Design And Study Of Tumor Acidity-activated Membranolytic Polymers

Membranolytic polymers(MPs)can kill tumor cells through a detergent-like mechanism,which ignores their metabolic heterogeneity and drug-resistance spectrum,opening up a promising strategy for cancer treatment.However,it is a challenge to achieve high selectivity for MPs in the context of subtle differences between tumor and normal tissues.Herein,we developed tumor acidity-activated macromolecular drugs that can be selectively activated in the acidic tumor microenvironment for cancer therapy.The work and main conclusions of this thesis are divided into the following two parts:(1)A series of block polymers with a poly(ethylene glycol)(PEG)block and a pH-responsive polymethacrylate block pendant with ionizable tertiary amine groups were prepared by Reversible Addition Fragmentation Chain Transfer(RAFT)polymerization.The cytotoxicity of these polymers is highly dependent on their protonation degree(PD,showing strong cytotoxicity at high PD and low cytotoxicity at low PD.Through the screening of different tertiary amines segments,we found that ethylpiperidine(C6)-contained polymer showed high selectivity at the characteristic pH of normal tissues(pH 7.4)and tumor tissues(pH 6.8)with PD at 22%and 95%,respectively;(2)A series of membranolytic polymers P(C6-R_x)(x is the proportion of hydrophobic monomers)which is comprised of a poly(ethylene glycol)(PEG)block and a pH-responsive membranolytic block(MB)with ionizable tertiary amine segments and hydrophobic segments were obtained through RAFT polymerization.At pH 7.4,the polymer was assembled into a nanoparticle with inactive MBs shielded in the compact micelle core by a PEG shell when majority of C6 were deprotonated and hydrophobic,exhibiting low membranolytic activity.At pH 6.8,the polymer transforms into a cationic nanoparticle with activated MB exposed after a sharp increase in the protonation of C6,resulting in potent membranolytic activity.We performed a screening and identified the top-performing polymer,P(C6-Bn₂₀)with benzyl group as the R group at a molar ratio at 20%,showing minimal toxicity at physiological pH(pH 7.4)and high toxicity at tumor acidity(pH 6.8)The all-atom molecular dynamics revealed that the cation-?interaction facilitated the insertion of benzyl groups-containing hydrophobic domains into the cell membranes.In vivo experiments have proved that P(C6-Bn₂₀)effectively inhibit the growth of tumors with minimal toxicity against normal tissues.In this thesis,we successfully designed a tumor acidity activated membranolytic polymer.