Synthesis and application of a non-viral gene delivery system for immunogene therapy of cancer

Fewell, Jason G.; Matar, Majed; Slobodkin, Gregory; Han, Sang-oh; Rice, Jennifer; Hovanes, Bruce A.; Lewis, Danny; Anwer, Khursheed

doi:10.1016/j.jconrel.2005.09.024

Cited by 54 publications

(39 citation statements)

References 28 publications

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“…In 2005, Fewell et al investigated the ability of synthetic polymeric delivery vehicle (PPC) for interleukin-12 gene (pmIL-12) delivery (67). PPC was synthesized by covalently conjugating a low molecular weight branched polyethylenimine (PEI) with cholesterol (CHOL) and methoxypolyethyleneglycol (PEG).…”

Section: The Privileges Of Interleukin-12 Genementioning

confidence: 99%

Nanoparticle-Mediated Interleukin-12 Cancer Gene Therapy

Hallaj‐Nezhadi¹,

Lotfipour²,

Dass³

2010

J Pharm Pharm Sci

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Interleukin-12 (Il-12) is a heterodimeric cytokine which has been proved to possess antitumor effects in various animal models via stimulating the immune system. The main problem associated with Il-12 protein delivery is its instability as well as cytotoxicity subsequent to systemic administration in rodents and in human clinical trials. However, gene delivery can be used to deliver genes of interest to the tumor site. Hence, a large number of studies have been undertaken to deliver genes of interest to the tumor site through viral or non-viral vectors. Viral DNA delivery systems suffer from safety concern due to the toxicity of the viruses and strong immune response; while non-viral gene delivery systems proffer lower transfection efficiency. Nevertheless, nanometer-size complex of therapeutic DNA may demonstrate more efficient for administration of therapeutic genes to solid tumors compared to administration of naked plasmid DNA. Nanoparticle-based gene delivery systems might be more pertinent, due to the enhanced tissue penetrability, improved cellular uptake. Il-12 gene delivery has already been reported with different nanoparticles containing DNA. This article provides a review on the in vivo and in vitro studies using various nanoparticles, for delivery of the Il-12 genes to neoplastic cells. The future of these promising approaches lies in the development of better techniques for preparing il-12 gene delivery systems with complete efficiency of viral vectors in addition to the highest safety for cancer patients.

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Section: The Privileges Of Interleukin-12 Genementioning

confidence: 99%

Nanoparticle-Mediated Interleukin-12 Cancer Gene Therapy

Hallaj‐Nezhadi¹,

Lotfipour²,

Dass³

2010

J Pharm Pharm Sci

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“…31 Local delivery of IL-12 by IP administration of IL-12 plasmid/PPC provides IL-12 expression specifically in the tumor environment for achieving increased efficacy while minimizing systemic toxicity. Local gene delivery of IL-12 by intratumoral injection was also found safe and clinically beneficial for some metastatic melanoma patients.…”

Section: à2mentioning

confidence: 99%

“…31,44 The clinical lot of the plasmid was manufactured under cGMP by Strathmann Biotech (Hannover, Germany). The plasmid was grown in DH10b Escherichia coli, isolated by alkaline lysis and purified by ion-exchange chromatography.…”

Section: Manufacturing Of Phil-12/ppcmentioning

confidence: 99%

“…The delivery polymer PPC was manufactured by Durect Corporation (Birmingham, AL, USA) using the manufacturing scheme described previously. 31 The plasmid was formulated with PPC by mixing the two solutions at a mixing speed of 225 ml min À1 using an in-line mixing apparatus. The formulated plasmid/PPC complexes were lyophilized to dry powder and stored at À80 1C.…”

Section: Manufacturing Of Phil-12/ppcmentioning

confidence: 99%

“…We have recently described a gene-based IL-12 therapeutic that produces local concentrations of IL-12 and IFN-g without causing systemic toxicity in a mouse model of ovarian cancer. 31,32 This IL-12 therapeutic comprises a human IL-12 plasmid (phIL-12) that encodes for functional IL-12 protein and a synthetic DNA-delivery system, polyethyleneglycolpolyethyleneimine-cholesterol (PPC). Comprehensive safety/toxicity and biodistribution studies using normal mice show that phIL-12/PPC delivery is safe and localized at the injection site.…”

Section: Introductionmentioning

confidence: 99%

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Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer

Anwer¹,

Barnes

Fewell³

et al. 2009

Gene Ther

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A phase-I trial to assess the safety and tolerability of human interleukin-12 (IL-12) plasmid (phIL-12) formulated with a synthetic lipopolymer, polyethyleneglycol-polyethyleneimine-cholesterol (PPC), was conducted on women with chemotherapy-resistant recurrent ovarian cancer. A total of 13 patients were enrolled in four dose-escalating cohorts and treated with 0.6, 3, 12 or 24 mg m À2 of the formulated plasmid once every week for 4 weeks. Administration of phIL-12/PPC was generally safe and well-tolerated. Common side effects included low-grade fever and abdominal pain. Stable disease and reduction in serum CA-125 levels were clinically observed in some patients. Measurable levels of IL-12 plasmid were detectable in PF samples collected throughout the course of phIL-12/PPC treatment. In comparison, serum samples either did not contain detectable amounts of plasmid DNA or contained o1% of the amount found in the corresponding PF samples. Treatment-related increases in IFN-g levels were observed in PF but not in serum. These data demonstrate that IL-12 gene delivery with a synthetic delivery system is feasible for ovarian cancer patients.

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Dosage Formulation

Lyubimov¹

2010

Pharmaceutical Sciences Encyclopedia

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Drug formulation aims to determine experimentally all the variables necessary to develop an optimal formula and working directions for making the pharmaceutical product. Pharmaceutical technology applied to developing a drug formulation comprises selection of materials and procedures that are adaptable to various processes that lend themselves to inclusion in specific dosage forms. This article focuses on new dosage formulations, their function and characterization, absorption mechanisms, and novel routes of delivery.

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Synthesis and application of a non-viral gene delivery system for immunogene therapy of cancer

Cited by 54 publications

References 28 publications

Nanoparticle-Mediated Interleukin-12 Cancer Gene Therapy

Nanoparticle-Mediated Interleukin-12 Cancer Gene Therapy

Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer

Dosage Formulation

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