Study On Multifunctional Polymer Nanocarriers To Improve Antitumor Effect

Although nanocarriers and even smart nanocarriers have achieved great success in tumor treatment,the low permeability and retention capacity of nanocarriers under a variety of biological barriers,especially in complex tumor microenvironment,lead to low drug delivery efficiency,which directly affects the effect of tumor treatment.Low delivery efficiency may also bring systemic toxicity,drug resistance are challenges in cancer treatment.In addition,the nucleotide excision repair pathway of nuclear genome weakens the effect of chemotherapy drugs on tumor treatment with the nucleus as the target,and the tumor treatment and anti-tumor metastasis with the organelles including mitochondria,lysosomes and endoplasmic reticulum as the target show a good prospect.This thesis is devoted to design a series of intelligent nanocarriers to overcome the barriers of drug delivery in blood,tumor and intracellular delivery,especially in complex tumor environment,and to achieve a significant increase of drug concentration in deep tumor.The target therapy of mitochondrial genome without nuclear gene repair mechanism and the coordinated regulation of lysosome and endoplasmic reticulum are realized in the cell,which seriously destroys the cell homeostasis and improves the therapeutic effect and anti-tumor metastasis.The second chapter of this paper aims to solve the problem that various barriers formed by complex tumor microenvironment hinder the delivery of nanoparticles(NPs)in deep tumors,which leads to the low efficiency of drug delivery and the low accumulation in solid tumors.In this chapter,a newly developed size-changeable collagenase-modified polymer micelle is employed to enhance the penetration and retention of nanomedicine in deep tumor tissue.The TCPPB micelle is firstly formed by self-assembly of maleimide-terminated poly(ethylene glycol)-block-poly(?-amino ester)(MAL-PEG-PBAE)and succinic anhydride modified cisplatin conjugated poly(?-caprolactone)-block-poly(ethylene oxide)-triphenylphosphonium(CDDP-PCL-PEO-TPP).Next,Col-TCPPB NPs are prepared through a"click"chemical combination of thiolated collagenase and maleimide groups on TCPPB micelle.Finally,biocompatible chondroitin sulfate(CS)is coated to obtain CS/Col-TCPPB NPs for avoiding collagenase inactivation in blood circulation.In tumor acidic microenvironment,the hydrophobic PBAE segments of the resultant micelles become hydrophilic,leading to a dissociation and subsequent dissolution of partial collagenase containing components(Col-PEG-PBAE)from NPs.The dissolved Col-PEG-PBAE promotes the digestion of collagen fibers in tumor tissue like a scavenger,which enhances the NPs penetration.Simultaneously,the increased hydrophilicity of residual Col-PEG-PBAE in the micellar matrix causes an expansion of the NPs,resulting in an enhanced intratumoral retention.In tumor cells,the NPs target to release the cisplatin drugs into mitochondria,achieving an excellent anticancer efficacy.Compared with the median value of the drug accumulation reported in the literature,the drug tumor accumulation drug increased by 257.9%in the tissue distribution analysis,reaching 15.03±0.83 ID%g^-1.In vivo antitumor evaluation,the size-changeable collagenase-modified polymer nanoparticles achieved a tumor suppression effect of up to 94.6%.The third chapter of this paper proposes a new therapeutic approach for organelle therapy to fight tumors and inhibit tumor metastasis.Here,a p H-responsive polymersome co-delivering hydroxychloroquine(HCQ)and tunicamycin(Tuni)drugs is developed to induce endoplasmic reticulum(ER)stress and autophagic flux blockade simultaneously for achieving an antitumor effect and inhibiting tumor metastasis.The p H response of poly(?-amino ester)and HCQ synergistically de-acidifies the lysosomes,thereby blocking the fusion of autophagosomes and lysosomes and finally blocking autophagic flux.The function mechanism of regulating autophagy was systematically investigated on orthotopic luciferase gene-transfected 4T1(4T1-Luc)tumor-bearing BALB/c mice through western blot and immunohistochemistry analyses.The Tuni triggers ER stress to regulate the PERK/Akt signaling pathway to increase the autophagic level.The“autophagic stress”generated by triggering ER-stress-induced autophagy and blocking autophagic flux is effective against tumors.In addition,the reduced expression of matrix metalloproteinase-2 owing to ER stress and reduced focal adhesions(FAs)turnover owing to the blockade of autophagic flux synergistically inhibit tumor metastasis.The in vivo antitumor effect on 4T1-Luc in tumor-bearing BALB/c mice showed that approximately 60.0%of the tumors were completely cured,and the tumor growth inhibition rate was as high as 97.5%.In terms of inhibiting tumor metastasis,the smart polymersomes also successfully inhibited tumor metastasis,and the number of metastatic nodules was zero.The experimental results show that the multifunctional polymer nanocarrier constructed in this paper can effectively improve the anti-tumor effect,thereby providing a new treatment strategy and experimental basis for further improving the tumor treatment effect.