Dual‐Function CXCR4 Antagonist Polyplexes To Deliver Gene Therapy and Inhibit Cancer Cell Invasion

Li, Jing; Zhu, Yu; Hazeldine, Stuart; Li, Chunying; Oupický, David

doi:10.1002/anie.201203463

Cited by 77 publications

(76 citation statements)

References 28 publications

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“…We have recently reported synthesis of bioreducible poly(amido amine)s using commercial bicyclam CXCR4 antagonist Plerixafor as the main building block of the polymers (29). The synthesized polymers exhibited effective CXCR4 antagonism and demonstrated the ability to prevent invasion of cancer cells in vitro and metastasis in vivo (30).…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that bioreducible PAMD and PAMD/DNA polyplexes effectively inhibit cancer cell invasion mediated by SDF-1 (29). Using a Boyden chamber method, here we investigated how PEGylation affects the ability of PAMD polyplexes to inhibit invasion of cancer cells (Figure 8).…”

Section: Resultsmentioning

confidence: 99%

“…By devising systems capable of simultaneous CXCR4 inhibition and delivery of antitumor agents, it should be possible to improve the overall anticancer activity (26). As part of our long-term efforts to develop dually functioning polycations for combination drug/gene delivery (27, 28), we have recently reported synthesis of polycations based on a bicyclam CXCR4 antagonist Plerixafor (PAMD) (29, 30). The PAMD polymers showed dual functionality as efficient gene delivery vectors and CXCR4 antagonists that inhibited invasion of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Polymeric Plerixafor: Effect of PEGylation on CXCR4 Antagonism, Cancer Cell Invasion, and DNA Transfection

Wang

Oupický

2014

Pharm Res

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Purpose To determine the effect of PEG modification on pharmacologic and gene delivery properties of polymeric CXCR4 antagonist based on Plerixafor. Methods Polymeric Plerixafor (PAMD) was synthesized from Plerixafor (AMD3100) and grafted with different amounts of PEG (2 kDa). CXCR4 antagonism of the synthesized polymers was determined using receptor redistribution assay. Inhibition of cancer cell invasion by the polyplexes of the synthesized polymers was assessed using Boyden-chamber method. Transfection activity of DNA polyplexes formed with the synthesized polymers was evaluated in U2OS osteosarcoma and B16F10 melanoma cells. Results Our results demonstrate that modification of PAMD with PEG decreased toxicity of the polymers, while preserving their CXCR4 antagonism. Polyplexes prepared with PEG-PAMD inhibited invasion of cancer cells to an extent similar to the commercial CXCR4 antagonist Plerixafor. Negative effect of PEG on transfection activity of PEG-PAMD polyplexes could be overcome by using polyplexes formulated with a mixture of PAMD and PEG-PAMD. Conclusion Modification of PAMD with PEG is a viable strategy to preserve the desirable CXCR4 antagonism and ability to inhibit cancer cell invasion of PAMD, while improving safety and colloidal stability of the PAMD polyplexes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Polymeric Plerixafor: Effect of PEGylation on CXCR4 Antagonism, Cancer Cell Invasion, and DNA Transfection

Wang

Oupický

2014

Pharm Res

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“…In a competitive binding experiment, we have shown that saturating CXCR4 receptors by preincubation with a small molecule inhibitor had no effect on cell uptake or transfection activity of the DNA polyplexes. 27, 28 However, because cholesterol modification may alter the mechanism of interaction of polyplexes with cell membranes and membrane-bound receptors, it was essential to determine if the CXCR4 trafficking was involved and if any significant amount of siRNA polyplexes was trapped at the cell membrane.…”

Section: Resultsmentioning

confidence: 99%

Balancing polymer hydrophobicity for ligand presentation and siRNA delivery in dual function CXCR4 inhibiting polyplexes

Wang

Chen

et al. 2015

Biomater. Sci.

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In the present study, a series of copolymers (PAMD-Ch) was synthesized by grafting polymeric Plerixafor/AMD3100 (PAMD) with different amounts of cholesterol and the effect of cholesterol modification on siRNA delivery was investigated. PAMD-Ch/siRNA polyplexes exhibited improved colloidal and enzymatic stability when compared with PAMD/siRNA polyplexes containing no cholesterol. PAMD-Ch with low (17 wt%) and medium (25 wt%) cholesterol content exhibited CXCR4 antagonism comparable to unmodified PAMD. Cholesterol modification increased cell uptake of siRNA polyplexes and significantly decreased sensitivity of siRNA transfection to the presence of serum. When used to deliver anticancer siRNA against polo-like kinase 1 (PLK1), polyplexes based on PAMD-Ch with 17 wt% cholesterol exhibited the highest cancer cell killing activity both in serum-free and serum-containing conditions. Overall, the results of this study validate cholesterol modified PAMD as dual-function delivery vectors suitable for efficient delivery of anticancer siRNA and simultaneous CXCR4 inhibition for combined anticancer therapies.

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“…The PAMD polymers showed dual functionality as efficient nucleic acid (gene and siRNA) delivery vectors and CXCR4 antagonists that inhibited invasion of cancer cells in vitro and decreased metastasis in several tumor models in vivo (Li et al 2012; Li and Oupicky 2014). Modification of PAMD with PEG was used to improve the in vivo applicability (Wang et al 2014).…”

Section: Inhibition Of Cxcr4 In Anticancer Therapiesmentioning

confidence: 99%

Potential of CXCR4/CXCL12 Chemokine Axis in Cancer Drug Delivery

2016

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This review discusses the potential of CXCR4 chemokine receptor in the design of anticancer and antimetastatic drug delivery systems. The role of CXCR4 in cancer progression and metastasis is discussed in the context of the development of several types of drug delivery strategies. Overview of drug delivery systems targeted to cancers that overexpress CXCR4 is provided, together with the main types of CXCR4-binding ligands used in targeting applications. Drug delivery applications that take advantage of CXCR4 inhibition to achieve enhanced anticancer and antimetastatic activity of combination treatments are also discussed.

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Dual‐Function CXCR4 Antagonist Polyplexes To Deliver Gene Therapy and Inhibit Cancer Cell Invasion

Cited by 77 publications

References 28 publications

Polymeric Plerixafor: Effect of PEGylation on CXCR4 Antagonism, Cancer Cell Invasion, and DNA Transfection

Polymeric Plerixafor: Effect of PEGylation on CXCR4 Antagonism, Cancer Cell Invasion, and DNA Transfection

Balancing polymer hydrophobicity for ligand presentation and siRNA delivery in dual function CXCR4 inhibiting polyplexes

Potential of CXCR4/CXCL12 Chemokine Axis in Cancer Drug Delivery

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