| According to the report by World Health Organization's International Agency for Research on Cancer(IARC),there were 19.29 million new cases of cancer globally and 9.96 million deaths reported in 2020.Cancer seriously threatens human health and life.Cisplatin(CDDP)has been widely used in the treatment of numerous solid tumors due to its broad-spectrum anticancer potency and strong antitumor activity.At the same time,the CDDP-loaded poly(glutamic acid)nanoformulations can effectively increase the blood circulation time of the drug,facilitate its aggregation in tumor tissue,and reduce its toxic and side effects.However,the application of poly(glutamic acid)-cisplatin nanoformulations is affected by limited drug delivery.To address this problem,we designed and synthesized three poly(glutamic acid)-cisplatin-based nanoformulations,and achieved the following research results:1.Calcium phosphate-cured poly(L-glutamic acid)-cisplatin and arsenic trioxide(ATO)nanoparticles.We used the calcium phosphate-cured technology to encapsulate CDDP-loaded polyethylene glycol monomethyl ether-block-poly(L-glutamic acid)(mPEG-b-PLG)nanoparticles and ATO in the core of calcium phosphate.The intracellular acid-sensitive nanofumulaiton NPPGN-Pt+As was developed for synergistic treatment of peritoneal metastasis of ovarian cancer in mice.NPPGN-Pt+As could circulate in blood for a long time,accumulate in tumor tissues,synergistically inhibit the tumor growth,and reduce its accumulation in normal organs,which thereby reduced toxic side effects.After NPPGN-Pt+As was endocytosed by tumor cells,PGN-Pt and ATO were released under the acidic environment of the cells.PGN-Pt slowly released CDDP in cells to maintain its effective concentration.CDDP and ATO synergistically increased the level of cellular ROS to kill tumor cells while enhancing the efficacy of CDDP to synergistically inhibit tumor progression,which finally improved tumor treatment effects;2.Enzyme-responsive dePEGylated PEG-grafted-poly(glutamic acid)-cisplatin nanoformulation.We designed and synthesized poly(L-glutamic acid)with matrix metalloproteinase(MMP)-sensitive dePEGylation,PEG-MMP-PLG.The bridging chemical bond between PEG and PLG was the peptide,PLGLAG with MMP-sensitive degradability.It could cause dePEGylation of PEG-MMP-PLG with overexpressed MMP-2 in the tumor microenvironment.CDDP was incorporated into the copolymer to form a polymer-metal composite nanoformulation,namely PEG-MMP-PLG-Pt.The PEGylated PLG-CDDP nanoformulations showed prolonged blood circulation time and increased CDDP content in tumor tissues.When entering tumor tissues,the overexpressed MMP in the tumor microenvironment cut off the bridging chemical bond between PEG and PLG,and the released PLG-Pt showed enhanced drug delivery efficiency and up-regulated anti-tumor efficacy.Compared with the undetachable PEG-PLG-Pt,the detachable PEGylated PEG-MMP-PLG-Pt with tumor microenvironment responsiveness showed improved antitumor efficacy.3.pH-responsive dePEGylated PEG-grafted-poly(glutamic acid)-cisplatin nanoformulation.We developed a pH-responsive dePEGylated poly(L-glutamic acid),PEG-pHe-PLG.Compare with PEG-MMP-PLG,the synthetic route of PEG-pHe-PLG was more convenient and cheaper.The bridging chemical bond between PEG and PLG was extracellular pH(pHe)-responsive 2,5-dihydroxy-4-methyl-2,5-dioxo-3-furanpropionic acid(CDM).The polypeptide could be dePEGylated in the acidic tumor microenvironment.CDDP was incorporated into the copolymer to form a polymer-metal complex nanoformulation,namely PEG-pHe-PLG-Pt.It showed prolonged blood circulation time and increased accumulation in tumor tissue.In the acidic microenvironment of tumor tissue the bridging chemical bond between PEG and PLG was cut off,and the released PLG-Pt had increased drug delivery efficiency and enhanced anti-tumor efficacy.Compared with PEG-MMP-PLG-Pt,the preparation of PEG-pHe-PLG-Pt was simpler,and due to better drug delivery efficiency,it showed stronger tumor suppression effects and lower toxicity. |
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