Study On PH-Responsive Aliphatic Polycarbonate Anti-Tumor Nano-Drug Carriers

Since the 20th century,the incidence of cancer has been increasing year by year,and the treatment methods of cancer have been constantly updated.However,chemotherapy is still one of the main methods for malignant tumors in clinical practice at this stage.Common chemotherapeutic drugs are distributed throughout the body after injection because they are not targeted,causing toxic and side effects on the whole body while killing tumor cells.In order to solve these problems,nano drug carriers came into being.As a carrier of drug transport,polymer nanoparticles overcome the shortcomings of small molecule drugs such as rapid metabolism,serious toxic and side effects,low bioavailability and unstable blood drug concentration.In addition,it can effectively avoid the immune reaction of the organism,and the release residues in the human body can be degraded into innoxious small molecules and be expelled from the body.Aaliphatic polycarbonate with good biocompatibility is nontoxic,so is its degradation products.A series of polymers with different molecular weights can be prepared by changing the number of carbon atoms in the main chain of polycarbonate.Besides,the physical,chemical and biological properties of polycarbonate can be adjusted by changing the group in the side chain,so as to better adapt to the adhesion and growth of cells or tissues and organs and broaden its application scope in the medical field.Before drug-loaded nanoparticles enter tumor cells,they have to pass through complex biological barriers.Therefore,how to design intelligent drug-loaded nanoparticles has become a research hotspot.Based on the above research background,pH-responsive nano drug carriers taking advantage of the specific stimulation response at the tumor site were designed to enhance the uptake of drugs by tumor cells,optimize the drug release process,and achieve efficient treatment of tumors.This also provides a new research direction and design strategy for the development of intelligent nanocarriers.In the second chapter,an acid-sensitive polycarbonate-doxorubicin conjugate with tertiary amine and amino in the side chain(PMCC-P3)was synthesized and its molecular structure was determined by FT-IR and 1H NMR spectra.Then PMCC-P3 self-assembled and encapsulated lapatinib(LAP)to form double-drug nanoparticles DOX+LAP-M,which had high drug loading rate and significantly increased drug release rate under acidic conditions in vitro drug release experiments.DLS was used to monitor the charge conversion behavior from negative to positive under acidic pH.It was proved that DOX+LAP-M could reverse the charge under acidic conditions to promote endocytosis.In vitro fluorescence imaging showed that DOX+LAP-M nanoparticles could be highly enriched in the tumor site,reducing the toxic and side effects of multiple organs,and the effect of intracellular entry in tumor tissue was greatly enhanced.In vitro cytotoxicity tests showed that DOX+LAP-M nanoparticles had a pH-dependent inhibitory effect on tumor cells,and the nanoparticles had a significant drug synergistic effect.In vivo anti-tumor experiments in 4T1 tumor-bearing mice proved that charge-reversal nanoparticles had stronger targeting and cell-entry ability,and double-drug nanoparticles had better therapeutic effect than single-drug nanoparticles.During drug therapy,drug-loaded nanoparticles can effectively inhibit tumor growth with a lower systemic toxic and side effects.In the third chapter,an amphiphilic polycarbonate-doxorubicin conjugate DOX-P1 with tertiary amine group on its side chain was prepared.The main chain of the polymer carbonate was connected with DOX by benzimine bond,and the molecular structure was determined by FT-IR and 1H NMR spectra.DOX-P1 forms homogeneous spherical nanoparticles DOX-P1 NPS with negative charge on the surface through self-assembly.The nanoparticles have good dispersibility and stability under pH 7.4.Also,they have a narrow particle size distribution and high drug loading rate.In vitro drug release and cellular uptake tests showed that when DOX-P1 NPS was in pH 5.0 environment,the protonation of the tertiary amine generated charge repulsion,resulting in particle size expansion to fully expose the benzimine bond.This can promote the fracture of the benzimine bond and accelerate the ultra-fast release of the drug.In addition,in vitro cytotoxicity studies showed that the polymer P1 had good cytocompatibility and DOX-P1 NPS had obvious inhibitory effect on the proliferation of 4T1 cells.