Hydrazone-containing Biodegradable Polymeric Nanomicelles For Drug Delivery

Cancerous tissue is slightly acidic compared with normal tissue. Therefore, drug carriers of pH-sensitivity can delivery anti-tumor drugs in an efficient way. As a proof-of-concept, the work begins with rational designing of PEG-based marcroinitiators and applying ring-opening polymerization technique to construct hydrazone-containing biodegradable block polymers. Novel micelles are made from the polymers and used as pH responsive drug carriers.Different from traditional ones which hydrazone bonds were just to connect DOX to polymer matrix on side-chains, our micelles containing hydrazone bonds on backbone are suitable for to encapsule other kinds of anti-cancer drugs.Three macroinitiators containing hydrazone:PEG-Hzl, PEG-Hz2,PEG-DiHz were synthesized. Then, four polymers containing hydrazone were synthesized by the ring-opening polymerization of monomers,these copolymers are high biocompatible and degradable.This process allows for adjustment of the molecular weight of copolymers.From these polymers,pH-sensitive polymeric micelles were prepared with low critical micelle concentrations(CMC),the size of less than 100nm and uniform size distribution. There is a notable change in particle size of pH-sensitive polymer micelles in acidic condition (pH4.0 and pH5.0), while no change or significant change of non pH-sensitive polymeric micelles.Finally, this thesis report a pH-sensitive micelles with doxorubicin or paclitaxel as the model drug. The size of drug loaded micelles are within 100-200nm,larger than the non-drug loaded micelles, and the particle distribution is narrow. The experiment of drug release shows that drug release behavior of pH-sensitive drug loaded micelles present pH-dependent. At the same time, structure of polymer and hydrazone with different substituents have an impact on the release behavior. MTT assay shows that there is very small inhibiting effect of the blank micelles on Hela cells and RAW 264.7 cells,while Doxorubicin loaded micelles can inhibit both of the two cells:the inhibiting effect of drug loaded micelles is higher than the free drug, and the pH-sensitive drug loaded micelles is higher than the non pH-sensitive drug loaded micelles, PEG-Hzl-PLA drug loaded micelles is higher than PEG-Hz2-PLA drug loaded micelles. In conclusion, the chemical environment of hydrazone impacts the anti-tumor effect.