title: Matrix metalloproteinases-2/9-sensitive peptide-conjugated polymer micelles for site-specific release of drugs and enhancing tumor accumulation: preparation and in vitro and in vivo evaluation.
abstract: Since elevated expression of matrix metalloproteinase (MMP)-2 and MMP-9 is commonly observed in several malignant tumors, MMPs have been widely reported as key factors in the design of drug delivery systems. Several strategies have been proposed to develop MMPs-responsive nanoparticles to deliver chemotherapeutics to malignant solid tumors. A stimuli-responsive drug delivery system, which could be cleaved by MMPs, was proposed in this study. By inserting an MMP-2/9 cleavable oligopeptide GPVGLIGK-NH2 (GK8) as spacer between α-tocopherol succinate (α-TOS) and methoxy-polyethylene glycol molecular weight (MW 2000 Da) activated by N-hydroxysuccinimide (mPEG2K-NHS), mPEG2K-GK8-α-TOS (TGK) was synthesized as the primary ingredient for MMP-2/9-sensitive micelles composed of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and TGK (n:n =40:60, TGK micelles). mPEG2K-α-TOS (T2K) was similarly synthesized as nonsensitive control. The TGK micelles showed better stability than nonsensitive micelles composed of TPGS and T2K (n:n =40:60, T2K micelles) owing to the inserted peptide. Fluorescence resonance energy transfer results indicated that TGK micelles could be successfully cleaved by MMP-2/9. Effective drug release was demonstrated in the presence of collagenase type IV, a mixture of MMP-2 and MMP-9. Compared with nonsensitive micelles, docetaxel (DTX)-loaded TGK micelles showed a fold higher cellular uptake in HT1080 cells. While the half-maximal inhibitory concentration (IC50) of TGK and T2K micelles were similar (P>0.05) in MCF-7 cells (MMP-2/9 underexpression), the IC50 values of the aforementioned micelles were 0.064±0.006 and 0.122±0.009 μg/mL, respectively, in HT1080 cells (MMP-2/9 overexpression). The MMP-2/9-sensitive micelles also demonstrated desired tumor targeting and accumulation ability in vivo. The results of in vivo antitumor effect evaluation indicate that TGK micelles are potent against solid tumors while maintaining minimum systemic toxicity compared with T2K micelles and DTX.
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education and People's Liberation Army of China, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education and People's Liberation Army of China, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education and People's Liberation Army of China, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Weitong
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education and People's Liberation Army of China, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Ren
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education and People's Liberation Army of China, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xianyi
authors.initials: X
authors.lastname: Sha
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education and People's Liberation Army of China, School of Pharmacy, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Fang
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003952:Diagnostic Imaging; D000077143:Docetaxel; D016503:Drug Delivery Systems; D065546:Drug Liberation; D004705:Endocytosis / Q000187:drug effects; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D013347:Subcellular Fractions / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D014810:Vitamin E / Q000737:chemistry; D024502:alpha-Tocopherol / Q000737:chemistry
chemical_list: D008823:Micelles; D010455:Peptides; D011108:Polymers; D043823:Taxoids; D014810:Vitamin E; D000077143:Docetaxel; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D024502:alpha-Tocopherol; C014225:tocophersolan
keywords: FRET; TPGS; matrix metalloproteinases; nanocarriers; stimuli responsive