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1.
J Control Release ; 214: 85-93, 2015 Sep 28.
Article in English | MEDLINE | ID: mdl-26184049

ABSTRACT

This project uses an ex vivo human perfusion model for studying transport in benign, fibrous tumors. The uterine arteries were cannulated to perfuse the organ with a buffer solution containing blood vessel stain and methylene blue to analyze intratumoral transport. Gross examination revealed tissue expansion effects and a visual lack of methylene blue in the fibroids. Some fibroids exhibited regions with partial methylene blue penetration into the tumor environment. Histological analysis comparing representative sections of fibroids and normal myometrium showed a smaller number of vessels with decreased diameters within the fibroid. Imaging of fluorescently stained vessels exposed a stark contrast between fluorescence within the myometrium and relatively little within the fibroid tissues. Imaging at higher magnification revealed that fibroid blood vessels were indeed perfused and stained with the lipophilic membrane dye; however, the vessels were only the size of small capillaries and the blood vessel coverage was only 12% that of the normal myometrium. The majority of sampled fibroids had a strong negative correlation (Pearson's r=-0.68 or beyond) between collagen and methylene blue staining. As methylene blue was able to passively diffuse into fibroid tissue, the true barrier to transport in these fibroids is likely high interstitial fluid pressure, correlating with high collagen content and solid stress observed in the fibroid tissue. Fibroids had an average elevated interstitial fluid pressure of 4mmHg compared to -1mmHg in normal myometrium. Our findings signify relationships between drug distribution in fibroids and between vasculature characteristics, collagen levels, and interstitial fluid pressure. Understanding these barriers to transport can lead to developments in drug delivery for the treatment of uterine fibroids and tumors of similar composition.


Subject(s)
Leiomyoma/blood supply , Uterus/blood supply , Capillaries/metabolism , Collagen/metabolism , Coloring Agents , Extracellular Fluid/metabolism , Female , Humans , Hydrostatic Pressure , L-Lactate Dehydrogenase/metabolism , Leiomyoma/pathology , Methylene Blue , Models, Biological , Myometrium/metabolism , Perfusion , Pharmaceutical Preparations/metabolism , Regional Blood Flow , Uterine Artery/metabolism , Uterus/pathology
2.
Anticancer Res ; 26(5A): 3223-8, 2006.
Article in English | MEDLINE | ID: mdl-17094433

ABSTRACT

The in vivo feasibility of the previously established ID8 and ID8-VEGF ovarian cancer models for non-viral IL-12 gene delivery by itself or in combination with paclitaxel chemotherapy, was investigated in C57BL/6 black mice. The syngeneic mouse ovarian epithelium (MOSE) cancer cell line and its more aggressive variant, a VEGF-modified strain, were used to perform these experiments. Tumor growth and survival were observed in C57/BL6 mice, inoculated with both ID8 substrains. The superiority of IL-12 gene therapy in comparison to conventional paclitaxel chemotherapy in terms of tumor size and survival was demonstrated.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents, Phytogenic/therapeutic use , Disease Models, Animal , Genetic Therapy , Interleukin-12/therapeutic use , Ovarian Neoplasms/therapy , Paclitaxel/therapeutic use , Angiogenesis Inhibitors/genetics , Animals , Combined Modality Therapy , Epithelial Cells/drug effects , Epithelial Cells/pathology , Female , Humans , Interleukin-12/genetics , Mice , Mice, Inbred C57BL , Mice, Nude , Ovarian Neoplasms/pathology , Plasmids/genetics , Polymers/chemistry , Survival Rate , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A/genetics
3.
Anticancer Res ; 26(4B): 2785-9, 2006.
Article in English | MEDLINE | ID: mdl-16886597

ABSTRACT

Attempts to develop novel immunotherapeutic mouse models have been hampered by the lack of an adequate in vivo system. This study was performed to establish an immunocompetent mouse model for the testing of immunotherapy concepts. The in vivo system was based on a svngeneic mouse ovarian surface epithelium (MOSE) cancer, physiologically and biologically closely resembling human epithelial ovarian cancer. In addition, a more aggressive variant containing a mutated form of vascular epithelial growth factor was also evaluated. The growth patterns of these ovarian cancer cells in mice were compared to the established, highly aggressive 4T1 breast cancer model. A clinically-relevant tool for the study of different growth patterns in ovarian cancer, with potential significance for the development of novel immunological methods, was successfully developed.


Subject(s)
Disease Models, Animal , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Animals , Cell Growth Processes/genetics , Cell Growth Processes/physiology , Cell Line, Tumor , Epithelial Cells/pathology , Female , Green Fluorescent Proteins/biosynthesis , Green Fluorescent Proteins/genetics , Humans , Immunocompetence , Mice , Mice, Inbred C57BL , Neoplasm Transplantation , Ovarian Neoplasms/genetics , Paclitaxel/pharmacology , Transfection , Vascular Endothelial Growth Factor A/genetics
4.
J Control Release ; 103(1): 221-33, 2005 Mar 02.
Article in English | MEDLINE | ID: mdl-15710513

