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Gabizon A.,Shaare Zedek Medical Center | Gabizon A.,Hebrew University of Jerusalem | Tzemach D.,Shaare Zedek Medical Center | Gorin J.,Shaare Zedek Medical Center | And 6 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2010

Purpose The folate receptor (FR) is overexpressed in a broad spectrum of malignant tumors and represents an attractive target for selective delivery of anti-cancer agents to FR-expressing tumors. Targeting liposomes to the FR has been proposed as a way to enhance the effects of liposome-based chemotherapy. Methods Folate-polyethylene glycol-distearoyl-phosphatidyl-ethanolamine conjugate was inserted into pegylated liposomal doxorubicin (PLD). The therapeutic activity of folate-targeted (FT-PLD) and non-targeted (PLD) pegylated liposomal doxorubicin was tested in two human tumor models (KB, KB-V) and in one mouse ascitic tumor model (FR-expressing J6456) by the i.v. systemic route in all models, and by the i.p. intracavitary route in the ascitic tumor model only. Results Consistent with previous studies, PLD was clearly superior to free doxorubicin in all tumor models. When targeted and non-targeted liposome formulations were compared, FT-PLD was more effective than PLD in the KB and KB-V xenograft models, and in the J6456 intra-cavitary therapy model. The therapeutic effect was dose-dependent in the KB model and schedule-dependent in the J6456 intra-cavitary therapy model. In some experiments, toxic deaths aggravated by folate-depleted diet were a major confounding factor. In a non-FR expressing J6456 model, FT-PLD was as active as PLD indicating that its activity is not limited to FR-expressing tumors. Conclusion Folate-targeting confers a significant albeit modest therapeutic improvement to PLD in FR-expressing tumor models, which appears particularly valuable in intracavitary therapy. The potential clinical added value of this approach has yet to be determined. © Springer-Verlag 2009.

Brown J.L.,Astrazeneca | Cao Z.A.,Astrazeneca | Pinzon-Ortiz M.,Astrazeneca | Kendrew J.,Astrazeneca | And 10 more authors.
Molecular Cancer Therapeutics | Year: 2010

Localized angiopoietin-2 (Ang2) expression has been shown to function as a key regulator of blood vessel remodeling and tumor angiogenesis, making it an attractive candidate for antiangiogenic therapy. A fully human monoclonal antibody (3.19.3) was developed, which may have significant pharmaceutical advantages over synthetic peptide-based approaches in terms of reduced immunogenicity and increased half-life to block Ang2 function. The 3.19.3 antibody potently binds Ang2 with an equilibrium dissociation constant of 86 pmol/L, leading to inhibition of Tie2 receptor phosphorylation in cell-based assays. In preclinical models, 3.19.3 treatment blocked blood vessel formation in Matrigel plug assays and in human tumor xenografts. In vivo studies with 3.19.3 consistently showed broad antitumor activity as a single agent across a panel of diverse subcutaneous and orthotopic xenograft models. Combination studies of 3.19.3 with cytotoxic drugs or anti-vascular endothelial growth factor agents showed significant improvements in antitumor activity over single-agent treatments alone with no apparent evidence of increased toxicity. Initial pharmacokinetic profiling studies in mice and nonhuman primates suggested that 3.19.3 has a predicted human half-life of 10 to 14 days. These studies provide preclinical data for 3.19.3 as a potential new antiangiogenic therapy as a single agent or in combination with chemotherapy or vascular endothelial growth factor inhibitors for the treatment of cancer. ©2010 AACR.

Compositions and methods are provided for treatment of diseases involving unwanted neovascularization (NV). The invention provides treatments that control NV through selective inhibition of pro-angiogenic biochemical pathways, including inhibition of the VEGF pathway gene expression and inhibition localized at pathological NV tissues. Tissue targeted nanoparticle compositions comprising polymer conjugates and nucleic acid molecules that induce RNA interference (RNAi) are provided. The nanoparticle compositions of the invention can be used alone or in combination with other therapeutic agents such as VEGF pathway antagonists. The compositions and methods can be used for the treatment of NV diseases such as cancer, ocular disease, arthritis, and inflammatory diseases.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 124.82K | Year: 2005

