title: Solid tumor penetration by integrin-mediated pegylated poly(trimethylene carbonate) nanoparticles loaded with paclitaxel.
abstract: Limited penetration of antineoplastic agents is one of the contributing factors for chemotherapy failure of many solid tumors. In order to enhance drug penetration into solid cancer, especially, into the avascular regions inside tumors, we proposed cyclic RGD peptide functionalized PEGylated poly(trimethylene carbonate) nanoparticles (c(RGDyK)-NP). By integrin-mediated transcytosis and enhanced drug permeation, c(RGDyK)-NP could access the neoplastic cells distant from blood vessels, and consequently, avoiding the capability of cancer regeneration from these tumor cells. In the present study, the solid tumor penetration, homing specificity and anticancer efficacy were evaluated both on the ex vivo 3D tumor spheroids and on the subcutaneous xenograft mice model. In comparison with conventional nanoparticles (NP/PTX) and Taxol, c(RGDyK)-NP/PTX showed the strongest penetration and accumulation into 3D tumor spheroids, a marked tumor-homing specificity in vivo and the greatest tumor growth inhibitory effect in vitro and in vivo. Histochemistry analysis revealed that no obvious histopathological abnormalities or lesions were observed in major organs after intravenous administration with the treatment doses. In conclusion, cyclic RGD peptide-conjugated PEG-PTMC nanoparticle could facilitate drug penetration and accumulation in tumor tissues and may be a promising vehicle for enhancing the chemotherapy of solid cancers.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Jiang
authors.forename: Hongliang
authors.initials: H
authors.lastname: Xin
authors.forename: Jijin
authors.initials: J
authors.lastname: Gu
authors.forename: Ximing
authors.initials: X
authors.lastname: Xu
authors.forename: Weiyi
authors.initials: W
authors.lastname: Xia
authors.forename: Shuo
authors.initials: S
authors.lastname: Chen
authors.forename: Yike
authors.initials: Y
authors.lastname: Xie
authors.forename: Liangcen
authors.initials: L
authors.lastname: Chen
authors.forename: Yanzuo
authors.initials: Y
authors.lastname: Chen
authors.forename: Xianyi
authors.initials: X
authors.lastname: Sha
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Fang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D004146:Dioxanes / Q000737:chemistry*; D005260:Female; D016023:Integrins / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D009369:Neoplasms / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D004146:Dioxanes; D016023:Integrins; D011108:Polymers; C059299:polytrimethylene carbonate; D011092:Polyethylene Glycols; D017239:Paclitaxel