ABSTRACT

Biodegradable cationic polymers have become promising alternatives to traditional polycationic gene delivery systems in which the high charge densities of high molecular weight polymers contribute significantly to cellular toxicities. Previous research has shown that biodegradable, multiblock copolymers (MBC), PEG-PLL-g-16% His, are efficient gene carriers with negligible cellular toxicities. The present research was designed to characterize the polymer degradation as well as to determine the biodistribution of the MBC after systemic administration. Polymer degradation was performed in buffer as a function of pH, in serum and within polymer/pDNA complexes. The MBC exhibited exponential decay with a half-life (t1/2) of approximately 14 min at pH 9.0, approximately 5 h at pH 7.4 and approximately 2 h in serum. However, there was little or no degradation observed at pH 4.0 and the MBC within the complexes degraded between 4 and 8 h in serum. Biodistribution data performed with fluorescently labeled polymer and pDNA revealed that intact complexes remained in the blood up to 3 days, which was also reflected in the organs as a function of time. Therefore, the cumulative data suggest that PEG may be sterically stabilizing complexes in vivo via dysopsonization in which serum proteins mask the complexes from elements of the reticuloendothelial system (RES).


Subject(s)
DNA/blood , DNA/genetics , Gene Transfer Techniques , Polymers/administration & dosage , Animals , Biotransformation , DNA/administration & dosage , Drug Carriers/administration & dosage , Female , Mice , Mice, Inbred BALB C , Polymers/metabolism
5.
J Control Release ; 101(1-3): 273-85, 2005 Jan 03.
Article in English | MEDLINE | ID: mdl-15588911

ABSTRACT

Development of improved gene transfer methods is needed for gene therapy to achieve its clinical potential. The use of biocompatible polymeric gene carriers has shown effectiveness in overcoming the current problems associated with viral vectors in safety, immunogenicity and mutagenesis. Previous work has demonstrated that repeated, local, non-viral interleukin-12 (IL-12) gene delivery successfully slows down tumor progression, while improving immunogenicity. Combining IL-12 gene delivery with systemic paclitaxel (PCT) chemotherapy as a treatment for various subcutaneous mouse mammary carcinomas, we used PCT with either a biodegradable polymeric solubilizer, HySolv or Cremophor EL for systemic treatment and injected water soluble lipopolymer (WSLP)/plasmid-encoding IL-12 gene (p2CMVmIL-12) complexes local once every week. The amount of lung metastases being essential for survival as well as subcutaneous tumor volume were compared against untreated controls. We showed inhibition of tumor growth and decreased lung metastases in the combined WSLP/p2CMVmIL-12/HySolv group compared to the controls and the PCT only treated groups. Compared to Cremophor, HySolv performed better alone or in combination with IL-12. Using polymeric vectors as gene carrier systems in combination with improved systemic therapies provide evidence for the efficacy and feasibility of polymer-based drug delivery systems. Especially local cytokine gene delivery showed augmentation of systemic chemotherapy while reducing the hosts risk for further systemic toxicity.


Subject(s)
Drug Carriers , Genetic Therapy , Interleukin-12/genetics , Neoplasms, Experimental/therapy , Paclitaxel/administration & dosage , Animals , Combined Modality Therapy , Female , Gene Expression , Interferon-gamma/biosynthesis , Mice , Mice, Inbred BALB C , Polymers/administration & dosage , Solubility
6.
Mol Ther ; 9(6): 829-36, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15194049

ABSTRACT

Repeated, local, nonviral IL12 (interleukin-12) gene delivery decreased tumor progression and increased immunogenicity. We combined our IL12 gene delivery with systemic paclitaxel chemotherapy as a treatment for paclitaxel (PCT)-resistant 4T1 subcutaneous mouse mammary carcinomas and PCT-sensitive, immunogenic/nonimmunogenic tumors. We mixed PCT with either a biodegradable polymeric solubilizer, HySolv, or Cremophor EL for bimonthly systemic treatments and injected water-soluble lipopolymer (WSLP)/p2CMVmIL-12 (plasmid encoding IL12 gene) complexes locally every week. We compared treated subcutaneous tumor volume and lung metastasis with controls. HySolv alone performed better compared to Cremophor EL in combination with WSLP/p2CMVmIL-12. We showed inhibition of 4T1 tumor growth and lung metastases in the combined WSLP/p2CMVmIL-12/HySolv group compared to the controls and the paclitaxel-only treated groups. In parallel experiments we also demonstrated additive responses for tumor growth and number of lung metastases within other PCT-sensitive mammary tumor models using this combination strategy. Our combination therapy provides evidence for the efficacy and feasibility of improved drug delivery systems. Local cytokine gene delivery can augment local and systemic chemotherapy without placing the host at risk for further systemic toxicity.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma/therapy , Genetic Therapy/methods , Glycerol/analogs & derivatives , Interleukin-12/genetics , Mammary Neoplasms, Experimental/therapy , Paclitaxel/therapeutic use , Polyethyleneimine/analogs & derivatives , Animals , Carcinoma/secondary , Cell Line, Tumor , Combined Modality Therapy/methods , Female , Glycerol/therapeutic use , Lipids/therapeutic use , Lung Neoplasms/secondary , Lung Neoplasms/therapy , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Plasmids/genetics , Polyethyleneimine/therapeutic use
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