of P-glycoprotein was repressed by the nanocombination both at the protein and gene levels. This combination also offered significant cytotoxic response on breast cancer primary cells, indicating its translational value. From the Clinical Editor: Breast cancer is the most common cancer in women worldwide. As well as surgery, chemotherapy plays a major role in the treatment of breast cancer. The authors investigated in this article the combination use of a chemotherapeutic agent, Paclitaxel (Ptx), and an inhibitor of NF-?B pathway, packaged in a targeted nano-based delivery platform. The positive results provided a new pathway for future clinical use of combination chemotherapy in breast cancer. © 2015 Elsevier Inc.

More »»

2014

Dr. Sahadev Shankarappa, Dr. Manzoor K., and Shantikumar V Nair, “Efficacy versus Toxicity - The Yin and Yang in translating nanomedicines,”, Nanomaterials and Nanotechnology, vol. 4, no. 23, 2014.[Abstract]


Nanomedicine, as a relatively new offshoot of nanotechnology, has presented vast opportunities in biomedical research for developing novel strategies to treat diseases. In the past decade, there has been a significant increase in in vitro and preclinical studies addressing the benefits of nanomedicines. In this commentary, we focus specifically on the efficacy- and toxicity-related translational challenges of nanocarrier-mediated systems, and briefly discuss possible strategies for addressing such issues at in vitro and preclinical stages. We address questions related specifically to the balance between toxicity and efficacy, a balance that is expected to be substantially different for nanomedicines compared to that for a free drug. Using case studies, we propose a ratiometric assessment tool to quantify the overall benefit of nanomedicine as compared to free drugs in terms of efficacy and toxicity. The overall goal of this commentary is to emphasize the strategies that promote the translation of nanomedicines, especially by learning lessons from previous translational failures of other drugs and devices, and to apply these lessons to critically assess data at the basic stages of nanomedicinal research.

More »»

2014

Girish C. M., Iyer, S., Thankappan, K., Rani, V. V. D., Gowd, G. S., Menon, D., Nair, S., and Dr. Manzoor K., “Rapid Detection of Oral Cancer using Ag-TiO2 Nanostructured Surface-enhanced Raman Spectroscopic Substrates”, Journal of Materials Chemistry B, vol. 2, pp. 989-998, 2014.[Abstract]


The unique vibrational signatures of the biochemical changes in tissue samples may enable the Raman spectroscopic detection of diseases, like cancer. However, the Raman scattering cross-section of tissues is relatively low and hence the clinical translation of such methods faces serious challenges. In this study, we report a simple and efficient surface-enhanced Raman scattering (SERS) substrate, for the rapid and label-free detection of oral cancer. Raman active silver (Ag) surfaces were created on three distinct titania (TiO 2) hierarchical nanostructures (needular, bipyramidal and leaf-like) by a process involving a hydrothermal reaction, followed by the sputter deposition of Ag nanoparticles (average size: 30 nm). The resulting SERS substrate efficiencies, measured using crystal violet (CV) as an analyte molecule, showed a highest analytical enhancement factor of ∼106, a detection limit ∼1 nM and a relative standard deviation of the Raman peak maximum of ∼13% for the nano-leafy structure. This substrate was used to analyze tissue sections of 8 oral cancer patients (squamous cell carcinoma of tongue) comprising a total of 24 normal and 32 tumor tissue sections and the recorded spectra were analyzed by principal component analysis and discriminant analysis. The tissue spectra were correctly classified into tumor and normal groups, with a diagnostic sensitivity of 100%, a specificity of 95.83% and the average processing time per patient of 15-20 min. This indicates the potential translation of the SERS method for the rapid and accurate detection of cancer. © 2014 The Royal Society of Chemistry.

More »»

2014

N. Ganesh, Anusha Ashokan, R kannan, R., Chennazhi, K., Shantikumar V Nair, and Dr. Manzoor K., “Magnetic Resonance Functional Nano-hydroxyapatite Incorporated Poly(caprolactone) Composite Scaffolds for in Situ Monitoring of Bone Tissue Regeneration by MRI”, Tissue Engineering - Part A, vol. 20, pp. 2783-2794, 2014.[Abstract]


In this study, we have reported the incorporation of a multi-modal contrast agent based on hydroxyapatite nanocrystals, within a poly(caprolactone)(PCL) nanofibrous scaffold by electrospinning. The multifunctional hydroxyapatite nanoparticles (MF-nHAp) showed simultaneous contrast enhancement for three major molecular imaging techniques. In this article, the magnetic resonance (MR) contrast enhancement ability of the MF-nHAp was exploited for the purpose of potentially monitoring as well as for influencing tissue regeneration. These MF-nHAp containing PCL scaffolds were engineered in order to enhance the osteogenic potential as well as its MR functionality for their application in bone tissue engineering. The nano-composite scaffolds along with pristine PCL were evaluated physico-chemically and biologically in vitro, in the presence of human mesenchymal stem cells (hMSCs). The incorporation of 30-40 nm sized MF-nHAp within the nanofibers showed a substantial increase in scaffold strength, protein adsorption, proliferation, and osteogenic differentiation of hMSCs along with enhanced MR functionality. This preliminary study was performed to eventually exploit the MR contrast imaging capability of MF-nHAp in nanofibrous scaffolds for real-time imaging of the changes in the tissue engineered construct. © Copyright 2014, Mary Ann Liebert, Inc.

More »»

2014

S. A. Shankarappa, Dr. Manzoor K., and Nair, S. V., “Efficacy versus Toxicity-The Ying and Yang in Translating Nanomedicines”, Nanomaterials and Nanotechnology, vol. 4, pp. 4–23, 2014.[Abstract]


Nanomedicine, as a relatively new offshoot of nanotechnology, has presented vast opportunities in biomedical research for developing novel strategies to treat diseases. In the past decade, there has been a significant increase in in vitro and preclinical studies addressing the benefits of nanomedicines. In this commentary, we focus specifically on the efficacy- and toxicity-related translational challenges of nanocarrier-mediated systems, and briefly discuss possible strategies for addressing such issues at in vitro and preclinical stages. We address questions related specifically to the balance between toxicity and efficacy, a balance that is expected to be substantially different for nanomedicines compared to that for a free drug. Using case studies, we propose a ratiometric assessment tool to quantify the overall benefit of nanomedicine as compared to free drugs in terms of efficacy and toxicity. The overall goal of this commentary is to emphasize the strategies that promote the translation of nanomedicines, especially by learning lessons from previous translational failures of other drugs and devices, and to apply these lessons to critically assess data at the basic stages of nanomedicinal research. More »»

