Abstract
Inefficient nanoparticle accumulation in solid tumors hinders the clinical translation of cancer nanomedicines. Herein, we proposed that sildenafil, a vasodilator ampholyte, could be used to promote nanoparticle accumulation by inducing vasodilation after its tumor acidity-triggered release from the nanocarriers. To confirm this, sildenafil was first encapsulated in a cisplatin-incorporated polymeric micelle. The dense PEG shell of the micelle reduced its endocytosis by cancer cells, which in return resulted in accumulative extracellular release of protonated sildenafil in the acidic tumor microenvironment. The released sildenafil was found to be more effective in enlarging the tumor blood vessels than could be achieved without sildenafil. As a result, we demonstrated considerable improvement in the intratumoral accumulation of the sildenafil-cisplatin co-loaded nanoparticle and its enhanced cancer therapeutic efficacy over the control group. Given the generality of a dense PEG shell and a hydrophobic part in most clinically developed nanomedicines, this work implies the great potential of sildenafil as a simple and universal adjuvant to selectively promote the intratumoral accumulation of nanomedicines, thus improving their clinical translation.
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Biological Transport
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Blood Vessels / physiology
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Cell Line, Tumor
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Cisplatin / administration & dosage*
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Cisplatin / chemistry
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Cisplatin / pharmacokinetics
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Drug Liberation
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Female
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Hydrogen-Ion Concentration
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Melanoma, Experimental / blood supply
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Melanoma, Experimental / chemistry
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Melanoma, Experimental / drug therapy
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Melanoma, Experimental / metabolism*
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Mice, Inbred C57BL
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Micelles
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Nanoparticles / administration & dosage*
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Nanoparticles / chemistry
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Polyethylene Glycols / administration & dosage
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Polyethylene Glycols / chemistry
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Polyethylene Glycols / pharmacokinetics
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Polyglutamic Acid / administration & dosage
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Polyglutamic Acid / analogs & derivatives
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Polyglutamic Acid / chemistry
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Polyglutamic Acid / pharmacokinetics
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Rats, Sprague-Dawley
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Sildenafil Citrate / administration & dosage*
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Sildenafil Citrate / chemistry
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Sildenafil Citrate / pharmacokinetics
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Tissue Distribution
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Vasodilation
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Vasodilator Agents / administration & dosage*
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Vasodilator Agents / chemistry
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Vasodilator Agents / pharmacokinetics
Substances
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Antineoplastic Agents
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Micelles
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Vasodilator Agents
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poly-gamma-benzyl-L-glutamate
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Polyglutamic Acid
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Polyethylene Glycols
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monomethoxypolyethylene glycol
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Sildenafil Citrate
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Cisplatin