Dual controlled delivery of squalenoyl-gemcitabine and paclitaxel using thermo-responsive polymeric micelles for pancreatic cancer.

Mandana Emamzadeh,George Pasparakis,Didier Desmaële,Patrick Couvreur

doi:10.1039/c7tb02899g

Abstract

In this study we report the synthesis of a themroresponsive block copolymer by reversible addition fragmentation transfer polymerization comprising poly(2-ethylhexyl methacrylate)-b-poly[di(ethylene glycol)methyl ether methacrylate-co-oligo(ethylene glycol)methyl ether methacrylate] as hydrophobic and thermoresponsive blocks respectively. The polymer self-assembles into sub-50 micelles and can carry simultaneously two drug molecules, namely squalene-gemcitabine and paclitaxel. Both drugs can be released from the micellar compartment in a thermally controlled manner owing to the controllable disruption of the micellar corona above the lower critical solution temperature of the polymer. We demonstrate that the formulation augments synergistically the cytotoxicity of the two drugs in vitro against a model pancreatic cancer cell line. More importantly, it is shown that the polymer exerts a direct interaction with the cell membrane which further augments the cytotoxicity of the drug cargo in a thermally controlled manner.

Highlights

The combination of GEM with other chemotherapeutic agents has been explored as an aggressive means to maximize the potency of therapeutic protocols, with the most notable examples the FOLFIRINOX7 protocol, and the co-administration of GEM with paclitaxel
Our proposed system comprises the synthesis of a thermoresponsive block copolymer with a hydrophobic block serving as the core and is made of poly(2-ethylhexyl methacrylate) (p(EHMA))
This polymer synthon was chosen by preliminary experiments which were performed with laurylmethacrylate and n-butyl methacrylate as potential hydrophobic building blocks; p(EHMA) was shortlisted as it exhibited the lowest critical micelle concentration and optimum colloidal stability compared to the other two candidates

Summary

Introduction

The combination of GEM with other chemotherapeutic agents has been explored as an aggressive means to maximize the potency of therapeutic protocols, with the most notable examples the FOLFIRINOX7 protocol, and the co-administration of GEM with paclitaxel (in the form of an albumin carrying PTX vehicle, nab-PTX). The polymers (5 mg) were dissolved in 1 mL of phosphatebuffered saline (PBS) pH 7.4 and gradually heated by immersing the solution in water bath of predetermined temperature and the LCST value was determined as the onset of optical turbidity for each sample by a Agilent Cary series UV-vis spectrophotometer at 550 nm. Drug loaded micelles (polymer 5 mg mLÀ1, and PTX/Sq-Gem 500 mg mLÀ1 each) dispersed in 5 mL of PBS pH 7.4 (0.01 M) were transferred in the dialysis cassette by using a syringe, which was immersed in 200 mL PBS pH 7.4 (0.01 M) containing 1% Tween 20. The free drugs were dissolved in DMSO and diluted in the medium; briefly, concentrated stock solutions of Sq-Gem and PTX were prepared (1 mg/200 mL of DMSO). By determining the PE, the survival fraction of the single cells seeded in the plates was calculated (eqn (3)) by dividing the PE of the treated cells by the PE of the control and multiplying by 100:

Results and discussion

Conflicts of interest

Conclusions