Quatramer™ encapsulation of dual‐targeted PI3‐Kδ/HDAC6 inhibitor, HSB‐510, suppresses growth of breast cancer
Abstract Multiple studies have shown that the progression of breast cancer depends on multiple signaling pathways, suggesting that therapies with multitargeted anticancer agents will offer improved therapeutic benefits through synergistic effects in inhibiting cancer growth. Dual‐targeted inhibitors...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-09-01
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| Series: | Bioengineering & Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/btm2.10541 |
| _version_ | 1797689793585348608 |
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| author | Sachchidanand Tiwari Suiyang Liu Mohd Anees Neha Mehrotra Ashish Thakur Gregory J. Tawa Gurmit Grewal Richard Stone Surender Kharbanda Harpal Singh |
| author_facet | Sachchidanand Tiwari Suiyang Liu Mohd Anees Neha Mehrotra Ashish Thakur Gregory J. Tawa Gurmit Grewal Richard Stone Surender Kharbanda Harpal Singh |
| author_sort | Sachchidanand Tiwari |
| collection | DOAJ |
| description | Abstract Multiple studies have shown that the progression of breast cancer depends on multiple signaling pathways, suggesting that therapies with multitargeted anticancer agents will offer improved therapeutic benefits through synergistic effects in inhibiting cancer growth. Dual‐targeted inhibitors of phosphoinositide 3‐kinase (PI3‐K) and histone deacetylase (HDAC) have emerged as promising cancer therapy candidates. However, poor aqueous solubility and bioavailability limited their efficacy in cancer. The present study investigates the encapsulation of a PI3‐Kδ/HDAC6 dual inhibitor into hybrid block copolymers (polylactic acid‐methoxy polyethylene glycol; polylactic acid‐polyethylene glycol‐polypropylene glycol‐polyethylene glycol‐polylactic acid) (HSB‐510) as a delivery system to target PI3‐Kδ and HDAC6 pathways in breast cancer cells. The prepared HSB‐510 showed an average diameter of 96 ± 3 nm, a zeta potential of −17 ± 2 mV, and PDI of ˂0.1 with a slow and sustained release profile of PI3‐Kδ/HDAC6 inhibitors in a nonphysiological buffer. In vitro studies with HSB‐510 have demonstrated substantial growth inhibition of breast cancer cell lines, MDA‐MB‐468, SUM‐149, MCF‐7, and Ehrlich ascites carcinoma (EAC) as well as downregulation of phospho‐AKT, phospho‐ERK, and c‐Myc levels. Importantly, bi‐weekly treatment of Balb/c wild‐type mice harboring EAC cells with HSB‐510 at a dose of 25 mg/kg resulted in significant tumor growth inhibition. The treatment with HSB‐510 was without any significant effect on the body weights of the mice. These results demonstrate that a novel Quatramer encapsulation of a PI3‐Kδ/HDAC6 dual inhibitor (HSB‐510) represents an approach for the successful targeting of breast cancer and potentially other cancer types. |
| first_indexed | 2024-03-12T01:51:29Z |
| format | Article |
| id | doaj.art-9ea6ae878c664a8b9f6fe4a6d201ee36 |
| institution | Directory Open Access Journal |
| issn | 2380-6761 |
| language | English |
| last_indexed | 2024-03-12T01:51:29Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Bioengineering & Translational Medicine |
| spelling | doaj.art-9ea6ae878c664a8b9f6fe4a6d201ee362023-09-08T13:29:53ZengWileyBioengineering & Translational Medicine2380-67612023-09-0185n/an/a10.1002/btm2.10541Quatramer™ encapsulation of dual‐targeted PI3‐Kδ/HDAC6 inhibitor, HSB‐510, suppresses growth of breast cancerSachchidanand Tiwari0Suiyang Liu1Mohd Anees2Neha Mehrotra3Ashish Thakur4Gregory J. Tawa5Gurmit Grewal6Richard Stone7Surender Kharbanda8Harpal Singh9Centre for Biomedical Engineering Indian Institute of Technology Delhi New Delhi IndiaDana Farber Cancer Institute, Harvard Medical School Boston Massachusetts USACentre for Biomedical Engineering