2014

G. L. Malarvizhi, Retnakumari, A. P., Nair, S., and Dr. Manzoor K., “Transferrin Targeted Core-shell Nanomedicine for Combinatorial Delivery of Doxorubicin and Sorafenib Against Hepatocellular Carcinoma”, Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 10, pp. 1649-1659, 2014.[Abstract]


Combinatorial drug delivery is an attractive, but challenging requirement of next generation cancer nanomedicines. Here, we report a transferrin-targeted core-shell nanomedicine formed by encapsulating two clinically used single-agent drugs, doxorubicin and sorafenib against liver cancer. Doxorubicin was loaded in poly(vinyl alcohol) nano-core and sorafenib in albumin nano-shell, both formed by a sequential freeze-thaw/coacervation method. While sorafenib from the nano-shell inhibited aberrant oncogenic signaling involved in cell proliferation, doxorubicin from the nano-core evoked DNA intercalation thereby killing >. 75% of cancer cells. Upon targeting using transferrin ligands, the nanoparticles showed enhanced cellular uptake and synergistic cytotoxicity in  . 92% of cells, particularly in iron-deficient microenvironment. Studies using 3D spheroids of liver tumor indicated efficient penetration of targeted core-shell nanoparticles throughout the tissue causing uniform cell killing. Thus, we show that rationally designed core-shell nanoparticles can effectively combine clinically relevant single-agent drugs for exerting synergistic activity against liver cancer. From the Clinical Editor: Transferrin-targeted core-shell nanomedicine encapsulating doxorubicin and sorafenib was studied as a drug delivery system against hepatocellular carcinoma, resulting in enhanced and synergistic therapeutic effects, paving the way towards potential future clinical applications of similar techniques. © 2014 Elsevier Inc.

More »»

2013

Anusha Ashokan, Gowd, G. S., Somasundaram, V. H., Bhupathi, A., Peethambaran, R., Unni, A. K. K., ,, Shantikumar V Nair, and Dr. Manzoor K., “Multifunctional Calcium Phosphate Nano-contrast agent for Combined Nuclear, Magnetic and Near-Infrared Invivo Imaging”, Biomaterials, vol. 34, pp. 7143-7157, 2013.[Abstract]


Combination of three imaging techniques such as nuclear, magnetic and near-infrared fluorescence can aid in improved diagnosis of disease by synergizing specific advantages of each of these techniques such as deep tissue penetration of radiation signals, anatomical and functional details provided by magnetic contrast and better spatial resolution of optical signals. In the present work, we report the development of a multimodal contrast agent based on calcium phosphate nanoparticles (nCP), doped with both indocyanine green (ICG) and Gadolinium (Gd3+), and labeled with 99m-Technetium-methylene diphosphonate (99mTc-MDP) for combined optical, magnetic and nuclear imaging. In order to obtain the desired tri-modal contrast properties, the concentrations of ICG, Gd3+ and 99mTc were optimized at  0.15wt%, 3.38at% and  0.002ng/mg of nCP, respectively. The leaching-out of ICG was protected by an additional coating of polyethyleneimine (PEI). Toxicological evaluation of the final construct carried out on healthy human mononuclear cells, red-blood cells and platelets, showed excellent hemocompatibility. Invivo multimodal imaging using mice models revealed the ability to provide near-infrared, magnetic and nuclear contrast simultaneously. The nanoparticles also showed the potential for improved MR based angio-imaging of liver. Retention of intravenously administrated nanoparticles in the liver was reduced with PEGylation and the clearance was observed within 48h without causing any major histological changes in vital organs. Thus, we developed a non-toxic tri-modal nano-contrast agent using calcium phosphate nanoparticles and demonstrated its potential for combined nuclear, magnetic and near-infrared imaging invivo. © 2013 Elsevier Ltd.

More »»

2013

A. Sasidharan, Girish C. M., Gowd, G. S., Nair, S., and Dr. Manzoor K., “Confocal Raman Imaging Study Showing Macrophage Mediated Biodegradation of Graphene in Vivo”, Advanced Healthcare Materials, vol. 2, pp. 1489-1500, 2013.[Abstract]


This study is focused on the crucial issue of biodegradability of graphene under in vivo conditions. Characteristic Raman signatures of graphene are used to three dimensionally (3D) image its localization in lung, liver, kidney and spleen of mouse and identified gradual development of structural disorder, happening over a period of 3 months, as indicated by the formation of defect-related D'band, line broadening of D and G bands, increase in ID/IG ratio and overall intensity reduction. Prior to injection, the carboxyl functionalized graphene of lateral size ∼200 nm is well dispersed in aqueous medium, but 24 hours post injection, larger aggregates of size up to 10 μm are detected in various organs. Using Raman cluster imaging method, temporal development of disorder is detected from day 8 onwards, which begins from the edges and grows inwards over a period of 3 months. The biodegradation is found prominent in graphene phagocytosed by tissue-bound macrophages and the gene expression studies of pro-inflammatory cytokines indicated the possibility of phagocytic immune response. In addition, in vitro studies conducted on macrophage cell lines also show development of structural disorder in the engulfed graphene, reiterating the role of macrophages in biodegradation. This is the first report providing clear evidence of in vivo biodegradation of graphene and these results may radically change the perspective on potential biomedical applications of graphene. © 2013 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.

More »»

2013

Pa Chandran, Kavalakatt, Aa, Malarvizhi, G. La, Vasanthakumari, D. R. V. Na, Retnakumari, A. Pa, Sidharthan, Nb, Pavithran, Kb, Nair, Sa, and Dr. Manzoor K., “Epigenetics targeted protein-vorinostat nanomedicine inducing apoptosis in heterogeneous population of primary acute myeloid leukemia cells including refractory and relapsed cases”, Nanomedicine: Nanotechnology, Biology, and Medicine, 2013.[Abstract]


Aberrant epigenetics play a key role in the onset and progression of acute myeloid leukemia (AML). Herein we report in silico modelling based development of a novel, protein-vorinostat nanomedicine exhibiting selective and superior anti-leukemic activity against heterogeneous population of AML patient samples (n = 9), including refractory and relapsed cases, and three representative cell lines expressing CD34+/CD38- stem cell phenotype (KG-1a), promyelocytic phenotype (HL-60) and FLT3-ITD mutation (MV4-11). Nano-vorinostat having   100 nm size exhibited enhanced cellular uptake rendering significantly lower IC50 in AML cell lines and patient samples, and induced enhanced HDAC inhibition, oxidative injury, cell cycle arrest and apoptosis compared to free vorinostat. Most importantly, nanomedicine showed exceptional single-agent activity against the clonogenic proliferative capability of bone marrow derived leukemic progenitors, while remaining non-toxic to healthy bone marrow cells. Collectively, this epigenetics targeted nanomedicine appears to be a promising therapeutic strategy against various French-American-British (FAB) classes of AML. © 2013 Elsevier Inc. All rights reserved.

