Targeting PD-1 in CD8+T Cells with a Biomimetic Bilirubin-5-fluoro-2-deoxyuridine-Bovine Serum Albumin Nanoconstruct for Effective Chemotherapy against Experimental Lymphoma

Prateek Srivastava; Ankush Paladhi; Ranjeet Singh; Divesh Narayan Srivastava; Ram Adhar Singh; Sumit Kumar Hira; Partha Pratim Manna

doi:10.1021/acs.molpharmaceut.1c00050

Targeting PD-1 in CD8⁺T Cells with a Biomimetic Bilirubin-5-fluoro-2-deoxyuridine-Bovine Serum Albumin Nanoconstruct for Effective Chemotherapy against Experimental Lymphoma

Prateek Srivastava, Ankush Paladhi, Ranjeet Singh, Divesh Narayan Srivastava, Ram Adhar Singh, Sumit Kumar Hira, Partha Pratim Manna

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

We fabricated bilirubin-bovine serum albumin (BR-BSA) nanocomplexes as candidates for the delivery of 5-fluoro-2-deoxyuridine (5FUdr) against experimental murine lymphoma. BR was attached to 5FUdr via acid-labile ester bonds mimicking small-molecule drug conjugates. The construct was self-assembled with BSA through strong noncovalent interactions with high drug occupancy in the core and labeled with folic acid (FA) to target cancer cells. The BR-5FUdr-BSA-FA nanoconstruct exhibits excellent biocompatibility, prevents nephrotoxicity, and is tolerated by red blood cells and mononuclear cells. The construct also showed increased accumulation in lymph nodes and tumor cells. BR-5FUdr-BSA-FA caused prolonged growth inhibition and apoptosis, enhanced mitochondrial reactive oxygen species generation, and minimized the viability of parental and doxorubicin-resistant Dalton's lymphoma cells. Treatment of tumor-bearing mice with BR-5FUdr-BSA-FA significantly increased the life span of the animals, improved their histopathological parameters, and downregulated PD-1 expression, suggesting the potential of the construct for 5FUdr delivery to treat lymphoma.

Original language	English
Pages (from-to)	2053-2065
Number of pages	13
Journal	Molecular Pharmaceutics
Volume	18
Issue number	5
DOIs	https://doi.org/10.1021/acs.molpharmaceut.1c00050
State	Published - 3 May 2021
Externally published	Yes

Keywords

5FUdr
PD-1
bilirubin
bovine serum albumin
growth inhibition
lymphoma

ASJC Scopus subject areas

Molecular Medicine
Pharmaceutical Science
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/acs.molpharmaceut.1c00050

Cite this

Srivastava, P., Paladhi, A., Singh, R., Srivastava, D. N., Singh, R. A., Hira, S. K., & Manna, P. P. (2021). Targeting PD-1 in CD8⁺T Cells with a Biomimetic Bilirubin-5-fluoro-2-deoxyuridine-Bovine Serum Albumin Nanoconstruct for Effective Chemotherapy against Experimental Lymphoma. Molecular Pharmaceutics, 18(5), 2053-2065. https://doi.org/10.1021/acs.molpharmaceut.1c00050

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title = "Targeting PD-1 in CD8+T Cells with a Biomimetic Bilirubin-5-fluoro-2-deoxyuridine-Bovine Serum Albumin Nanoconstruct for Effective Chemotherapy against Experimental Lymphoma",

