Pluronic block copolymers enhance the anti-myeloma activity of proteasome inhibitors

Hangting Hu, Armen Petrosyan, Natalia A. Osna, Tong Liu, Appolinaire A. Olou, Daria Y. Alakhova, Pankaj K. Singh, Alexander V. Kabanov, Edward A. Faber, Tatiana K. Bronich

Research output: Contribution to journalArticle

Abstract

Proteasome inhibitors (PIs) have markedly improved response rates as well as the survival of multiple myeloma (MM) patients over the past decade and have become an important foundation in the treatment of MM patients. Unfortunately, the majority of patients either relapses or becomes refractory to proteasome inhibition. This report describes that both PI sensitive and resistant MM cells display enhanced sensitivity to PI in the presence of synthetic amphiphilic block copolymers, Pluronics (SP1017). SP1017 effectively overcomes both acquired resistance and tumor microenvironment-mediated resistance to PIs. The combination of bortezomib and SP1017 augments accumulation of ubiquitinated proteins, increases markers of proteotoxic and ER stress, and ultimately induces both the intrinsic and extrinsic drug-induced apoptotic pathways in MM cells. Notably, co-treatment of bortezomib and SP1017 intensifies SP1017-induced disorganization of the Golgi complex and significantly reduces secretion of paraproteins. Using a human MM/SCID mice model, the combination of bortezomib and SP1017 exerted enhanced antitumor efficacy as compared to bortezomib alone, delaying disease progression, but without additional toxicity. Collectively, these findings provide proof of concept for the utility of combining PI with SP1017 and present a new approach to enhance the efficacy of current treatment options for MM patients.

Original languageEnglish (US)
Pages (from-to)149-164
Number of pages16
JournalJournal of Controlled Release
Volume306
DOIs
StatePublished - Jul 28 2019

Fingerprint

Poloxamer
Proteasome Inhibitors
Multiple Myeloma
Ubiquitinated Proteins
Paraproteins
Tumor Microenvironment
SCID Mice
Golgi Apparatus
Proteasome Endopeptidase Complex
SP1017
Disease Progression
Recurrence
Survival
Bortezomib
Therapeutics
Pharmaceutical Preparations

Keywords

  • Drug resistance
  • Multiple myeloma
  • Pluronic block copolymers
  • Proteasome inhibitors
  • Sensitization

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Pluronic block copolymers enhance the anti-myeloma activity of proteasome inhibitors. / Hu, Hangting; Petrosyan, Armen; Osna, Natalia A.; Liu, Tong; Olou, Appolinaire A.; Alakhova, Daria Y.; Singh, Pankaj K.; Kabanov, Alexander V.; Faber, Edward A.; Bronich, Tatiana K.

In: Journal of Controlled Release, Vol. 306, 28.07.2019, p. 149-164.

Research output: Contribution to journalArticle

Hu, Hangting ; Petrosyan, Armen ; Osna, Natalia A. ; Liu, Tong ; Olou, Appolinaire A. ; Alakhova, Daria Y. ; Singh, Pankaj K. ; Kabanov, Alexander V. ; Faber, Edward A. ; Bronich, Tatiana K. / Pluronic block copolymers enhance the anti-myeloma activity of proteasome inhibitors. In: Journal of Controlled Release. 2019 ; Vol. 306. pp. 149-164.
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