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

JOURNAL OF CONTROLLED RELEASE

卷:293

Article

Li, Lian¹  Yang, Jiyuan¹  Soodvilai, Sirima^1,2  Wang, Jiawei¹  Opanasopit, Praneet²  Kopecek, Jindrich^1,3 

[1] Univ Utah, Dept Pharmaceut & Pharmaceut Chem, Ctr Controlled Chem Delivery, Salt Lake City, UT 84112 USA

[2] Silpakorn Univ, Fac Pharm, Amphoe Muang, Nakhon Pathom, Thailand

[3] Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA

关键词: Drug-free macromolecular therapeutics;    Receptor crosslinking;    Chemosensitization;    Human serum albumin;    Signal transduction;   

DOI  :  10.1016/j.jconrel.2018.11.015

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free