Synthesis Of Stimuli-Responsive Polymers And Their Applications In Drug Delivery

The key to efficient cancer drug delivery is to make the carrier hold the drug tightly during in the blood circulation but be able to release the carried drug quickly once inside the cells or the intracellular targeted sites. Herein, we designed and synthesized two stimuli-resonsive polymers to resolve this paradox.1) Cationic polymers have been widely explored as non-viral gene delivery vectors. However, cationic polymers are highly cytotoxic because of high density of cationic charges and large molecules. Furthermore, the two characters make them efficiently condense DNA into nanosized polyplexes, which can facilitate its cellular internalization but on the other hand hardly dissociate inside cells, hindering the DNA access to the DNA transcription machine for gene expression. In this study, we synthesized linear quaternized ammonium-based cationic polymers from 2,6-dibromomethylphenolic esters using Menschutkin Reaction. The cationic polymer packed DNA into polyplexes; once in the cytosol, the esterases hydrolyzed the phenolic ester, triggering a self-immolative chain fragmentation and leading to the quick release of the packed DNA for efficient transcription. At the same time, the fragmentation and the removal of the quaternary amine cationic charges decreased the polycation cytotoxicity.2) The micelles of block copolymers of poly(ethylene glycol) (PEG) are characteristic of long blood circulation time and have been extensively used as vehicles for drug delivery. However, micelles are also inherently dynamic and thus instable in the blood stream but slow release of the carried drugs once inside cells.Taking advantage of high concentrations of reactive oxygen species in cancer cells and easy oxidation of phenylboronic acid groups, we synthesized PEG-block-poly(phenylboronic acids) and fabricated micelles crosslinked with three kinds of polyphenols, including nordihydroguaiaretic acid (NDGA), epigallocatechin gallate (EGCG) and tannic acid (TA). The stable micelles could carry the anticancer drug doxorubicin (Dox) at very high loading efficiencies and loading contents up to 36% as well as loading camptothecin(CPT). The drug-loaded micelles had a pH-sensitive and H2O2-sensitive fast release behavior. In vitro MTT assays demonstrated that the drug loaded micelles inhibited the growth of MCF-7 breast cancer cells, and particularly, TA-crosslinked micelles could overcome multidrug resistance in MCF-7/ADR cells. Animal studies demonstrated that TA-crosslinked micelles increased antitumor activity against MCF-7/ADR xenograft tumors, compared to Dox.