Synthesis of plga-peg-plga polymer nano-micelles – carriers of combretastatin-like antitumor agent 16z

Abstract

One of the most important tendencies for the development of modern chemistry is related to the new trends in biomedicine and pharmacy. Today, significant advances have been made in the development of biodegradable and biocompatible polymer materials and the synthesis of corresponding polymer nano-micelles. In this work we aimed to synthesize new biodegradable and biocompatible block copolymers based on poly(lactide-co-glycolide) (PLGA) and poly (ethylene glycol) (PEG) with linear (ABA-type) architecture, to investigate their ability to form nanosized micelles and its aptitude to acts as carriers of combretastatin-like antitumor agents. The synthesis of linear PLGA1000-PEG1000-PLGA1000 block copolymer was carried out in line with standard procedures. The size and morphology of the obtained micelles were determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The capability of obtained micelles to adsorb and deliver combretastatin-like antitumor agents into living cells was also demonstrated. We showed that the obtained copolymers formed nanosized micelles with the combretastatin-like antitumor agent 16Z. In vitro biocompatibility results denote that all tested blank-nano-micelles are devoid of cytotoxic effects and may be used as non-toxic drug carriers to target cells. Cellular uptake of 16Z-loaded PLGA1000-PEG1000-PLGA1000 micelles by HepG2 cells showed continuous uptake up to 72 h and a delay in the cytotoxic effect of 16Z. In an attempt to design new biomimetic analogs of natural combretastatin A-4 (CA-4) and its synthetic amino-derivatives, we selected benzothiazolone heterocycles as a scaffold for a bioisosteric replacement. In silico, drug-likeness and toxicity predictions showed better properties of benzothioazolone CA-4 analogs. The obtained results are very promising and need future detailed investigations.