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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.


Levy D.E.,Intradigm Corporation | Ding Z.,Intradigm Corporation | Hu C.,Intradigm Corporation | Zalipsky S.,Intradigm Corporation
Bioorganic and Medicinal Chemistry Letters | Year: 2010

Self-assembling nanoparticles comprising cationic polymers are of interest for the delivery of oligonucleotide-based therapeutics. Unfortunately, exposure of the nanoparticle cationic surface to plasma and plasma proteins compromises particle stability and circulating half-life. Herein, we report that improved nanoparticle stability can be achieved through temporary grafting of PEG to the nanoparticle surface. Grafting is induced through zinc complexation between PEG-IDA and the exposed polyhistidylated polylysine (H-K) cationic polymer of pre-formed nanoparticles. © 2010 Elsevier Ltd. All rights reserved.


Levy D.E.,Intradigm Corporation | Frederick B.,Intradigm Corporation | Luo B.,Intradigm Corporation | Zalipsky S.,Intradigm Corporation
Bioorganic and Medicinal Chemistry Letters | Year: 2010

The desire to develop nanoparticle and liposomal formulations as drug carriers capitalizing on active transport mechanisms requires constant development of novel heterobifunctional polyethyleneglycol (PEG) constructs. Such constructs should be capable of sequentially reacting with extracellular binding ligands and structural components of nanoparticles and/or liposomes. This paper describes two syntheses of heterobifunctional PEGs useful for tethering small molecule ligands to synthetic lysine-bearing polymers. © 2010 Elsevier Ltd. All rights reserved.


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.


PubMed | Intradigm Corporation
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2010

Self-assembling nanoparticles comprising cationic polymers are of interest for the delivery of oligonucleotide-based therapeutics. Unfortunately, exposure of the nanoparticle cationic surface to plasma and plasma proteins compromises particle stability and circulating half-life. Herein, we report that improved nanoparticle stability can be achieved through temporary grafting of PEG to the nanoparticle surface. Grafting is induced through zinc complexation between PEG-IDA and the exposed polyhistidylated polylysine (H-K) cationic polymer of pre-formed nanoparticles.


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