RALA-Mediated Delivery of FKBPL Nucleic Acid Therapeutics

Bennett, R. Avery; Yakkundi, Anita; McKeen, Hayley D.; McClements, Lana; McKeogh, Thomas J; McCrudden, Cian M.; Arthur, Kenneth; Robson, Tracy; McCarthy, Helen

doi:10.2217/nnm.15.115

Cited by 65 publications

(52 citation statements)

References 37 publications

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“…Incubation of RALA with plasmid DNA in water resulted in the formation of nanoparticles with physical characteristics suitable for cellular internalization (Figure 1A) 1, 2, 21…”

Section: Resultsmentioning

confidence: 99%

“…The nucleic acid delivery ability of RALA is unquestionable. Beyond utility as a reporter gene delivery vehicle, 1 it effectively delivers small interfering RNAs (siRNAs), 2 and RALA/DNA nanoparticles were evaluated as components of a DNA vaccination device 21 . However, this is the first report validating systemically delivered RALA/nucleic acid therapeutics.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated the remedial potential of RALA-delivered therapeutic cargoes. Growth of ZR-75-1 breast cancer xenografts was abrogated by plasmid FK506-binding protein-like ( FKBPL ), 2 whereas nanocomplexation of anionic bisphosphonates with RALA afforded the agents cytotoxicity against PC-3 prostate cancer cells in vitro and in xenografts following intratumoral injection 3 . In this study, we aimed to provoke a therapeutic benefit in a model of aggressive breast cancer by nanocomplexation of plasmid inducible nitric oxide synthase ( iNOS ) with RALA.…”

Section: Introductionmentioning

confidence: 99%

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Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment

McCrudden

McBride

McCaffrey

et al. 2017

Molecular Therapy - Nucleic Acids

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This study aimed to determine the therapeutic benefit of a nanoparticular formulation for the delivery of inducible nitric oxide synthase (iNOS) gene therapy in a model of breast cancer metastasis. Nanoparticles comprising a cationic peptide vector, RALA, and plasmid DNA were formulated and characterized using a range of physiochemical analyses. Nanoparticles complexed using iNOS plasmids and RALA approximated 60 nm in diameter with a charge of 25 mV. A vector neutralization assay, performed to determine the immunogenicity of nanoparticles in immunocompetent C57BL/6 mice, revealed that no vector neutralization was evident. Nanoparticles harboring iNOS plasmids (constitutively active cytomegalovirus [CMV]-driven or transcriptionally regulated human osteocalcin [hOC]-driven) evoked iNOS protein expression and nitrite accumulation and impaired clonogenicity in the highly aggressive MDA-MB-231 human breast cancer model. Micrometastases of MDA-MB-231-luc-D3H1 cells were established in female BALB/c SCID mice by intracardiac delivery. Nanoparticulate RALA/CMV-iNOS or RALA/hOC-iNOS increased median survival in mice bearing micrometastases by 27% compared with controls and also provoked elevated blood nitrite levels. Additionally, iNOS gene therapy sensitized MDA-MB-231-luc-D3H1 tumors to docetaxel treatment. Studies demonstrated that systemically delivered RALA-iNOS nanoparticles have therapeutic potential for the treatment of metastatic breast cancer. Furthermore, detection of nitrite levels in the blood serves as a reliable biomarker of treatment.

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“…Incubation of RALA with plasmid DNA in water resulted in the formation of nanoparticles with physical characteristics suitable for cellular internalization (Figure 1A) 1, 2, 21…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment

McCrudden

McBride

McCaffrey

et al. 2017

Molecular Therapy - Nucleic Acids

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“…Among a number of cationic peptides, RALA has been reported to form nanoscale particles, following an interaction with nucleic acids. In addition, the amphipathic character of RALA has been demonstrated to ease the contact with the lipid phase of the membrane, allowing DNA transport across cellular membranes and in consequence, enabling DNA transfer to the nucleus following endosomal disruption . Two functional biomimetic polymers with identical sequences and different targeting motifs were engineered (Figure A).…”

Section: Resultsmentioning

confidence: 99%

Development of a ZHER3‐Affibody‐Targeted Nano‐Vector for Gene Delivery to HER3‐Overexpressed Breast Cancer Cells

Nazari

Koukhaloo

Mousavi

et al. 2019

Macromolecular Bioscience

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Despite the initial successes of gene delivery applications, they faced on several intrinsic drawbacks including toxicity and immunogenicity. Therefore, alternative gene‐delivery systems derived from recombinant peptides have emerged and is rapidly developing. Human epidermal growth factor receptor‐3 (HER3) shows high activity in tumor resistance to anti‐human epidermal growth factor receptor 2 (HER2) therapies. In this study, an affibody molecule against HER3 is conjugated to a biomimetic peptide RALA (an amphipathic and cationic peptide enriched with arginine) and the ability of the fusion vector for targeting HER3 and afterward delivering specific genes in breast cancer cells is evaluated. The results demonstrate that the biopolymeric platform, which contains an affibody‐conjugated RALA peptide, can effectively condense DNA into nanoparticles and target the overexpressed HER3 receptors in breast cancer cells and transfer specific genes. The use of such a recombinant biopolymer may pave the way for the development of sensitive and effective diagnostic and treatment tool for breast cancer.

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“…RALA was used to deliver the FK506-binding protein like -FKBPL gene (pFKBPL) -a novel member of the immunophilin protein family [90].…”

Section: Enhancing Endosomal Escapementioning

confidence: 99%

Delivery of Nucleic Acids for Cancer Gene therapy: Overcoming extra- and intra-cellular Barriers

2016

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The therapeutic potential of cancer gene therapy has been limited by the difficulty of delivering genetic material to target sites. Various biological and molecular barriers exist which need to be overcome before effective non-viral delivery systems can be applied successfully in oncology.Herein, various barriers are described and strategies to circumvent such obstacles are discussed, considering both the extracellular and intracellular setting. Development of multifunctional delivery systems holds much promise for the progression of gene delivery, and a growing body of evidence supports this approach involving rational design of vectors, with a unique molecular architecture. In addition, the potential application of composite gene delivery platforms is highlighted which may provide an alternative delivery strategy to traditional systemic administration.

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RALA-Mediated Delivery of FKBPL Nucleic Acid Therapeutics

Abstract: RALA is an effective delivery system for both FKBPL DNA and RNAi and highlights an alternative therapeutic approach to harnessing FKBPL's antiangiogenic and antistemness activity.

Cited by 65 publications

References 37 publications

Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment

Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment

Development of a ZHER3‐Affibody‐Targeted Nano‐Vector for Gene Delivery to HER3‐Overexpressed Breast Cancer Cells

Delivery of Nucleic Acids for Cancer Gene therapy: Overcoming extra- and intra-cellular Barriers

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