More »»

2013

P. Chandran, Gupta, N., Retnakumari, A. P., Malarvizhi, G. L., Keechilat, P., Nair, S., and Dr. Manzoor K., “Simultaneous Inhibition of Aberrant Cancer Kinome Using Rationally Designed Polymer-Protein Core-shell Nanomedicine”, Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 9, pp. 1317-1327, 2013.[Abstract]


Simultaneous inhibition of deregulated cancer kinome using rationally designed nanomedicine is an advanced therapeutic approach. Herein, we have developed a polymer-protein core-shell nanomedicine to inhibit critically aberrant pro-survival kinases (mTOR, MAPK and STAT5) in primitive (CD34+/CD38-) Acute Myeloid Leukemia (AML) cells. The nanomedicine consists of poly-lactide-co-glycolide core ( 250nm) loaded with mTOR inhibitor, everolimus, and albumin shell ( 25nm thick) loaded with MAPK/STAT5 inhibitor, sorafenib and the whole construct was surface conjugated with monoclonal antibody against CD33 receptor overexpressed in AML. Electron microscopy confirmed formation of core-shell nanostructure ( 290nm) and flow cytometry and confocal studies showed enhanced cellular uptake of targeted nanomedicine. Simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells, was demonstrated using immunoblotting, cytotoxicity and apoptosis assays. This cell receptor plus multi-kinase targeted core-shell nanomedicine was found better specific and tolerable compared to current clinical regime of cytarabine and daunorubicin. From the Clinical Editor: These authors demonstrate simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells by using rationally designed polymer-protein core-shell nanomedicine, provoding an advanced method to eliminate cancer cells, with the hope of future therapeutic use. © 2013 Elsevier Inc.

More »»

2012

V. G. Deepagan, Sarmento, B., Menon, D., Nascimento, A., Jayasree, A., Sreeranganathan, M., Dr. Manzoor K., Nair, S. V., and Dr. Jayakumar Rangasamy, “In Vitro Targeted Imaging and Delivery of Camptothecin using Cetuximab-Conjugated Multifunctional PLGA-ZnS Nanoparticles”, Nanomedicine, vol. 7, pp. 507-519, 2012.[Abstract]


Background: Targeted cancer therapy has been extensively developed to improve the quality of treatment by reducing the systemic exposure of cytotoxic drug. Polymeric nanoparticles with conjugated targeting agents are widely investigated because they offer tunability in particle size, drug release profile and biocompatibility. Materials &amp; methods: Here, we have prepared targeted multifunctional nanoparticles composed of a poly(lactic-co-glycolic acid) matrix, ZnS:Mn 2+ quantum dots and camptothecin, and targeted them to EGF receptor overexpressing cells with a cetuximab antibody. Results: Physicochemical characterization of multifunctional nanoparticles showed stable particles with sizes of &lt;200 nm. In vitro drug release and blood contact studies showed a sustained release profile, with limited hemolysis. In vitro cytotoxicity and cell uptake studies were carried out in A549, KB and MFC-7 cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, FACS, fluorescent microscopic images and spectroflourimetry. Conclusion: Our studies revealed higher camptothecin activity and uptake in cell lines that overexpress the EGF receptor. All these results suggest that anti-EGF receptor cetuximab-conjugated poly(lactic-co-glycolic acid) multifunctional nanoparticles can be used as a potential nanomedicine against cancer. © 2012 Future Medicine Ltd.

More »»

2012

Aa Sasidharan, Panchakarla, L. Sb, Sadanandan, A. Ra, Ashokan, Aa, Chandran, Pa, Girish, C. Ma, Menon, Da, Shantikumar V. Nair, Rao, C. N. Rb, and Dr. Manzoor K., “Hemocompatibility and macrophage response of pristine and functionalized graphene”, Small, vol. 8, pp. 1251-1263, 2012.[Abstract]


Graphene and its derivatives are being proposed for several important biomedical applications including drug delivery, gene delivery, contrast imaging, and anticancer therapy. Most of these applications demand intravenous injection of graphene and hence evaluation of its hemocompatibility is an essential prerequisite. Herein, both pristine and functionalized graphene are extensively characterized for their interactions with murine macrophage RAW 264.7 cells and human primary blood components. Detailed analyses of the potential uptake by macrophages, effects on its metabolic activity, membrane integrity, induction of reactive oxygen stress, hemolysis, platelet activation, platelet aggregation, coagulation cascade, cytokine induction, immune cell activation, and immune cell suppression are performed using optimized protocols for nanotoxicity evaluation. Electron microscopy, confocal Raman spectral mapping, and confocal fluorescence imaging studies show active interaction of both the graphene systems with macrophage cells, and the reactive oxygen species mediated toxicity effects of hydrophobic pristine samples are significantly reduced by surface functionalization. In the case of hemocompatibility, both types of graphene show excellent compatibility with red blood cells, platelets, and plasma coagulation pathways, and minimal alteration in the cytokine expression by human peripheral blood mononuclear cells. Further, both samples do not cause any premature immune cell activation or suppression up to a relatively high concentration of 75 μg mL -1 after 72 h of incubation under in vitro conditions. This study clearly suggests that the observed toxicity effects of pristine graphene towards macrophage cells can be easily averted by surface functionalization and both the systems show excellent hemocompatibility. Surface functionalization reduces the toxicity of pristine graphene towards macrophage cells in vitro. Macrophages show relatively high intracellular uptake of functionalized, hydrophilic graphene compared to hydrophobic pristine graphene. The excellent compatibility of both types of graphene with human blood components is demonstrated. Copyright © 2012 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.