abstract = "We fabricated bilirubin-bovine serum albumin (BR-BSA) nanocomplexes as candidates for the delivery of 5-fluoro-2-deoxyuridine (5FUdr) against experimental murine lymphoma. BR was attached to 5FUdr via acid-labile ester bonds mimicking small-molecule drug conjugates. The construct was self-assembled with BSA through strong noncovalent interactions with high drug occupancy in the core and labeled with folic acid (FA) to target cancer cells. The BR-5FUdr-BSA-FA nanoconstruct exhibits excellent biocompatibility, prevents nephrotoxicity, and is tolerated by red blood cells and mononuclear cells. The construct also showed increased accumulation in lymph nodes and tumor cells. BR-5FUdr-BSA-FA caused prolonged growth inhibition and apoptosis, enhanced mitochondrial reactive oxygen species generation, and minimized the viability of parental and doxorubicin-resistant Dalton's lymphoma cells. Treatment of tumor-bearing mice with BR-5FUdr-BSA-FA significantly increased the life span of the animals, improved their histopathological parameters, and downregulated PD-1 expression, suggesting the potential of the construct for 5FUdr delivery to treat lymphoma.",

keywords = "5FUdr, PD-1, bilirubin, bovine serum albumin, growth inhibition, lymphoma",

author = "Prateek Srivastava and Ankush Paladhi and Ranjeet Singh and Srivastava, {Divesh Narayan} and Singh, {Ram Adhar} and Hira, {Sumit Kumar} and Manna, {Partha Pratim}",

note = "Publisher Copyright: {\textcopyright} 2021 American Chemical Society.",

year = "2021",

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doi = "10.1021/acs.molpharmaceut.1c00050",

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Srivastava, P, Paladhi, A, Singh, R, Srivastava, DN, Singh, RA, Hira, SK & Manna, PP 2021, 'Targeting PD-1 in CD8⁺T Cells with a Biomimetic Bilirubin-5-fluoro-2-deoxyuridine-Bovine Serum Albumin Nanoconstruct for Effective Chemotherapy against Experimental Lymphoma', Molecular Pharmaceutics, vol. 18, no. 5, pp. 2053-2065. https://doi.org/10.1021/acs.molpharmaceut.1c00050

Targeting PD-1 in CD8⁺T Cells with a Biomimetic Bilirubin-5-fluoro-2-deoxyuridine-Bovine Serum Albumin Nanoconstruct for Effective Chemotherapy against Experimental Lymphoma. / Srivastava, Prateek; Paladhi, Ankush; Singh, Ranjeet et al.
In: Molecular Pharmaceutics, Vol. 18, No. 5, 03.05.2021, p. 2053-2065.

Research output: Contribution to journal › Article › peer-review

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T1 - Targeting PD-1 in CD8+T Cells with a Biomimetic Bilirubin-5-fluoro-2-deoxyuridine-Bovine Serum Albumin Nanoconstruct for Effective Chemotherapy against Experimental Lymphoma

AU - Srivastava, Prateek

AU - Paladhi, Ankush

AU - Singh, Ranjeet

AU - Srivastava, Divesh Narayan

AU - Singh, Ram Adhar

AU - Hira, Sumit Kumar

AU - Manna, Partha Pratim

PY - 2021/5/3

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AB - We fabricated bilirubin-bovine serum albumin (BR-BSA) nanocomplexes as candidates for the delivery of 5-fluoro-2-deoxyuridine (5FUdr) against experimental murine lymphoma. BR was attached to 5FUdr via acid-labile ester bonds mimicking small-molecule drug conjugates. The construct was self-assembled with BSA through strong noncovalent interactions with high drug occupancy in the core and labeled with folic acid (FA) to target cancer cells. The BR-5FUdr-BSA-FA nanoconstruct exhibits excellent biocompatibility, prevents nephrotoxicity, and is tolerated by red blood cells and mononuclear cells. The construct also showed increased accumulation in lymph nodes and tumor cells. BR-5FUdr-BSA-FA caused prolonged growth inhibition and apoptosis, enhanced mitochondrial reactive oxygen species generation, and minimized the viability of parental and doxorubicin-resistant Dalton's lymphoma cells. Treatment of tumor-bearing mice with BR-5FUdr-BSA-FA significantly increased the life span of the animals, improved their histopathological parameters, and downregulated PD-1 expression, suggesting the potential of the construct for 5FUdr delivery to treat lymphoma.

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