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 journalArticlepeer-review

1 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 languageEnglish
Pages (from-to)2053-2065
Number of pages13
JournalMolecular Pharmaceutics
Volume18
Issue number5
DOIs
StatePublished - 3 May 2021
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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