title: A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation.
abstract: Antagonizing MDM2 and MDMX to activate the tumor suppressor protein p53 is an attractive therapeutic paradigm for the treatment of glioblastoma multiforme (GBM). However, challenges remain with respect to the poor ability of p53 activators to efficiently cross the blood-brain barrier and/or blood-brain tumor barrier and to specifically target tumor cells. To circumvent these problems, we developed a cyclic RGD peptide-conjugated poly(ethylene glycol)-co-poly(lactic acid) polymeric micelle (RGD-M) that carried a stapled peptide antagonist of both MDM2 and MDMX (sPMI). The peptide-carrying micelle RGD-M/sPMI was prepared via film-hydration method with high encapsulation efficiency and loading capacity as well as ideal size distribution. Micelle encapsulation dramatically increased the solubility of sPMI, thus alleviating its serum sequestration. In vitro studies showed that RGD-M/sPMI efficiently inhibited the proliferation of glioma cells in the presence of serum by activating the p53 signaling pathway. Further, RGD-M/sPMI exerted potent tumor growth inhibitory activity against human glioblastoma in nude mouse xenograft models. Importantly, the combination of RGD-M/sPMI and temozolomide--a standard chemotherapy drug for GBM increased antitumor efficacy against glioblastoma in experimental animals. Our results validate a combination therapy using p53 activators with temozolomide as a more effective treatment for GBM.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China; Institute of Human Virology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Xishan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China; School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Lingyu
authors.initials: L
authors.lastname: Tai
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Jianchang
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Mingfei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China.
authors.forename: Cao
authors.initials: C
authors.lastname: Xie
authors.affiliation: Institute of Integrative Medicine, Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200041, PR China.
authors.forename: Linwei
authors.initials: L
authors.lastname: Lu
authors.affiliation: Institute of Human Virology, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, United States. Electronic address: wlu@ihv.umaryland.edu.
authors.forename: Wuyuan
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, PR China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, PR China; Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Shanghai 201203, PR China; State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 200433, PR China. Electronic address: wylu@shmu.edu.cn.
authors.forename: Weiyue
authors.initials: W
authors.lastname: Lu
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000737:chemistry; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D000077204:Temozolomide; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008823:Micelles; D010456:Peptides, Cyclic; D016159:Tumor Suppressor Protein p53; C507169:cyclic arginine-glycine-aspartic acid peptide; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols; D003606:Dacarbazine; D051736:Proto-Oncogene Proteins c-mdm2; D000077204:Temozolomide
keywords: Chemosensitization; Glioma-targeting delivery; Micelle; Stapled peptide; Temozolomide; p53