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 SrivastavaAnkush PaladhiRanjeet SinghDivesh Narayan SrivastavaRam Adhar SinghSumit Kumar HiraPartha Pratim MannaPublished in: Molecular pharmaceutics (2021)
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.
Keyphrases
- cell cycle arrest
- diffuse large b cell lymphoma
- induced apoptosis
- small molecule
- oxidative stress
- lymph node
- endoplasmic reticulum stress
- reactive oxygen species
- cell death
- red blood cell
- positron emission tomography
- cancer therapy
- drug delivery
- pi k akt
- poor prognosis
- drug induced
- emergency department
- squamous cell carcinoma
- insulin resistance
- cell proliferation
- mouse model
- locally advanced
- skeletal muscle
- radiation therapy
- high fat diet induced
- pet imaging
- adverse drug