More »»

2012

Anusha Ashokan, Parwathy Chandran, Sadanandan, A. R., Chaitanya K. Koduri, Retnakumari, A. P., Menon, D., Shantikumar V Nair, and Dr. Manzoor K., “Development and Haematotoxicological Evaluation of Doped Hydroxyapatite based Multimodal Nanocontrast Agent for Near-infrared, Magnetic Resonance and X-ray Contrast Imaging”, Nanotoxicology, vol. 6, pp. 652-666, 2012.[Abstract]


Multimodal molecular imaging provides both anatomical and molecular information, aiding early stage detection and better treatment planning of diseased conditions. Here, we report development and nanotoxicity evaluation of a novel hydroxyapatite nanoparticle (nHAp) based multimodal contrast agent for combined near-infrared (NIR), MR and X-ray imaging. Under optimised wet-chemical conditions, we achieved simultaneous doping of nHAp (size ∼50 nm) with indocyanine green and Gd3+ contributing to NIR contrast (∼750–850 nm), paramagnetic behaviour and X-ray absorption suitable for NIR, MR and X-ray contrast imaging, respectively. Haematocompatibility studies using stem cell viability, haemolysis, platelet activation, platelet aggregation and coagulation time analysis indicated excellent compatibility of doped nHAp (D-nHAp). Further, the immunogenic function studies using human lymphocytes (in vitro) showed that D-nHAp caused no adverse effects. Collectively, our studies suggest that D-nHAp with excellent biocompatibility and multifunctional properties is a promising nanocontrast agent for combined NIR, MR and X-ray imaging applications

More »»

2012

A. P. Retnakumari, Hanumanthu, P. L., Malarvizhi, G. L., Prabhu, R., Sidharthan, N., Thampi, M. V., Menon, D., Mony, U., Krishnakumar N. Menon, Keechilat, P., Nair, S., and Dr. Manzoor K., “Rationally Designed Aberrant Kinase-Targeted Endogenous Protein Nanomedicine Against Oncogene Mutated/Amplified Refractory Chronic Myeloid Leukemia”, Molecular Pharmaceutics, vol. 9, pp. 3062-3078, 2012.[Abstract]


Deregulated protein kinases play a very critical role in tumorigenesis, metastasis, and drug resistance of cancer. Although molecularly targeted small molecule kinase inhibitors (SMI) are effective against many types of cancer, point mutations in the kinase domain impart drug resistance, a major challenge in the clinic. A classic example is chronic myeloid leukemia (CML) caused by BCR-ABL fusion protein, wherein a BCR-ABL kinase inhibitor, imatinib (IM), was highly successful in the early chronic phase of the disease, but failed in the advanced stages due to amplification of oncogene or point mutations in the drug-binding site of kinase domain. Here, by identifying critical molecular pathways responsible for the drug-resistance in refractory CML patient samples and a model cell line, we have rationally designed an endogenous protein nanomedicine targeted to both cell surface receptors and aberrantly activated secondary kinase in the oncogenic network. Molecular diagnosis revealed that, in addition to point mutations and amplification of oncogenic BCR-ABL kinase, relapsed/refractory patients exhibited significant activation of STAT5 signaling with correlative overexpression of transferrin receptors (TfR) on the cell membrane. Accordingly, we have developed a human serum albumin (HSA) based nanomedicine, loaded with STAT5 inhibitor (sorafenib), and surface conjugated the same with holo-transferrin (Tf) ligands for TfR specific delivery. This dual-targeted "transferrin conjugated albumin bound sorafenib" nanomedicine (Tf-nAlb-Soraf), prepared using aqueous nanoprecipitation method, displayed uniform spherical morphology with average size of ∼150 nm and drug encapsulation efficiency of ∼74%. TfR specific uptake and enhanced antileukemic activity of the nanomedicine was found maximum in the most drug resistant patient sample having the highest level of STAT5 and TfR expression, thereby confirming the accuracy of our rational design and potential of dual-targeting approach. The nanomedicine induced downregulation of key survival pathways such as pSTAT5 and antiapoptotic protein MCL-1 was demonstrated using immunoblotting. This study reveals that, by implementing molecular diagnosis, personalized nanomedicines can be rationally designed and nanoengineered by imparting therapeutic functionality to endogenous proteins to overcome clinically important challenges like molecular drug resistance. © 2012 American Chemical Society.

More »»

2011

Abhilash Sasidharan, Chandran, P., Menon, D., Raman, S., Nair, S., and Dr. Manzoor K., “Rapid Dissolution of ZnO Nanocrystals in Acidic Cancer Microenvironment Leading to Preferential Apoptosis”, Nanoscale, vol. 3, pp. 3657-3669, 2011.[Abstract]


The microenvironment of cancer plays a very critical role in the survival, proliferation and drug resistance of solid tumors. Here, we report an interesting, acidic cancer microenvironment-mediated dissolution-induced preferential toxicity of ZnO nanocrystals (NCs) against cancer cells while leaving primary cells unaffected. Irrespective of the size-scale (5 and 200 nm) and surface chemistry differences (silica, starch or polyethylene glycol coating), ZnO NCs exhibited multiple stress mechanisms against cancer cell lines (IC50 ∼150 μM) while normal human primary cells (human dermal fibroblast, lymphocytes, human umbilical vein endothelial cells) remain less affected. Flow cytometry and confocal microscopy studies revealed that ZnO NCs undergo rapid preferential dissolution in acidic (pH ∼5-6) cancer microenvironment causing elevated ROS stress, mitochondrial superoxide formation, depolarization of mitochondrial membrane, and cell cycle arrest at S/G2 phase leading to apoptosis. In effect, by elucidating the unique toxicity mechanism of ZnO NCs, we show that ZnO NCs can destabilize cancer cells by utilizing its own hostile acidic microenvironment, which is otherwise critical for its survival.

More »»

2011

P. Chandran, Abhilash Sasidharan, Anusha Ashokan, Menon, D., Shantikumar V Nair, and Dr. Manzoor K., “Highly Biocompatible TiO2:Gd3+ Nano-contrast Agent with Enhanced Longitudinal Relaxivity for Targeted Cancer Imaging”, Nanoscale, vol. 3, pp. 4150-4161, 2011.[Abstract]


We report the development of a novel magnetic nano-contrast agent (nano-CA) based on Gd3+ doped amorphous TiO2 of size ∼25 nm, exhibiting enhanced longitudinal relaxivity (r1) and magnetic resonance (MR) contrasting together with excellent biocompatibility. Quantitative T1 mapping of phantom samples using a 1.5 T clinical MR imaging system revealed that the amorphous phase of doped titania has the highest r 1 relaxivity which is ∼2.5 fold higher than the commercially used CA Magnevist™. The crystalline (anatase) samples formed by air annealing at 250 °C and 500 °C showed significant reduction in r1 values and MR contrast, which is attributed to the loss of proton-exchange contribution from the adsorbed water and atomic re-arrangement of Gd 3+ ions in the crystalline host lattice. Nanotoxicity studies including cell viability, plasma membrane integrity, reactive oxygen stress and expression of pro-inflammatory cytokines, performed on human primary endothelial cells (HUVEC), human blood derived peripheral blood mononuclear cells (PBMC) and nasopharyngeal epidermoid carcinoma (KB) cell line showed excellent biocompatibility up to relatively higher doses of 200 μg ml-1. The potential of this nano-CA to cause hemolysis, platelet aggregation and plasma coagulation were studied using human peripheral blood samples and found no adverse effects, illustrating the possibility of the safe intravenous administration of these agents for human applications. Furthermore, the ability of these agents to specifically detect cancer cells by targeting molecular receptors on the cell membrane was demonstrated on folate receptor (FR) positive oral carcinoma (KB) cells, where the folic acid conjugated nano-CA showed receptor specific accumulation on cell membrane while leaving the normal fibroblast cells (L929) unstained. This study reveals that the Gd3+ doped amorphous TiO2 nanoparticles having enhanced magnetic resonance contrast and high biocompatibility is a promising candidate for molecular receptor targeted MR imaging. © 2011 The Royal Society of Chemistry.

