Drug-free albumin-triggered sensitization of cancer cells to anticancer drugs

Lian Li, Jiyuan Yang, Sirima Soodvilai, Jiawei Wang, Praneet Opanasopit, Jindrich Kopecek

Research output: Contribution to journalArticle

Abstract

Chemosensitization strategies have been used to sensitize cancer cells to conventional drugs, but their utility is often obstructed by additional off-target toxicity, limited access to intracellular targets and heterogeneous tumor pathogenesis. To address these challenges, we rationally developed a drug-free human serum albumin (HSA)-based therapeutic (KH-1) that functions extracellularly and exhibits pleiotropic effect on multiple intracellular signaling pathways. It is a two-step touch-trigger system that consists of a pretargeting anchor on surface receptor CD20 (anti-CD20 Fab’ conjugated with a morpholino oligonucleotide 1) and a CD20 clustering actuator (HSA grafted with multiple copies of complementary morpholino oligonucleotide 2). The extracellular actuation by surface CD20 crosslinking boosts robust activations of numerous intracellular responses, and promotes cancer cell susceptibility to various anticancer drugs, including docetaxel (microtubule stabilizer), gemcitabine (nucleoside analogue) and GDC-0980 (PI3K/mTOR inhibitor). The broad applicability of KH-1 is demonstrated to result from simultaneous inhibition of survival pathways and augmentation of apoptotic pathways. In addition, KH-1 covalently conjugated with anthracycline anticancer agent, epirubicin, integrates the advantages of both chemosensitization function and improved intracellular drug delivery in a single system and takes effect on the same cell. Therefore, in the present study, we have provided mechanistic demonstration that crosslinking of surface receptors can be leveraged to elicit chemosensitization.

LanguageEnglish (US)
Pages84-93
Number of pages10
JournalJournal of Controlled Release
Volume293
DOIs
StatePublished - Jan 10 2019

Fingerprint

Cytology
Signal transduction
Oligonucleotides
Body fluids
Body Fluids
Drug delivery
Drug products
Cell Biology
Albumins
Signal Transduction
Cells
Morpholinos
Crosslinking
docetaxel
gemcitabine
Serum Albumin
Pharmaceutical Preparations
Neoplasms
Anchors
Epirubicin

Keywords

  • Chemosensitization
  • Drug-free macromolecular therapeutics
  • Human serum albumin
  • Receptor crosslinking
  • Signal transduction

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Drug-free albumin-triggered sensitization of cancer cells to anticancer drugs. / Li, Lian; Yang, Jiyuan; Soodvilai, Sirima; Wang, Jiawei; Opanasopit, Praneet; Kopecek, Jindrich.

In: Journal of Controlled Release, Vol. 293, 10.01.2019, p. 84-93.

Research output: Contribution to journalArticle

Li, Lian ; Yang, Jiyuan ; Soodvilai, Sirima ; Wang, Jiawei ; Opanasopit, Praneet ; Kopecek, Jindrich. / Drug-free albumin-triggered sensitization of cancer cells to anticancer drugs. In: Journal of Controlled Release. 2019 ; Vol. 293. pp. 84-93.
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