title: iRGD-mediated core-shell nanoparticles loading carmustine and O6-benzylguanine for glioma therapy.
abstract: iRGD (internalizing RGD) with high affinity to αν integrins was reported to enhance tumor penetrability by binding to neuropilin-1 (NRP-1). Based on our previous study, chitosan surface-modified poly (lactide-co-glycolides) nanoparticles (PLGA/CS NPs), loaded with carmustine (BCNU) and its sensitizer (O6-benzylguanine, BG) showed stronger anti-tumor effect than free drugs. In present study, PLGA/CS NPs (NPs) with core-shell structure were prepared and modified with iRGD or mPEG. F98, C6 or U87 cell lines with different receptors levels were selected for in vitro and in vivo studies. After administration of iRGD-mediated NPs, including iRGD-modified NPs (iRGD-NPs) and co-administration of iRGD and NPs (iRGD + NPs), their effects on glioma were compared with NPs. iRGD-NPs showed stronger cytotoxicity and cellular uptake than other groups. iRGD-NPs and iRGD + NPs displayed deeper tumor penetration and stronger anti-invasion effect on three dimensional (3D) glioma spheroids than NPs. On F98 glioma-bearing mice model, iRGD-mediated NPs showed enhanced crossing BBB ability and brain tumor accumulation levels. Correspondingly, the median survival time of iRGD + NPs, iRGD-NPs and NPs groups were 58, 49 and 34.5 days, respectively. Present studies supported the iRGD-mediated strategy to improve the efficacy of antitumor drug delivery system. Importantly, co-administration of iRGD may be a greater way over the conjugation of iRGD.
authors.affiliation: a Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Department of pharmaceutics , School of Pharmacy, Fudan University , Shanghai , China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: a Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Department of pharmaceutics , School of Pharmacy, Fudan University , Shanghai , China.
authors.forename: Sen
authors.initials: S
authors.lastname: Yao
authors.affiliation: a Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Department of pharmaceutics , School of Pharmacy, Fudan University , Shanghai , China.
authors.forename: Xuqian
authors.initials: X
authors.lastname: Li
authors.affiliation: a Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Department of pharmaceutics , School of Pharmacy, Fudan University , Shanghai , China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: a Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, Department of pharmaceutics , School of Pharmacy, Fudan University , Shanghai , China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002330:Carmustine / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004337:Drug Carriers; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry*; D059016:Tumor Microenvironment
chemical_list: D004337:Drug Carriers; C569656:N-end cysteine peptide tumor-homing peptide; D009842:Oligopeptides; C064976:O(6)-benzylguanine; D006147:Guanine; D002330:Carmustine
keywords: carmustine; glioma; iRGD; nanoparticle; tumor-penetrating peptide