More »»

2010

S. Setua, Menon, D., Asok, A., Nair, S., and Dr. Manzoor K., “Folate Receptor Targeted, Rare-earth Oxide Nanocrystals for Bi-modal Fluorescence and Magnetic Imaging of Cancer Cells”, Biomaterials, vol. 31, pp. 714-729, 2010.[Abstract]


Targeted cancer imaging using rare-earth oxide nanocrystals, free from heavy metals (Cd, Se, Te, Hg and Pb), showing bright red-fluorescence and magnetic resonance imaging (MRI) is presented. Y2O3 nanocrystals (YO NC) doped in situ with fluorescent (Eu3+) and paramagnetic (Gd3+) impurities and conjugated with a potential cancer targeting ligand, folic acid (FA), were prepared using an all-aqueous wet-chemical process. Structural, optical and magnetic properties of these multifunctional nanocrystals were investigated by X-ray diffraction, electron microscopy, photoluminescence and magnetization studies. Highly monodisperse nanocrystals of size w20 nm with cubic bixbyite crystal structure showed bright red-fluorescence when doped with Eu3{thorn}. Co-doping with Gd3+ and mild air drying resulted significantly enhanced fluorescence quantum efficiency of w60% together with paramagnetic functionality, enabling T1-weighted MR contrast withw5 times higher spin-lattice relaxivity compared to the clinically used Gd3+ contrast agent. Cytotoxicity and reactive oxygen stress studies show no toxicity by YO NC in both normal and cancer cells up to higher doses of 500 mM and longer incubation time, 48 h. Cancer targeting capability of FA conjugated NCs was demonstrated on folate receptor positive (FR+) human nasopharyngeal carcinoma cells (KB) with FR depressed KB (FRd) and FR negative (FR-) lung cancer cells A549 as controls. Fluorescence microscopy and flow-cytometry data show highly specific binding and cellular uptake of large concentration of FA conjugated NCs on FR+ve cells compared to the controls. Thus, the present study reveals, unique bi-modal contrast imaging capability, non-toxicity and cancer targeting capability of multiple impurities doped rare-earth oxide nanocrystals that can find promising application in molecular imaging.

More »»

2010

Anusha Ashokan, Menon, D., Nair, S., and Dr. Manzoor K., “A Molecular Receptor Targeted, Hydroxyapatite Nanocrystal based Multi-modal Contrast Agent”, Biomaterials, vol. 31, pp. 2606-2616, 2010.[Abstract]


Multi-modal molecular imaging can significantly improve the potential of non-invasive medical diagnosis by combining basic anatomical descriptions with in-depth phenotypic characteristics of disease. Contrast agents with multifunctional properties that can sense and enhance the signature of specific molecular markers, together with high biocompatibility are essential for combinatorial molecular imaging approaches. Here, we report a multi-modal contrast agent based on hydroxyapatite nanocrystals (nHAp), which is engineered to show simultaneous contrast enhancement for three major molecular imaging techniques such as magnetic resonance imaging (MRI), X-ray imaging and near-infrared (NIR) fluorescence imaging. Monodispersed nHAp crystals of average size ∼30 nm and hexagonal crystal structure were in situ doped with multiple rare-earth impurities by a surfactant-free, aqueous wet-chemical method at 100 °C. Doping of nHAp with Eu3+ (3 at%) resulted bright near-infrared fluorescence (700 nm) due to efficient 5D0-7F4 electronic transition and co-doping with Gd3+ resulted enhanced paramagnetic longitudinal relaxivity (r1 ∼12 mM-1 s-1) suitable for T1 weighted MR imaging together with ∼80% X-ray attenuation suitable for X-ray contrast imaging. Capability of MF-nHAp to specifically target and enhance the signature of molecular receptors (folate) in cancer cells was realized by carbodiimide grafting of cell-membrane receptor ligand folic acid (FA) on MF-nHAp surface aminized with dendrigraft polymer, polyethyleneimine (PEI). The FA-PEI-MF-nHAp conjugates showed specific aggregation on FR+ve cells while leaving the negative control cells untouched. Nanotoxicity evaluation of this multifunctional nHAp carried out on primary human endothelial cells (HUVEC), normal mouse lung fibroblast cell line (L929), human nasopharyngeal carcinoma (KB) and human lung cancer cell line (A549) revealed no apparent toxicity even upto relatively higher doses of 500 μg/mL and 48 h of incubation. Flow-cytometry based reactive oxygen species (ROS) analysis also showed no significant levels of ROS generation in the nHAp treated cells. The tri-modal contrast imaging functionality together with molecular receptor targeting capability and biocompatibility makes MF-nHAp a promising biomineral contrast agent for combinatorial molecular imaging. © 2009 Elsevier Ltd. All rights reserved.

More »»

Publication Type: Patent

Year of Publication Title

2018

Dr. Manzoor K., Malarvizhi, G. Loghanatha, and Shantikumar V Nair, “Nanoparticle Formulations for Delivering Multiple Therapeutic Agents”, 2018.[Abstract]


A formulation for treating a patient with hepatocellular carcinoma is disclosed. The formulation comprises therapeutic agents in the form of nanoparticles containing one or more proteins or polysaccharides. The therapeutic agent is conjugated to an active targeting agent causing the formulation to preferentially segregate to the hepatocellular carcinoma tissue to release the therapeutic agents. Methods of treating hepatocellular carcinoma using the formulations are also disclosed.

More »»

2017

Dr. Manzoor K., C.A.Bernard, C., Menon, K. N., Sadanandan, P., Payne, N. L., and Nair, S. V., “Composition and Methods for Autoimmune Disease Treatment”, U.S. Patent PCT/US17/477782017.

2017

Dr. Manzoor K., Nair, S., and Thayath, J., “Total Serum Protein Nanoparticle and Composition thereof for Therapeutic and Imaging Applications”, U.S. Patent 2017410146152017.

