Co-delivery of cisplatin and rapamycin for enhanced anticancer therapy through synergistic effects and microenvironment modulation.
The tumor microenvironment plays an important role in the tumor's progression and metastasis. Therefore, successful alteration of this delicate setting against the tumor's favor can open a window for therapeutic efficacy. We have developed a modality to bring about treatment-induced alterations in the tumor microenvironment by employing the synergistic effects between two drugs. Co-delivery of rapamycin (RAPA), an mTOR inhibitor that may offer notable therapy through antiangiogenic activity, alongside cisplatin can foster significant potency as RAPA sensitizes A375 melanoma cells to cisplatin therapy through microenvironment modulation. However, encapsulation of these drugs into poly(lactic-co-glycolic acid) (PLGA) NPs was inefficient due to the incompatibility between the two free drugs and the polymer matrix. Here, we show cisplatin can be made hydrophobic by coating a nanoprecipitate (cores) of the drug with dioleoylphosphatidic acid (DOPA). These DOPA coated cisplatin cores are compatible with PLGA and can be coencapsulated in PLGA NPs alongside RAPA at a molar ratio to promote synergistic antitumor activity. The presence of the cisplatin cores significantly improved the encapsulation of RAPA into PLGA NPs. Furthermore, PLGA NPs containing both cisplatin cores and RAPA induced significant apoptosis on A375-luc human melanoma cells in vitro. Additionally, they inhibited the growth of A375-luc melanoma in a xenograft tumor model through modulation of the tumor vasculature and permitted enhanced penetration of NPs into the tumor.
Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Shutao
S
Guo
C Michael
CM
Lin
Zhenghong
Z
Xu
Lei
L
Miao
Yuhua
Y
Wang
Leaf
L
Huang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000008:administration & dosage* / Q000737:chemistry; D004295:Dihydroxyphenylalanine / Q000737:chemistry; D018450:Disease Progression; D004337:Drug Carriers; D006801:Humans; D020287:In Situ Nick-End Labeling; D019344:Lactic Acid / Q000737:chemistry; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D020123:Sirolimus / Q000008:administration & dosage*; D012878:Skin Neoplasms / Q000188:drug therapy; D012997:Solvents / Q000737:chemistry; D059016:Tumor Microenvironment
D000970:Antineoplastic Agents; D004337:Drug Carriers; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012997:Solvents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004295:Dihydroxyphenylalanine; D002945:Cisplatin; D020123:Sirolimus