DESCRIPTION (provided by applicant): We are proposing this project to develop and commercialize a novel, histidine/lysine (HK) polymer based, siRNA transfection reagent. The goal of the phase I study of this project is to evaluate the feasibility of using PT88, a member of the HK polymer family, as siRNA transfection reagent. RNA interference (RNAi) is a process of sequence-specific gene silencing mediated by double-stranded RNA-molecules. In mammalian cells, the phenomenon can be invoked by introducing small 19-21 nucleotide long RNA duplexes, known as small interfering RNA (siRNA) into cells. Due to the high potency of siRNA, the use of siRNA to selectively silence gene expression at mRNA levels has rapidly replaced antisense and ribozyme in cell culture and animal models. Currently, there are several commercial available reagents for siRNA transfection that include liposome-based transfection reagents and polymer-based transfection reagents. In addition to its toxicity to the cells, the liposome-based transfection reagents are very sensitive to serum in the cell culture medium, thus require a complicated transfection procedure and are not suitable for high through- put studies. On the other hand, currently available polymer-based transfection reagents are highly toxic to the cells, and its toxicity to the host cells may well shadow the effect of siRNA-mediated gene silencing. Therefore, a high efficient, low toxic siRNA transfection reagent is highly desired and its commercialization will significantly advance the application of siRNA in the field of gene function study and development of new therapeutics. We have developed a group of HK polymers and utilized them as nucleic acid carrier for in vitro and in vivo delivery. The in vitro transfection efficiency of plasmid DNA mediated by the HK polymers is comparable to that of polymer-based transfection reagent, while the HK polymers give a much higher in vivo transfection efficiency than both polymer-based and liposome-based transfection reagents. More importantly, the HK polymers present strong serum tolerances and exhibit minimum, if any, cytotoxicity to the transfected cells. We found that PT88, a member of the HK polymers, demonstrates a great capability of mediating siRNA transfection and siRNA/plasmid DNA co-transfection in culture cells. This phase I project is therefore proposed to evaluate the feasibility of PT88 as a commercial siRNA transfection reagent. The specific aims of Phase I include 1) evaluate the efficiencies of PT88 mediated siRNA transfection and siRNA/DNA co-transfection in 10 cell lines that include cell lines believed easy to be transfected and cell lines believed difficult to be transfected, 2) perform comprehensive cytotoxicity study and serum tolerances study of PT88 in the cultured cells, and 3) investigate the feasibility of PT88 for high through- put siRNA transfection that include multiple transfection and co-transfection of plasmid DNA and siRNA duplexes. The success of the Phase I will lead to a Phase II project that focuses on commercial development of the PT88 HK polymer as a siRNA transfection and siRNA/DNA co-transfection reagent. The annual market value for a dominant siRNA transfection reagent is easily over tens of millions of dollars, giving the huge potentials of siRNA as a tool for biomedical research as well as a therapeutic modality.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 100.00K | Year: 2004

DESCRIPTION (provided by applicant): Angiogenesis of solid tumors is an important target of cancer therapy. It has been well recognized that growth and metastasis of solid tumors require persistent angiogenesis and that induction of angiogenesis is a discrete component of the tumor phenotype. Vascular endothelial growth factor and its cognate receptors (VEGFR1 and 2) are critical factors in promoting tumor angiogenesis. Our laboratory has recently identified a catalytic oligodeoxynucleotide (DNAzyme) that targets the VEGFR2 mRNA transcript. With intratumoral injections of subcutaneous implanted breast cancer, the VEGFR2 DNAzyme was found to inhibit tumor growth markedly in vivo. One objective of this proposal is to extend this therapy to a clinically relevant model, C6 gliomas. Our laboratory has also synthesized a polymer composed of histidine and lysine (HK polymer) that significantly increases transfection and oligonucleotide delivery. The linear and branched HK polymers offer the potential for effective delivery of therapeutic oligonucleotides including DNAzymes. Our overall aim and long term goal is to develop an effective antiangiogenic oligonucleotide approach to reduce tumor growth in vivo. Aim 1 is designed to improve the bioactivity efficiency of the DNAzyme targeting the mRNA of the VEGF 2 receptor. Although the DNAzyme targeting VEGFR2 developed by our laboratory effectively reduced tumor growth, modification of the annealing arms by the addition ofphosphorothioate linkages is expected to augment the potency of the DNAzyme. Therefore, the current VEGFR2 DNAzyme will be modified to augment its resistance to enzymatic degradation and thus increase its bioactivity. To transport the DNAzyme more effectively to tumor endothelial cells, Aim 2 will determine a more effective branched HK cartier of the DNAzyme. Several HK polymers that vary in the degree of branching and the histidine/lysine ratio will be tested for their ability to increase the efficacy of the DNAzyme. The most effective HK carrier will then be modified with a ligand to further augment the uptake of the complex into tumor endothelial cells. With improved design of HK-containing complexes, it is anticipated that this cartier in complex with the VEGFR DNAzyme will have more anfitumor efficacy toward an orthotopically implanted glioma.

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