The Controlled Synthesis And Biomedical Properties Of N-(2-Hydroxypropyl) Methacrylamide And Lactide/Glycolide Based Amphiphilic Diblock Copolymers

Along with the further research on anticancer drugs, the application of polymers as drug carriers also receive increasing interest, novel drug delivery systems (DDS) are established via the physical embedding or chemical conjugation of anticancer drugs. Poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA), poly D,L-lactide (PDLLA) and poly(lactide-co-glycolide) (PLGA) can be used in drug delivery systems as high-molecular polymers due to their good biocompatibility and non-immunogenic characters. The introduction of these polymers can improve solubility of hydrophobic drugs in water solutions, reduce the toxicity to normal organs and increase the tumor inhibition efficacy.In this thesis, amphiphilic diblock copolymers PDLLA-b-PHPMA with relatively narrow molecular weight distribution (PDI<1.2) were synthesized via the combination of ring-opening polymerization (ROP) and reversible addition chain transfer (RAFT) polymerization with the introduction of hydroxyl group functionalized chain transfer agent under a mild condition. Compared with the literature reported methods, this method can decrease the reaction steps. Moreover, more defined structure and narrow molecular weight distribution (PDI) also could be obtained. Based on this amphiphilic diblock copolymers, nanoparticles and micelles were prepared with the use of high-pressure homogenizer Microfluidics (MicrofluidizerTM M110P) and dialysis method, respectively. Hydrophobic fluorescent probes such as Nile Red, Cy7.5 are physically entrapped in these polymerparticles to investigate their biological characteristics in cells and Balb/c mice which bearing 4T1 murine breast cancer model. Compared with traditional PDLLA-b-PEG nanoparticles, PDLLA-b-PHPMA shares the similar blood circulation half-life and better biological distribution patterns. Therefore, it is of great prospects to take PDLLA-b-PHPMA as an alternative of PDLLA-b-PEG in the application of carrier materials of anticancer drugs.During the above research process, we found that the drug loading capacity of free drugs in PDLLA-b-PHPMA nanoparticles was low. To overcome this obstacle, low molecular weight PLGA was designed to conjugate anticancer drugs such as DOX, PTX and SN38 via chemical bonds. Then nanoparticles based on these polymer-drug conjugates were prepared with the RAFT polymerized VE-PHPMA as surfactant. In this way, the drug loading capacity of hydrophobic drugs in nanoparticles could be greatly improved. Besides, these nanoparticles can co-load several anticancer drugs and serve as the carriers of combination therapy which passively targeted to tumor sites via EPR effect. The preliminary cytotoxicity assay revealed that the combination of these polymer-drug conjugates also helped to overcome the multidrug resistance (MDR) of cancer cells and improve the antitumor effect.