Antitumor Polymeric Prodrugs Based On PEGylated Multifunctional Alphatic Polyesters

Nowadays the development of prodrug for improving the water solubility, low selectivity, specific and bioavailability of numerous anticancer drugs is urgent and has attracted rapidly increasing attention in biomedical areas.In this dissertation, a series of polymeric prodrug with high drug loading content, high stability and multiple stimuli-response have been synthesized through polycondensation, "click" reaction and host-guest interaction, based on PEGylated multifunctional aliphatic polyesters.A novel polymeric prodrug model with alternative hydrophilic blocks and hydrophobic drug moieties has been developed for the first time. A multifunctional PEG derivative with multiple reducible disulfides and reactive hydroxyl groups was synthesized by the polycondensation of oligo(ethylene glycol) (OEG) with malic acid and 3,3’-dithiodipropionic acid. Ibuprofen was used as a model drug to link to the polymer through hydrolytic ester bond, resulting in amphiphilic OEG-ibuprofen alternative copolymer. This polymeric prodrug can form stable "core-shell" micelles in aqueous media with a low critical micellar concentration (CMC:5.09 mg/L). Free ibuprofen molecules can also be steadily incorporated into the core of these micelles with a surprisingly high loading content (38.9 wt%). The in vitro release results indicate that there was a relatively rapid release of encapsulated ibuprofen molecules, while the conjugated ibuprofen moieties showed a slow and sustained release. Furthermore, the ibuprofen release could be accelerated in the presence of 10 mM DTT. Compared with the know form traditional polymeric prodrugs from amphiphilic block copolymer, this polymeric prodrug model with alternative hydrophile-hydrophobe architecture could achieve high drug loading content and high stability of the prodrug micelles simultaneously.Based on the above mentioned polymeric prodrug model, we have developed a series of antitumor polymeric prodrugs. DOX moieties were attached to the PEGylated multifunctional polyester via pH sensitive benzoic imine linkages, resulting in amphiphilic OEG-doxorubicin alternative copolymer, which can form stable micelles in aqueous solution. The micellar sizes could be well controlled by adjusting the chain length of OEG. The in vitro release results indicated only a minimal amount of DOX was released at physiological environment, but a rapid release of DOX occurred in acidic environment (tumor site).Considering the complexity and variability of in vivo environment, core-crosslinking was chosen to further improve the stability of the polymeric prodrug. Amphiphilic alternative multiblock copolymer with multi-enes and disulfides in hydrophobic blocks was synthesized by polycondensation, which can self-assemble into micelles in aqueous solution and encapsulated mercapto-modified doxorubicin and 1,6-hexanedithiol into the core for in situ drug conjugation and core crosslinking via thiol-ene "click" reaction, resulting in core crosslinked (CCL) nano-prodrug. As DOX was conjugated via a pH-sensitive hydrazone linkage, the in vitro release results showed a minimized release of DOX from polymeric prodrug at physiological environment, while a rapid release at tumor site (acidic pH and redox potential) with the cleavage of hydrazone linkage. Particularly, the release of DOX could also be significantly accelerated by treating with DTT, owing to the cleavage of the disulfide bonds, which leads to the disassociation of the micelles.However, the clinical outcomes of these polymeric prodrugs are discouraging because of the impossibility of pure polymeric prodrug for FDA approval. Herein we developed a novel pH sensitive CCL supramolecular polymeric prodrug by introducing anticancer drug into the polymer backbone through the host-guest interaction between β-cyclodextrin (β-CD) and adamatane (AD). Adamantine-modified doxorubicin (AD-DOX) was prepared as a small molecular prodrug by conjugating AD and DOX through a pH-sensitive hydrazone linkage. A β-CD derivative with multiple acryloyls (CD-acryl) was synthesized by the acylation of β-CD by acryloyl chloride. An amphiphilic alternative multiblock copolymer containing hydrophilic OEG block and hydrophobic polyester block with multiple thiol groups was synthesized by "one pot" polycondensation, which can self-assemble into micelles in aqueous solution. These micelles can encapsulate CD-acryl/AD-DOX complex for drug conjugation and in situ core crosslinking via thiol-ene "click" reaction, resulting in CCL supramolecular polymeric prodrug. In vivo studies suggested that this supramolecular polymeic prodrug possess significantly improved antitumor activity and security than DOX, which holds great promise to become a novel and smart nano-prodrug for clinical chemotherapy.