期刊
MOLECULAR PHARMACEUTICS
卷 17, 期 2, 页码 461-471出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.9b00883
关键词
pHLIP; tumor-targeted drug delivery; tumor acidity; transmembrane insertion; membrane permeability; drug size
资金
- NIH [R01-GM073857, R01-ES005775, R35-CA197574]
- NIH National Research Service Award [F30-CA196020]
- Yale University's NIH Medical Scientist Training Program grant [T32-GM007205]
- University of Connecticut
- UConn START PPOC award
- St. Baldrick's Foundation childhood cancer research grant
- [R01-CA037157]
Tumor-targeted drug delivery systems offer not only the advantage of an enhanced therapeutic index, but also the possibility of overcoming the limitations that have largely restricted drug design to small, hydrophobic, drug-like molecules. Here, we explore the ability of a tumor-targeted delivery system centered on the use of a pH-low insertion peptide (pHLIP) to directly deliver moderately polar, multi-kDa molecules into tumor cells. A pHLIP is a short, pH responsive peptide capable of inserting across a cell membrane to form a transmembrane helix at acidic pH. pHLIPs target the acidic tumor microenvironment with high specificity, and a drug attached to the inserting end of a pHLIP can be translocated across the cell membrane during the insertion process. We investigate the ability of wildtype pHLIP to deliver peptide nucleic acid (PNA) cargoes of varying sizes across lipid membranes. We find that pHLIP effectively delivers PNAs up to similar to 7 kDa into cells in a pH-dependent manner. In addition, pHLIP retains its tumor-targeting capabilities when linked to cargoes of this size, although the amount delivered is reduced for PNA cargoes greater than similar to 6 kDa. As drug-like molecules are traditionally restricted to sizes of similar to 500 Da, this constitutes an order-of-magnitude expansion in the size range of deliverable drug candidates.
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