학술논문
Combination of Polymeric Micelle Formulation of TGFβ Receptor Inhibitors and Paclitaxel Produce Consistent Response Across Different Mouse Models of TNBC.
Document Type
Author
Vinod N; Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, United States.; Joint UNC/NC State Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599, United States.; Hwang D; Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, United States.; Fussell SC; Department of Biology, Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.; Owens TC; Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, United States.; Tofade OC; Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, United States.; Copling S; Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, United States.; Ramsey JD; Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, United States.; Rädler PD; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, United States.; Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, United States.; Atkins HM; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, United States.; Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, United States.; Department of Pathology and Laboratory Medicine, Division of Comparative Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.; Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA.; Livingston EE; Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.; Ezzell JA; Histology Research Core, University of North Carolina, Chapel Hill, NC 27599, United States.; Sokolsky-Papkov M; Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, United States.; Yuan H; Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States.; Perou CM; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, United States.; Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, United States.; Kabanov AV; Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, United States.
Source
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
Triple-negative breast cancer (TNBC) is notoriously difficult to treat due to the lack of targetable receptors and sometimes poor response to chemotherapy. The transforming growth factor-beta (TGFβ) family of proteins and their receptors (TGFR) are highly expressed in TNBC and implicated in chemotherapy-induced cancer stemness. Here we evaluated combination treatments using experimental TGFR inhibitors (TGFβi), SB525334 (SB), and LY2109761 (LY) with Paclitaxel (PTX) chemotherapy. These TGFβi target TGFR-I (SB) or both TGFR-I&II (LY). Due to the poor water solubility of these drugs, we incorporated each of them in poly(2-oxazoline) (POx) high-capacity polymeric micelles (SB-POx and LY-POx). We assessed their anti-cancer effect as single agents and in combination with micellar Paclitaxel (PTX-POx) using multiple immunocompetent TNBC mouse models that mimic human subtypes (4T1, T11-Apobec and T11-UV). While either TGFβi or PTX showed a differential effect in each model as single agents, the combinations were consistently effective against all three models. Genetic profiling of the tumors revealed differences in the expression levels of genes associated with TGFβ, EMT, TLR-4, and Bcl2 signaling, alluding to the susceptibility to specific gene signatures to the treatment. Taken together, our study suggests that TGFβi and PTX combination therapy using high-capacity POx micelle delivery provides a robust anti-tumor response in multiple TNBC subtype mouse models.
Competing Interests: Conflict of Interest: A.V.K. is an inventor on patents pertinent to the subject matter of the present contribution, co-founder, stockholder and director of DelAqua Pharmaceuticals Inc. having intent of commercial development of POx-based drug formulations. A.V.K. is also a co-founder, stockholder and director of SoftKemo Pharma Corp. and BendaRx Pharma Corp., which develop polymeric drug formulation and a blood cancer drug. M.S.P. discloses potential interest in DelAqua Pharmaceuticals Inc., SoftKemo Pharma Corp. and BendaRx Pharma Corp. as a spouse of a co-founder. C.M.P is an equity stockholder and consultant of BioClassifier LLC; C.M.P is also listed as an inventor on patent applications for the Breast PAM50 Subtyping assay.
Competing Interests: Conflict of Interest: A.V.K. is an inventor on patents pertinent to the subject matter of the present contribution, co-founder, stockholder and director of DelAqua Pharmaceuticals Inc. having intent of commercial development of POx-based drug formulations. A.V.K. is also a co-founder, stockholder and director of SoftKemo Pharma Corp. and BendaRx Pharma Corp., which develop polymeric drug formulation and a blood cancer drug. M.S.P. discloses potential interest in DelAqua Pharmaceuticals Inc., SoftKemo Pharma Corp. and BendaRx Pharma Corp. as a spouse of a co-founder. C.M.P is an equity stockholder and consultant of BioClassifier LLC; C.M.P is also listed as an inventor on patent applications for the Breast PAM50 Subtyping assay.