2017

Dr. Manzoor K., ,, and Nair, S., “Total Serum Protein Nanoparticles and Compositions Thereof for Therapeutic and Imaging Applications ”, U.S. Patent 2017410146152017.

2017

Dr. Manzoor K., M, S., A, A., Harish, V., and Nair, S., “MRI and CT Contrast-enabled Composite Implants for Image Guided Tissue Regeneration and Therapy”, U.S. Patent WO2017152127, PCT/US2017/ (filed)2017.

2017

Dr. Manzoor K., Anusha Ashokan, Harish, V., and Nair, S., “Radio-wave Responsive Doped Nanoparticles for Image Guided Therapeutics ”, U.S. Patent WO2017096342A1 (Filed)2017.

2017

C. Madathil Girish, Dr. Manzoor K., and K, S., “Single Substrate for Combined Raman-Mass Spectroscopic Analysis of Biological and Chemical Samples”, 2017.

2017

Dr. Manzoor K., Bernard, D. Claude C., Menon, D. Krishnakum, Sadanandan, P., and Payne, N. L., “Compositions and Methods for Autoimmune Disease Treatment ”, U.S. Patent PCT/US17/47778 – PCT (Patent Filed)2017.

2017

Anusha Ashokan, Dr. Manzoor K., Shantikumar V Nair, M, S., and Harish, V., “MRI and CT Contrast-enabled Composite Implants for Image-guided Tissue Regeneration and Therapy (Filed)”, U.S. Patent PCT/US2017/0207932017.

2017

Anusha Ashokan, Dr. Manzoor K., Shantikumar V Nair, and Harish, V., “Non-Iodinated Radiolabeled Radiopaque Microbeads with MRI Contrast for Radioembolization (Filed)”, U.S. Patent PCT/US2017/0334862017.

2017

Shantikumar V Nair, Dr. Manzoor K., and P, A., “Core - shell particle formulation for delivering multiple therapeutic agents”, 2017.

2017

Dr. Manzoor K., Robinson, D. J., Sterenborg, H. J. C. M., Kascakova, S., and Nair, S., “Targeted nano-photomedicines for photodynamic therapy of cancer”, 2017.[Abstract]


The present invention relates to a photosensitizer-containing nanoparticle, comprising a photosensitizer covalently bonded throughout at least a part of said nanoparticle to the nanoparticle matrix material and incorporated therein in a quasi-aggregated state. The present invention further relates to methods for producing the invention nanoparticles, and to methods of killing cancer cells by PDT treatment using the said nanoparticles.

More »»

2017

Dr. Manzoor K., Malarvizhi, G. Loghanatha, and Shantikumar V Nair, “Nanoparticle formulations for delivering multiple therapeutic agents ”, 2017.[Abstract]


A formulation for treating a patient with hepatocellular carcinoma is disclosed. The formulation comprises therapeutic agents in the form of nanoparticles containing one or more proteins or polysaccharides. The therapeutic agent is conjugated to an active targeting agent causing the formulation to preferentially segregate to the hepatocellular carcinoma tissue to release the therapeutic agents. Methods of treating hepatocellular carcinoma using the formulations are also disclosed.

More »»

2017

Dr. Manzoor K., Malarvizhi, G. Loghanatha, and Shantikumar V Nair, “Cartridge Connection Method for Precise Delivery of Liquid”, 2017.[Abstract]


A formulation for treating a patient with hepatocellular carcinoma is disclosed. The formulation comprises therapeutic agents in the form of nanoparticles containing one or more proteins or polysaccharides. The therapeutic agent is conjugated to an active targeting agent causing the formulation to preferentially segregate to the hepatocellular carcinoma tissue to release the therapeutic agents. Methods of treating hepatocellular carcinoma using the formulations are also disclosed.

More »»

2016

Shantikumar V Nair, Dr. Manzoor K., and P, A., “Core-shell particle formulation for delivering multiple therapeutic”, 2016.

2016

Dr. Manzoor K., Harish, V., Anusha Ashokan, and Nair, S., “Non-iodinated Radiopaque Microbeads, Capable of Binding to Radioisotopes for Trans-arterial Embolization and Trans-arterial Radioembolization”, U.S. Patent PCT No 201641017865 (Filed)2016.

2016

Dr. Manzoor K., R, D., and Nair, S., “Targeted Nano-photomedicines for Photodynamic Therapy of Cancer”, 2016.

2016

Dr. Manzoor K., Chandran, P., Archana, P. R., and Nair, S., “Core-shell Particle Formulation for Delivering Multiple Therapeutic Agents”, U.S. Patent US20140363514A12016.[Abstract]


A core-shell particle formulation for delivering multiple therapeutic agents is disclosed. More particularly, core-shell particle formulation configured to independently release therapeutic agents from the core and the shell. Moreover, the core-shell particle bearing therapeutic agents enables treatment against the diseases such as cancer, inflammatory and auto-immune diseases.

More »»

2015

Dr. Manzoor K., Robinson, D. J., Sterenborg, H. J. C. M., Kascakova, S., and Nair, S., “Targeted nano-photomedicines for photodynamic therapy of cancer (Japanese)”, 2015.

2015

Dr. Manzoor K., Robinson, D. J., Sterenborg, H. J. C. M., Kascakova, S., and Shantikumar V Nair, “Targeted Nano-photomedicines for Photodynamic Therapy of Cancer (Chinese)”, 2015.[Abstract]


The present invention relates to nanoparticles containing a photosensitizer, said nanoparticles comprising: one photosensitizer, the photosensitizer through at least a portion of the nanoparticle is covalently bonded to the nanoparticle matrix material and state of aggregation and quasi- into the nanoparticle matrix. The present invention further relates to a process for preparing nanoparticles of the present invention, and the use of the nanoparticles photodynamic therapy method of killing cancer cells.

More »»

2015

Dr. Manzoor K., Anusha Ashokan, Harish, V., and Shantikumar V Nair, “Radio-Wave Responsive Doped Nanoparticles for Image Guided Therapeutics (Filed)”, U.S. Patent 6495/CHE/20152015.

2014

Dr. Manzoor K., Verma, A., Vedera, S. Raj, Kutty, T. Raman Nara, and Kumar, N., “A Method for Making Single-Source Precursor for Semiconductor Nanocrystals”, 2014.

2014

Dr. Manzoor K., Verma, A., Vedera, S. Raj, Kutty, T. Raman Nara, and Kumar, N., “Single-Source Precursor for Semiconductor Nanocrystals”, 2014.

