deregulated protein kinase signaling plays a key role in cancer progression, metastasis, and drug resistance . 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 . 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 . 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) . Albumin encapsulation could significantly improve the circulation kinetics of paclitaxel and also reduce its toxic side-
effects . 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 . The availability of hydrophilic functional groups in the protein nanocarriers also enable them to be conjugated with ligands suitable for cell-specific targeting . 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 . 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) . 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 . 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 . Interestingly, apart from the above said mechanisms, preferential activation of certain protein kinases has also shown to play critical roles in drug resistant CML . 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
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.