Indian Institute of Technology Delhi New Delhi IndiaCentre for Biomedical Engineering Indian Institute of Technology Delhi New Delhi IndiaNational Center for Advancing Translational Sciences National Institutes of Health Rockville Maryland USANational Center for Advancing Translational Sciences National Institutes of Health Rockville Maryland USANational Center for Advancing Translational Sciences National Institutes of Health Rockville Maryland USADana Farber Cancer Institute, Harvard Medical School Boston Massachusetts USADana Farber Cancer Institute, Harvard Medical School Boston Massachusetts USACentre for Biomedical Engineering Indian Institute of Technology Delhi New Delhi IndiaAbstract Multiple studies have shown that the progression of breast cancer depends on multiple signaling pathways, suggesting that therapies with multitargeted anticancer agents will offer improved therapeutic benefits through synergistic effects in inhibiting cancer growth. Dual‐targeted inhibitors of phosphoinositide 3‐kinase (PI3‐K) and histone deacetylase (HDAC) have emerged as promising cancer therapy candidates. However, poor aqueous solubility and bioavailability limited their efficacy in cancer. The present study investigates the encapsulation of a PI3‐Kδ/HDAC6 dual inhibitor into hybrid block copolymers (polylactic acid‐methoxy polyethylene glycol; polylactic acid‐polyethylene glycol‐polypropylene glycol‐polyethylene glycol‐polylactic acid) (HSB‐510) as a delivery system to target PI3‐Kδ and HDAC6 pathways in breast cancer cells. The prepared HSB‐510 showed an average diameter of 96 ± 3 nm, a zeta potential of −17 ± 2 mV, and PDI of ˂0.1 with a slow and sustained release profile of PI3‐Kδ/HDAC6 inhibitors in a nonphysiological buffer. In vitro studies with HSB‐510 have demonstrated substantial growth inhibition of breast cancer cell lines, MDA‐MB‐468, SUM‐149, MCF‐7, and Ehrlich ascites carcinoma (EAC) as well as downregulation of phospho‐AKT, phospho‐ERK, and c‐Myc levels. Importantly, bi‐weekly treatment of Balb/c wild‐type mice harboring EAC cells with HSB‐510 at a dose of 25 mg/kg resulted in significant tumor growth inhibition. The treatment with HSB‐510 was without any significant effect on the body weights of the mice. These results demonstrate that a novel Quatramer encapsulation of a PI3‐Kδ/HDAC6 dual inhibitor (HSB‐510) represents an approach for the successful targeting of breast cancer and potentially other cancer types.https://doi.org/10.1002/btm2.10541breast cancerHDAC6NanoformulationPI3‐KδPLA |
| spellingShingle | Sachchidanand Tiwari Suiyang Liu Mohd Anees Neha Mehrotra Ashish Thakur Gregory J. Tawa Gurmit Grewal Richard Stone Surender Kharbanda Harpal Singh Quatramer™ encapsulation of dual‐targeted PI3‐Kδ/HDAC6 inhibitor, HSB‐510, suppresses growth of breast cancer Bioengineering & Translational Medicine breast cancer HDAC6 Nanoformulation PI3‐Kδ PLA |
| title | Quatramer™ encapsulation of dual‐targeted PI3‐Kδ/HDAC6 inhibitor, HSB‐510, suppresses growth of breast cancer |
| title_full | Quatramer™ encapsulation of dual‐targeted PI3‐Kδ/HDAC6 inhibitor, HSB‐510, suppresses growth of breast cancer |
| title_fullStr | Quatramer™ encapsulation of dual‐targeted PI3‐Kδ/HDAC6 inhibitor, HSB‐510, suppresses growth of breast cancer |
| title_full_unstemmed | Quatramer™ encapsulation of dual‐targeted PI3‐Kδ/HDAC6 inhibitor, HSB‐510, suppresses growth of breast cancer |
| title_short | Quatramer™ encapsulation of dual‐targeted PI3‐Kδ/HDAC6 inhibitor, HSB‐510, suppresses growth of breast cancer |
| title_sort | quatramer™ encapsulation of dual targeted pi3 kδ hdac6 inhibitor hsb 510 suppresses growth of breast cancer |
| topic | breast cancer HDAC6 Nanoformulation PI3‐Kδ PLA |
| url | https://doi.org/10.1002/btm2.10541 |
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