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

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.

SUBMITTER: Hu H

PROVIDER: S-EPMC6822276 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Hu Hangting H Petrosyan Armen A Osna Natalia A NA Liu Tong T Olou Appolinaire A AA Alakhova Daria Y DY Singh Pankaj K PK Kabanov Alexander V AV Faber Edward A EA Bronich Tatiana K TK

Journal of controlled release : official journal of the Controlled Release Society 20190520

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 (SP101 ...[more]

PMID: 31121280

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Project description:In this work, we investigated the cytotoxicity, colloidal stability and optical property of gold nanorods before and after functionalizing them with thiolated PEG and Pluronic triblock copolymer (PEO-PPO-PEO) molecules. The morphology of functionalized gold nanorods was characterized by UV-visible absorption spectroscopy, transmission electron microscopy, and dynamic light scattering. Solution phase synthesis of gold nanorods has remained the method of choice for obtaining varying shapes and aspect ratios of rod nanoparticles. This method typically involves the use of cetyltrimethylammonium bromide (CTAB) surfactants as directing agents to grow gold nanorods in the solution phase. The as-synthesized gold nanorods surfaces are terminated with CTAB molecules and this formulation gives rise to adverse toxicity in vitro and in vivo. To employ the gold nanorods for biological studies, it is important to eliminate or minimize the exposure of CTAB molecules from the gold nanorods surface to the local environment such as cells or tissues. Complete removal of CTAB molecules from the gold nanorods surface is unfeasible as this will render the gold nanorods structurally unstable, causing the aggregation of particles. Here, we investigate the individual use of thiolated PEG and PEO-PPO-PEO as capping agents to reduce the cytotoxicity of gold nanorods formulation, while maintaining the optical, colloidal, and structural properties of gold nanorods. We found that encapsulating gold nanorods with the thiolated PEG or PEO-PPO-PEO molecules guarantees the stability and biocompatibility of the nanoformulation. However, excessive use of these molecules during the passivation process leads to a reduction in the overall cell viability. We also demonstrate the use of the functionalized gold nanorods as scattering probes for dark-field imaging of cancer cells thereby demonstrating their biocompatibility. Our results offer a unique solution for the future development of safe scattering color probes for clinical applications such as the long term imaging of cells and tissues.

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

Publications

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

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