Oseltamivir-conjugated polymeric micelles prepared by RAFT living radical polymerization as a new active tumor targeting drug delivery platform

Abstract

Targeted drug delivery using polymeric nanostructures has been at the forefront of cancer research, engineered for safer, more efficient and effective use of chemotherapy. Here, we designed a new polymeric micelle delivery system for active tumor targeting followed by micelle-drug internalization via receptor-induced endocytosis. We recently reported that oseltamivir phosphate targets and inhibits Neu1 sialidase activity associated with receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) which are overexpressed in cancer cells. By decorating micelles with oseltamivir, we investigated whether they actively targeted human pancreatic PANC1 cancer cells. Amphiphilic block copolymers with oseltamivir conjugated at the hydrophilic end, oseltamivir-pPEGMEMA-b-pMMA (oseltamivir-poly(polyethylene glycol methyl ether methacrylate)-block-poly(methyl methacrylate), were synthesized using reversible addition-fragmentation chain transfer (RAFT) living radical polymerization. Oseltamivir-conjugated micelles have self-assembling properties to give worm-like micellar structures with molecular weight of 80 000 g mol(-1). Oseltamivir-conjugated water soluble pPEGMEMA, dose dependently, both inhibited sialidase activity associated with Neu1, and reduced viability of PANC1 cells. In addition, oseltamivir-conjugated micelles, labelled with a hydrophobic fluorescent dye within the micelle core, were subsequently internalized by PANC1 cells. Blocking cell surface Neu1 with anti-Neu1 antibody, reduced internalization of oseltamivir-conjugated micelles, demonstrating that Neu1 binding linked to sialidase inhibition were prerequisite steps for subsequent internalization of the micelles. The mechanism of internalization is likely that of receptor-induced endocytosis demonstrating potential as a new nanocarrier system for not only targeting a tumor cell, but also for directly reducing viability through Neu1 inhibition, followed by intracellular delivery of hydrophobic cytotoxic chemotherapeutics.

Recent advances in "smart" delivery systems for extended drug release in cancer therapy

“…Multiple functionalities using complex hydrophobic/hydrophilic polymeric structures prepared with highly controlled molecular weights and defined architectures are needed to enable self-assembled, stimuli-responsive regions (CO 2 , pH, and temperature) for triggered drug release and reactive groups for drug conjugation cross-linking and "click" chemistry. To this end, Kapishon et al 184 designed a specific smart chemotherapeutic delivery platform for active tumor targeting. They fabricated a new polymeric micelle-delivery system for active tumor targeting followed by micelle-drug internalization via receptor-induced endocytosis.…”

Synthetic Advancement of Neuraminidase Inhibitor “Tamiflu”

“…Tamiflu ‐conjugated micelles also utilized for active targeted delivery of a hydrophobic chemotherapeutic agent such as doxorubicin and paclitaxel and found that polymer‐conjugated Tamiflu inhibit neuraminidase activity representing sialidase activity of Neu1 within the EGFR, and reduce the viability of PANC1 cells . So it exhibits dual functionality by exerting an anti‐tumour cell effect, and at the same time delivering and internalizing a hydrophobic chemotherapeutic anti‐cancer . Fe 3 O 4 @OA/ Tamiflu MNPs is also a promising candidate for anticancer drugs for use in targeted therapy …”

Advancements in Polymer Science: ‘Smart’ Drug Delivery Systems for the Treatment of Cancer

“…38 To expand these targeted effects on the free enzyme, PANC-1 pancreatic cancer cells treated with soluble OP-pPEGMEMA conjugates in a dose-dependent manner achieved up to 45% reduction in cell viability. The OP-conjugated polymeric micelles specifically targeted Neu-1 similar to that of free OP.…”

“…The OP-conjugated polymeric micelles specifically targeted Neu-1 similar to that of free OP. 38 These OP-conjugated micelles targeting Neu-1 in complex with EGFRs provided a novel way of specific targeting and delivering chemotherapeutic agents by receptor-induced internalization of OPmicelles via Neu-1 binding.…”