2014

Dr. Deepthy Menon, Shantikumar V. Nair, Dr. Manzoor K., Rani, V. V. Divya, and Lakshmanan, V. Kumar, “Nano surface modified metallic titanium implants for orthopaedic or dental applications and method of manufacturing thereof”, U.S. Patent PCT/IN2012/0007862014.[Abstract]


The present invention relates to a metallic implant product developed with surface nano features by means of wet hydrothermal technique, which provides better bio-compatibility and improved osteo-integration for specific use in orthopaedic and dental applications. Methods of creating nano features on surfaces of titanium di-oxide (Titania) on Ti implants and the corresponding improved implant behaviour as a consequence under in vivo conditions are demonstrated and proven in this invention.

More »»

2014

Dr. Manzoor K., Ashokan, A., Dr. Deepthy Menon, and Shantikumar V Nair, “The art, method, manner, process and system of multifunctional nanobiomaterial for molecular imaging and drug- delivery”, U.S. Patent PCT/IN2013/0001422014.[Abstract]


The present invention relates to a nano-sized material that can provide contrast enhancement for multiple molecular imaging mthods and also deliver therapeutic nucleic acids or chemodrugs at a specific site of disease such as cancer. In particular, the present invention relates to a nanosized synthetic calcium apatite based materials showing contrast imaging for visible to near-infrared fluroscence, magnetic resonance imaging and x-ray imaging together with targeted delivery of nucleic acid drugs (DNA or RNA) to specific cancer types.

More »»

2014

Dr. Manzoor K., Ashokan, A., and Shantikumar V Nair, “The art, method, manner, process and system of a nano-biomineral for multi-modal contrast imaging and drug delivery”, U.S. Patent PCT/IN2013/0001432014.[Abstract]


The present invention relates to a nano-sized material that can provide contrast enhancement for multple imaging methods and also deliver therapeutic molecules such as nucleic acids or chemo drugs to diseased sites such as cancer. In particular, the present invention relates to nano-sized synthetic calcium phosphates and calcium apatite nanomaterials showing simultaneous contrast for at least any two of the medical imaging modalities including radio, raman-, near-infrared fluroscence-, magnetic resonance and x-ray-imaging.

More »»

2014

V. Harish, Dr. Manzoor K., and Nair, S., “Stannous Doped Micro and Nano Particles for Augmented Radiofrequency Ablation”, U.S. Patent PCT/US2014/011153 (Filed)2014.[Abstract]


A composition for facilitating localized delivery of energy and of therapeutic agents to a lesion in tissue is disclosed comprising nanoparticles of a polysaccharide, gelatin or a polymer, wherein the nanoparticles are complexed with tin ions. The composition may comprise one or more therapeutic agents. The composition may be configured to improve the thermal effect of RF energy on a lesion and or to release the therapeutic agents to the lesion when RF energy is applied.

More »»

2014

Dr. Manzoor K., Retnakumari, A., and Shantikumar V Nair, “A core-shell nanostructure on the basis of proteins with corresponding therapeutic agents”, U.S. Patent PCT/IN2013/0001412014.[Abstract]


The present invention is related to the design and synthesis of nanomedicine comprising of a protein-protein composite or core-shell nanoparticle, where one protein carries one type of therapeutic molecule and second protein carries another type of therapeutic molecule. This nanomedicine formulation is intended for the treatment of diseases including cancer. To be specific, the current invention is designed to deliver two different types of therapeutic molecules in sequence or in combination using a single entity of nanoparticle formed by two different proteins that carry two therapeutic molecules separately

More »»

2013

Dr. Manzoor K., PARWATHY, C., Archana, P. R., and Shantikumar V Nair, “Polymer - polymer or polymer - protein core - shell nano medicine loaded with multiple drug molecules”, U.S. Patent PCT/IN2013/0001082013.[Abstract]


The present invention relates to the method of synthesis of core-shell nano medicine serving as a novel platform for the encapsulation of multiple therapeutic molecules enabling combinatorial therapy against diseases including cancer, inflammatory and auto-immune diseases and its associated manifestations. The core-shell nano-construct comprises of a biodegradable and biocompatible polymer as the core and another polymer or protein as the shell, aiding following constructs (i) polymer core-polymer shell and (ii) polymer core-protein shell. The core-shell nano medicine is developed in a manner to encapsulate at least one anti-cancer agent each in both the core and the shell

More »»

2013

R. Ramachandran, Dr. Manzoor K., and Shantikumar V Nair, “The art, method,manner process and system of fibrous bio-degradable polymeric wafers for the local delivery of therapeutic agents in combinations”, U.S. Patent PCT/IN2013/0001102013.[Abstract]


The present invention is related to flexible, fibrous, biocompatible and biodegradable polymeric wafer consisting of more than one polymeric fibres, each one loaded with different therapeutic agents having mutually exclusive synergistic activity. The wafer is capable of delivering the drugs locally in to the deceased site like tumor, inflammation, wound etc in a controlled and sustained fashion for enhanced therapeutic effect. The combination of drugs loaded in the wafer is chosen in such a way that the second or consecutive drugs will enhance or improve the therapeutic effect of the first drug

More »»

2012

Dr. Manzoor K., Chandran, P., and R, A. P., “Polymer-Polymer and Polymer-Protein Core-shell Nanomedicine loaded with Multiple Drug Molecule”, U.S. Patent Application # 644/CHE/2012 A, PCT/IN2013/0001082012.

2012

Dr. Manzoor K., Retnakumari, A., and Nair, S., “The Art, Method, Manner, Process and System of protein-protein nanomedicine comprising more than one therapeutic molecule”, U.S. Patent 2550/CHE/2012, US 14/585,0132012.

2012

Dr. Manzoor K., Shantikumar V Nair, Dr. Deepthy Menon, and Asok, A., “THE ART, METHOD, MANNER, PROCESS AND SYSTEM OF MULTIFUNCTIONAL NANOMEDICINE FOR MOLECULAR IMAGING AND SCINTILLATION THERAPY”, U.S. Patent 26/CHE/20122012.

2012

Dr. Manzoor K., Anusha Ashokan, and Shantikumar V Nair, “THE ART, METHOD, MANNER, PROCESS AND SYSTEM OF NANO-BIOMINERAL FOR MULTIMODAL CONTRAST IMGING AND DRUG DELIVERY (Filed)”, U.S. Patent 25/CHE/20122012.

2012

Dr. Manzoor K., Ramachandran, R., M, G. L., and Nair, S., “THE ART, METHOD, MANNER, PROCESS AND SYSTEM OF CORE-SHELL PHOTO-CHEMO NANOMEDICINE AND METHOD OF TREATING THE CANCER WITH THE SAME”, U.S. Patent 24/CHE/20122012.

