HIV microbicide;
Sustained release;
Silicone elastomer;
Sheep pharmacokinetics;
Protein drug delivery;
INTRAVAGINAL RING;
SILICONE ELASTOMER;
CONTROLLED-RELEASE;
POLYCAPROLACTONE MATRICES;
CURE CHARACTERISTICS;
DRUG RELEASE;
PROTEIN;
TENOFOVIR;
SAFETY;
PHARMACOKINETICS;
D O I:
10.1016/j.jconrel.2019.02.003
中图分类号:
O6 [化学];
学科分类号:
0703 ;
摘要:
Antiretroviral-releasing vaginal rings are at the forefront of ongoing efforts to develop microbicide-based strategies for prevention of heterosexual transmission of the human immunodeficiency virus (HIV). However, traditional ring designs are generally only useful for vaginal administration of relatively potent, lipophilic, and small molecular weight drug molecules that have sufficient permeability in the non-biodegradable silicone elastomer or thermoplastic polymers. Here, we report a novel, easy-to-manufacture 'exposed-core' vaginal ring that provides sustained release of the protein microbicide candidate 5P12-RANTES, an experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. In vitro release, mechanical, and stability testing demonstrated the utility and practicality of this novel ring design. In a sheep pharmacokinetic model, a ring containing two 1/4 -length excipient-modified silicone elastomer cores - each containing lyophilised 5P12-RANTES and exposed to the external environment by two large windows - provided sustained concentrations of 5P12-RANTES in vaginal fluid and vaginal tissue between 10 and 10,000 ng/g over 28days, at least 50 and up to 50,000 times the reported in vitro IC50 value.
机构:
Case Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA
Case Western Reserve Univ, Dept Med, Div Infect Dis, Cleveland, OH 44106 USACase Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA
Lobritz, Michael A.
Ratcliff, Annette N.
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机构:
Case Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA
Case Western Reserve Univ, Dept Med, Div Infect Dis, Cleveland, OH 44106 USACase Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA
Ratcliff, Annette N.
Marozsan, Andre J.
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Case Western Reserve Univ, Dept Med, Div Infect Dis, Cleveland, OH 44106 USA
Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USACase Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA
Marozsan, Andre J.
Dudley, Dawn M.
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Case Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USACase Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA
Dudley, Dawn M.
Tilton, John C.
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Case Western Reserve Univ, Ctr Prote & Bioinformat, Cleveland, OH 44106 USACase Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA
Tilton, John C.
Arts, Eric J.
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Case Western Reserve Univ, Dept Med, Div Infect Dis, Cleveland, OH 44106 USACase Western Reserve Univ, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA
机构:
Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Tan, Qiuxiang
Zhu, Ya
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Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Zhu, Ya
Li, Jian
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Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Li, Jian
Chen, Zhuxi
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Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Chen, Zhuxi
Han, Gye Won
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机构:
Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USAChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Han, Gye Won
Kufareva, Irina
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Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USAChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Kufareva, Irina
Li, Tingting
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Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Li, Tingting
Ma, Limin
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Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Ma, Limin
Fenalti, Gustavo
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Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USAChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Fenalti, Gustavo
Li, Jing
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Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Li, Jing
Zhang, Wenru
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Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Zhang, Wenru
Xie, Xin
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Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Xie, Xin
Yang, Huaiyu
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Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Yang, Huaiyu
Jiang, Hualiang
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机构:
Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Jiang, Hualiang
Cherezov, Vadim
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Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USAChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Cherezov, Vadim
Liu, Hong
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机构:
Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Liu, Hong
Stevens, Raymond C.
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机构:
Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA
ShanghaiTech Univ, iHuman Inst, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Stevens, Raymond C.
Zhao, Qiang
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Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
Zhao, Qiang
Wu, Beili
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Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R ChinaChinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China