Combination of polymeric micelle formulation of TGFβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of Triple‐negative breast cancer
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 (TGFRs) are highly expressed in TNBC and implicated i...
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| Format: | Article |
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Wiley
2024-09-01
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| Series: | Bioengineering & Translational Medicine |
| Online Access: | https://doi.org/10.1002/btm2.10681 |
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| author | Natasha Vinod Duhyeong Hwang Sloane Christian Fussell Tyler Cannon Owens Olaoluwa Christopher Tofade Thad S. Benefield Sage Copling Jacob D. Ramsey Patrick D. Rädler Hannah M. Atkins Eric E. Livingston J. Ashley Ezzell Marina Sokolsky‐Papkov Hong Yuan Charles M. Perou Alexander V. Kabanov |
| author_facet | Natasha Vinod Duhyeong Hwang Sloane Christian Fussell Tyler Cannon Owens Olaoluwa Christopher Tofade Thad S. Benefield Sage Copling Jacob D. Ramsey Patrick D. Rädler Hannah M. Atkins Eric E. Livingston J. Ashley Ezzell Marina Sokolsky‐Papkov Hong Yuan Charles M. Perou Alexander V. Kabanov |
| author_sort | Natasha Vinod |
| collection | DOAJ |
| description | 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 (TGFRs) 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 and TGFR‐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 anticancer effect as single agents and in combination with micellar PTX (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, epithelial to mesenchymal transition (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 antitumor response in multiple TNBC subtype mouse models. |
| format | Article |
| id | doaj-art-4d3e5270f8a24f30a1b80e2ded6ba463 |
| institution | Kabale University |
| issn | 2380-6761 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Bioengineering & Translational Medicine |
| spelling | doaj-art-4d3e5270f8a24f30a1b80e2ded6ba4632024-11-14T12:22:22ZengWileyBioengineering & Translational Medicine2380-67612024-09-0195n/an/a10.1002/btm2.10681Combination of polymeric micelle formulation of TGFβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of Triple‐negative breast cancerNatasha Vinod0Duhyeong Hwang1Sloane Christian Fussell2Tyler Cannon Owens3Olaoluwa Christopher Tofade4Thad S. Benefield5Sage Copling6Jacob D. Ramsey7Patrick D. Rädler8Hannah M. Atkins9Eric E. Livingston10J. Ashley Ezzell11Marina Sokolsky‐Papkov12Hong Yuan13Charles M. Perou14Alexander V. Kabanov15Division of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill North Carolina USADivision of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill North Carolina USADepartment of Biology, Department of Chemistry University of North Carolina at Chapel Hill Chapel Hill North Carolina USADivision of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill North Carolina USADivision of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill North Carolina USADepartment of Radiology University of North Carolina at Chapel Hill Chapel Hill North Carolina USADivision of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill North Carolina USADivision of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill North Carolina USALineberger Comprehensive Cancer Center University of North Carolina Chapel Hill North Carolina USALineberger Comprehensive Cancer Center University of North Carolina Chapel Hill North Carolina USADepartment of Radiology, Biomedical Research Imaging Center, UNC Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill North Carolina USAHistology Research Core University of North Carolina Chapel Hill North Carolina USADivision of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill North Carolina USADepartment of Radiology, Biomedical Research Imaging Center, UNC Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill North Carolina USALineberger Comprehensive Cancer Center University of North Carolina Chapel Hill North Carolina USADivision of Pharmacoengineering and Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill North Carolina USAAbstract 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 (TGFRs) 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 and TGFR‐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 anticancer effect as single agents and in combination with micellar PTX (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, epithelial to mesenchymal transition (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 antitumor response in multiple TNBC subtype mouse models.https://doi.org/10.1002/btm2.10681 |
| spellingShingle | Natasha Vinod Duhyeong Hwang Sloane Christian Fussell Tyler Cannon Owens Olaoluwa Christopher Tofade Thad S. Benefield Sage Copling Jacob D. Ramsey Patrick D. Rädler Hannah M. Atkins Eric E. Livingston J. Ashley Ezzell Marina Sokolsky‐Papkov Hong Yuan Charles M. Perou Alexander V. Kabanov Combination of polymeric micelle formulation of TGFβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of Triple‐negative breast cancer Bioengineering & Translational Medicine |
| title | Combination of polymeric micelle formulation of TGFβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of Triple‐negative breast cancer |
| title_full | Combination of polymeric micelle formulation of TGFβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of Triple‐negative breast cancer |
| title_fullStr | Combination of polymeric micelle formulation of TGFβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of Triple‐negative breast cancer |
| title_full_unstemmed | Combination of polymeric micelle formulation of TGFβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of Triple‐negative breast cancer |
| title_short | Combination of polymeric micelle formulation of TGFβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of Triple‐negative breast cancer |
| title_sort | combination of polymeric micelle formulation of tgfβ receptor inhibitors and paclitaxel produces consistent response across different mouse models of triple negative breast cancer |
| url | https://doi.org/10.1002/btm2.10681 |
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