2011

D. Menon, Shantikumar V. Nair, Dr. Manzoor K., V, D., and Lakshmanan, V. Kumar, “Nanosurface Modified Metallic Titanium Implants for Orthopedic or Dental Applications”, U.S. Patent #1644/CHE/20112011.

2011

Dr. Manzoor K., Retnakumari, A., and Shantikumar V Nair, “The Art, Method, Maner, Process and System of Protien-Sorafenib Nanomedicine”, U.S. Patent 3455/CHE/20112011.

2010

Dr. Jayakumar Rangasamy, Dr. Manzoor K., Shantikumar V Nair, Lakshmanan, V. K., Kumar, P. T. Sudheesh, and Abhilash, S., “The Art, Method, Manner, Process and System of Chitosan hydrogel / Nano Zinc Oxide Membranes for Wound Dressing Applications”, U.S. Patent 1025/CHE/20102010.

2009

Dr. Manzoor K., Anusha Ashokan, Menon, D., and Shantikumar V. Nair, “Multifunctional Nanobiomaterial for Molecular Imaging and Drug Delivery”, U.S. Patent # 2633/CHE/20092009.

Publication Type: Book Chapter

Year of Publication Title

2016

A. Retnakumari, Parwathy Chandran, Ramachandran, R., Malarvizhi, G. L., Nair, S., and Dr. Manzoor K., “Nanomedicines Targeted to Aberrant Cancer Signalling and Epigenetics”, in Handbook of Clinical Nanomedicine Nanoparticles, Imaging, Therapy, and Clinical Applications, vol. 1, Pan Stanford Publications USA, 2016.[Abstract]


deregulated protein kinase signaling plays a key role in cancer progression, metastasis, and drug resistance [4]. The past few decades witnessed an unprecedented emergence, success, and unfortunate failures of many small-molecule kinase inhibitors (SMI) targeting aberrantly activated protein kinase signaling in cancer [5, 6]. More than the pharmacological limitations, the failures associated with conventional drugs are related to the inability of these drugs to target multiple pathways activated in cancer cells. It is very clear that, successful management of cancer requires targeting of more than one key mechanistic pathway, almost simultaneously [7]. Most of the current work on cancer nanomedicine has focused on improving the efficacy of conventional chemotherapy drugs by encapsulating them in polymeric, protein, or liposomal carriers. Although this approach could greatly improve the potency of several chemodrugs such as Doxorubicin (Doxil®), Paclitaxel® (Abraxane®), and Daunorubicin (Daunoxome®), most of the complications of cancer remain unaddressed, mainly because none of these systems addresses molecular mechanisms of the disease [8-10]. It is believed that combinatorial therapy using multi-drug combinations against genomics, epigenomics, and aberrant proteomics may deliver a lethal blow to highly aggressive cancers. Under these circumstances, a single nanoconstruct carrying single drug may not be effective. A wide array of biocompatible polymers, proteins, or liposomes offer the versatility to create novel nano-architectures capable of carrying multiple drugs in a target specific fashion [11]. In this chapter, we review some of the recent developments in the area of multi-drug-loaded protein/polymer nanomedicines that can almost simultaneously target more than one key mechanistic pathway involved in cancer. 46.2 Protein Nanomedicine Targeted to

Aberrant Kinome Involved in Refractory CancerProteins are non-toxic drug delivery platforms intended for safe use in humans [12, 13]. A typical example of protein nanomedicine that revolutionized cancer therapy is Abraxane (paclitaxel-loaded

albumin) [20]. Albumin encapsulation could significantly improve the circulation kinetics of paclitaxel and also reduce its toxic side-

effects [14]. Celgene Inc, NJ, has developed nab-rapamycin having a mean particle size of ~100 nm, which is a saline dispersible nanoformulation intended for intravenous administration. nabrapamycin has shown excellent efficacy and safety profile in initial clinical trials in patients with unresectable advanced non-hematologic malignancies [15]. The availability of hydrophilic functional groups in the protein nanocarriers also enable them to be conjugated with ligands suitable for cell-specific targeting [16]. In most of the cases, nanomedicines were intended only to increase the circulation of drugs or reduce the toxic side effects by better targeting them in to diseased cells. However, nanomedicines have great potential in addressing critical issues in cancer such as metastasis and drug resistance, which are currently not much intervened.Drug resistance is a critical issue impeding cancer treatment [17]. The mode of evasion of cancer cells from the inhibitory effects of drugs can be attributed to pharmacokinetic, cytokinetic, cellular, and molecular mechanisms. Certain tumor cells may be inherently refractory to the inhibitory effects of cytotoxic chemodrugs and kinase inhibitors, owing to the presence of drug efflux proteins, highly active DNA repair mechanisms, presence of cancer stem cells etc. [18, 19]. Interestingly, certain cancers develop drug resistance owing to the activation of one or more alternative cell survival pathways other than the primary oncogenic pathway as in the case of chronic myeloid leukemia (CML) [20]. CML is a hematological malignancy attributed to the constitutive tyrosine kinase activity of BCR-ABL fusion protein. A small-molecule inhibitor, imatinib, had shown significant BCR-ABL kinase inhibition in vivo and has been the first-line therapy for newly diagnosed CML for the past few decades [21]. Although the drug is active in the early stages of the disease, a certain population of patients shows resistance to imatinib due to multitude of mechanisms such as point mutations in the BCRABL kinase domain and amplification of BCR-ABL oncogene [22]. Interestingly, apart from the above said mechanisms, preferential activation of certain protein kinases has also shown to play critical roles in drug resistant CML [23]. Among the preferentially activated survival kinases, STAT5 was over-expressed several folds in refractory cells compared to drug-sensitive cells [24, 25]. STAT5 is capable of transcriptionally regulating the expression of several other genes involved in cell cycle progression, anti-apoptotic

More »»

Publication Type: Book

Year of Publication Title

2012

Dr. Manzoor K., Abhilash Sasidharan, and Nair, S., Biomedical Applications of Graphene: Opportunities and Challenges. Wiley-VCH, 2012, pp. 373-408.[Abstract]


This chapter briefly reviews the opportunities and challenges involved in the use of graphene as a biomedical material. The opportunities are in drug delivery, biosensors, and other radiation therapies; but the challenges clearly will be the issues of systemic toxicity and long-term ill effects, such as carcinogenesis, and the problem of defining the physicochemical and structural characteristics of graphene that will minimize the toxicity and maximize whatever therapeutic advantages there are to be derived from this material

More »»