Nanoparticle modulation of the tumor microenvironment enhances therapeutic efficacy of cisplatin.
The tumor microenvironment (TME) serves as a multidrug resistant center for tumors under the assault of chemotherapy and a physiological barrier against the penetration of therapeutic nanoparticles (NPs). Previous studies have indicated the ability for therapeutic NP to distribute into, and deplete tumor-associated fibroblasts (TAFs) for improved therapeutic outcomes. However, a drug resistant phenotype gradually arises after repeated doses of chemotherapeutic NP. Herein, the acquisition of drug resistant phenotypes in the TME after repeated cisplatin NP treatment was examined. Particularly, this study was aimed at investigating the effects of NP damaged TAFs on neighboring cells and alteration of stromal structure after cisplatin treatment. Findings suggested that while off-targeted NP damaged TAFs and inhibited tumor growth after an initial dose, chronic exposure to cisplatin NP led to elevated secretion of Wnt16 in a paracrine manner in TAFs. Wnt16 upregulation was then attributed to heightened tumor cell resistance and stroma reconstruction. Results attest to the efficacy of Wnt16 knockdown in damaged TAFs as a promising combinatory strategy to improve efficacy of cisplatin NP in a stroma-rich bladder cancer model.
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Lei
L
Miao
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Yuhua
Y
Wang
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
C Michael
CM
Lin
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; School of Pharmacy, Zhejiang Chinese Medical University, 310053, China.
Yang
Y
Xiong
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Naihan
N
Chen
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Lu
L
Zhang
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
William Y
WY
Kim
Division of Molecular Pharmaceutics and Center of Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: leafh@unc.edu.
Leaf
L
Huang
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002945:Cisplatin / Q000627:therapeutic use*; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D053758:Nanoparticles; D034741:RNA, Small Interfering / Q000235:genetics; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; C417262:WNT16 protein, human; D051153:Wnt Proteins; C585687:Wnt16 protein, mouse; D002945:Cisplatin
Cisplatin; Nanoparticle; Tumor associated fibroblast; Tumor microenvironment; Wnt16