title: Preparation of a Thermosensitive Gel Composed of a mPEG-PLGA-PLL-cRGD Nanodrug Delivery System for Pancreatic Tumor Therapy.
abstract: It is hypothesized that a gel (NP-Gel) composed of thermosensitive gel (Gel) and nanoparticles (NP) can prolong drug release time and overcome the drug resistance of pancreatic tumor cells. Paclitaxel (PTX)-loaded monomethoxy (polyethylene glycol)-poly(d,l-lactide-co-glycolide)-poly(l-lysine)-cyclic peptide (arginine-glycine-aspartic-glutamic-valine acid) (mPEG-PLGA-PLL-cRGD) NP and NP-Gel were designed, optimized, and characterized using dynamic light scattering, transmission electron microscopy, high efficiency liquid chromatography, and rheological analyses. Aspc-1/PTX cell was used in a cell uptake test. A 3D cell model was used to mimic PTX elimination in tissue. The in vivo sustained release and antitumor effects were studied in Aspc-1/PTX-loaded nude mice with xerographic and in situ tumors. The NP were 133.7 ± 28.3 nm with 85.03% entrapped efficiency, 1.612% loaded ratio, and suitable rheological properties. PTX was released as NP from NP-Gel, greatly prolonging the release and elimination times to afford long-term effects. NP-Gel enhanced the uptake of PTX by Aspc-1/PTX cells more than using NP or the Gel alone. Gel and NP-Gel remained solid in the tumor and stayed over 50 days versus the several days of NP in solution. NP-Gel exhibited a much higher inhibition rate in vivo than in solution, NP, or the Gel alone. In conclusion, the antitumor effects of NP-Gel might arise from synergic effects from NP and the Gel. NP primarily reversed drug resistance, while the Gel prolonged release time considerably in situ. This preparation proved effective with a very small PTX dose (250 μg/kg) and exhibited few toxic effects in normal tissue.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200032, P. R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200032, P. R. China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200032, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of general Surgery, School of Medicine, Xinhua Hospital, Shanghai Jiao Tong University , Shanghai, 200092, P. R. China.
authors.forename: Bao-Shan
authors.initials: BS
authors.lastname: Han
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200032, P. R. China.
authors.forename: You-Rong
authors.initials: YR
authors.lastname: Duan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D005453:Fluorescence; D005782:Gels / Q000737:chemistry*; D006801:Humans; D008819:Mice, Nude; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000737:chemistry; D013696:Temperature
chemical_list: D000970:Antineoplastic Agents; D005782:Gels; D011091:Polyesters; C000609413:mPEG-PLGA-PLL-cRGD; D011107:Polylysine; D011092:Polyethylene Glycols; D017239:Paclitaxel
keywords: composite gel; nanoparticle; pancreatic tumor; sustained release; thermosensitive