Targeting CXCR4/SDF-1 axis by lipopolymer complexes of siRNA in acute myeloid leukemia

Landry, Breanne; Gul-Uludag, Hilal; Plianwong, Samarwadee; Kucharski, Cezary; Zak, Zoulika; Parmar, Manoj B.; Kutsch, Olaf; Jiang, Haochuan; Brandwein, Joseph; Uludağ, Hasan

doi:10.1016/j.jconrel.2015.12.052

Cited by 45 publications

(28 citation statements)

References 68 publications

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“…The levels of integrin‐β1 started to relapse with time, for 1.2PEI–tαLA and 1.2PEI–Lau polymers, but the silencing effect was significant and stable for the 1.2PEI–LA treatment. The presence of linoleic acid on the PEI is shown to improve the interaction of polymer with siRNA/DNA, which, in turn, has helped in better interaction with the cell membrane resulting in higher cellular uptake . In addition to this, better cytoplasmic localization as well as higher intracellular release of siRNA could have contributed for the effective silencing.…”

Section: Discussionmentioning

confidence: 99%

Polymeric Delivery of siRNA against Integrin‐β1 (CD29) to Reduce Attachment and Migration of Breast Cancer Cells

Sundaram

Kucharski

Parmar

et al. 2017

Macromolecular Bioscience

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Cell surface integrins, which play important roles in the survival, proliferation, migration, and invasion of cancer cells, are a viable target for treatment of metastatic breast cancer. This line of therapy still remains challenging due to the lack of proper identification and validation of effective targets as well as the lack of suitable therapeutic agents for treatment. The focus is on one such molecular target for this purpose, namely integrin-β1, and effective lowering of integrin-β1 levels on a breast cancer model (MDA-MB-231 cells) is achieved by delivering a dicer-substrate short interfering RNA (siRNA) targeting integrin-β1 with lipid-modified low molecular weight polyethylenimine polymers. Reduction of integrin-β1 levels leads to reduced adhesion of MDA-MB-231 cells to extracellular matrix component fibronectin as well as to human bone marrow cells. A reduced migration of the breast cancer cells is also observed after integrin-β1 silencing in "scratch" and "transwell" migration assays. These results highlight the importance of integrin-β1 for the migration of metastatic breast cancer cells by effectively silencing this target with a practical dose of siRNA.

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Section: Discussionmentioning

confidence: 99%

Polymeric Delivery of siRNA against Integrin‐β1 (CD29) to Reduce Attachment and Migration of Breast Cancer Cells

Sundaram

Kucharski

Parmar

et al. 2017

Macromolecular Bioscience

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“…Both wild-type (WT) and drug-resistant (DR) phenotypes of K562 were employed to investigate the differential response to BCR-Abl siRNA treatment. The proofof-principle of our approach was previously explored with other types of lipopolymers [31][32][33], where apoptosis induction in K562 cells was seen based on BCR-Abl-siRNA delivery alone [32,34]. In this study, we employ a more effective polymer for siRNA delivery and explore the possibility of combining siRNA therapy with TKI treatments on the drug-resistant K562 model.…”

Section: Introductionmentioning

confidence: 99%

BCR-AblSilencing by siRNA: A Potent Approach to Sensitize Chronic Myeloid Leukemia Cells to Tyrosine Kinase Inhibitor Therapy

Thapa

Ubeda

et al. 2019

Stem Cells and Development

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Nonviral gene therapy with specific short interfering RNAs (siRNAs) against BCR-Abl can be an alternative and/or supportive therapy of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs), given the often observed resistance to TKIs in clinical setting. In this study, we explored the feasibility of BCR-Abl siRNA therapy in CML K562 cells in vitro by employing a cationic polymer derived from cholesterol (Chol) grafted low-molecular weight polyethyleneimine (PEI). The first generation TKI imatinib upregulated the expression of BCR-Abl in K562 cells as expected. Delivery of BCR-Abl siRNA in both drug-sensitive and drugresistant K562 cells significantly downregulated the mRNA levels in both cell types. Similarly, the BCR-Abl siRNA treatment arrested the growth of both drug-sensitive and drug-resistant K562 cells with no obvious differences despite a large difference in drug responsiveness. The BCR-Abl gene silencing in combination with TKI treatments exhibited significant synergism in drug-resistant K562 cells in generating substantial antileukemic activity, where the TKIs on their own were not effective. The effect of BCR-Abl siRNA and TKIs on non-CML cells ( Jurkat and primary fibroblast) was negligible, indicating the specificity of the proposed therapy. This strategy can significantly overcome TKI resistance in CML cells, suggesting a feasible and effective treatment model for CML patients suffering from clinical resistances.

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“…As a result, the combination of CXCR4 gene silencing with cytarabine enhanced cytotoxicity effect when THP‐1 cells were co‐cultured with hBMSCs. In addition, lipid substituted PEI/siCXCR4 complex delivered siRNA to mononuclear cells derived from AML patients and resulted in significant CXCR4 downregulation in two out of five samples . Dahlman et al.…”

Section: Nanocarriersmentioning

confidence: 99%

Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment

Peng

Bariwal

Kumar

et al. 2020

Advanced Therapeutics

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Nanocarriers have the capability to deliver a variety of drugs to disease sites. Different biological barriers prevent the successful delivery of nanoformulations to target sites, thereby limiting effective therapeutic response. Although numerous efforts have been made to design novel nanocarriers by incorporating various functionalities to get better therapies, most strategies have failed to translate drug delivery systems to the clinic. Impediments such as the incapability to hold drugs stably in nanocarriers during circulation, non‐specific distribution, and inadequate delivery of therapeutic agents to target sites due to complex tumor microenvironment remain a challenge. Herein, different organic polymer and lipid‐based nanocarriers and their encouraging therapeutic effectiveness to treat cancer are discussed. Recent development in multifunctional and stimuli sensitive nanocarriers is also highlighted. Finally, the challenges and innovative strategies to overcome various obstacles and limitations for their successful translation into the clinic are discussed.

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Targeting CXCR4/SDF-1 axis by lipopolymer complexes of siRNA in acute myeloid leukemia

Cited by 45 publications

References 68 publications

Polymeric Delivery of siRNA against Integrin‐β1 (CD29) to Reduce Attachment and Migration of Breast Cancer Cells

Polymeric Delivery of siRNA against Integrin‐β1 (CD29) to Reduce Attachment and Migration of Breast Cancer Cells

BCR-AblSilencing by siRNA: A Potent Approach to Sensitize Chronic Myeloid Leukemia Cells to Tyrosine Kinase Inhibitor Therapy

Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment

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