Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Local, non-viral IL-12 gene therapy using a water soluble lipopolymer as carrier system combined with systemic paclitaxel for cancer treatment. 1558 11

A cholesterol-rich microemulsion or nanoparticle termed LDE concentrates in cancer tissues after injection into the bloodstream. Here the cytotoxicity, pharmacokinetics, toxicity to animals and therapeutic action of a paclitaxel lipophilic derivative associated to LDE is compared with those of the commercial paclitaxel. Results show that LDE-paclitaxel oleate is stable. The cytostatic activity of the drug in the complex is diminished compared with the commercial paclitaxel due to the cytotoxicity of the vehicle Cremophor EL used in the commercial formulation. Competition experiments in neoplastic cultured cells show that paclitaxel oleate and LDE are internalized together by the LDL receptor pathway. LDE-paclitaxel oleate arrests the G(2)/M phase of cell cycle, similarly to commercial paclitaxel. Tolerability to mice is remarkable, such that the lethal dose (LD(50)) was ninefold greater than that of the commercial formulation (LD(50) = 326 microM and 37 microM, respectively). LDE concentrates paclitaxel oleate in the tumor roughly fourfold relative to the normal adjacent tissues. At equimolar doses, the association of paclitaxel oleate with LDE results in remarkable changes in the drug pharmacokinetic parameters when compared to commercial paclitaxel (t(1/2)=218 min and 184 min, AUC=1,334 microg h/ml and 707 microg h/ml and CL=0.125 ml/min and 0.236 ml/min, respectively). Finally, the therapeutic efficacy of the complex is pronouncedly greater than that of the commercial paclitaxel, as indicated by the reduction in tumor growth, increase in survival rates and % cure of treated mice. In conclusion, LDE-paclitaxel oleate is a stable complex and compared with paclitaxel toxicity is considerably reduced and activity is enhanced, which may lead to improved therapeutic index in clinical use.
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PMID:Improvement of paclitaxel therapeutic index by derivatization and association to a cholesterol-rich microemulsion: in vitro and in vivo studies. 1572 68

Self-assembled nanoparticles based on hydrophobically modified glycol chitosan (HGC) were prepared as a carrier for paclitaxel. HGC conjugates were prepared by chemically linking 5beta-cholanic acid to glycol chitosan chains using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide chemistry. In phosphate-buffered saline (PBS; pH 7.4), the synthesized HGC conjugates formed nano-sized particles with a diameter of 200 nm and exhibited high thermodynamic stability as reflected by their low critical aggregation concentration (0.03 mg/ml). Paclitaxel was efficiently loaded into HGC nanoparticles up to 10 wt.% using a dialysis method. The paclitaxel-loaded HGC (PTX-HGC) nanoparticles were 400 nm in diameter and were stable in PBS for 10 days. These PTX-HGC nanoparticles also showed sustained release of the incorporated of paclitaxel (80% of the loaded dose was released in 8 days at 37 degrees C in PBS). Owing to sustained release, the PTX-HGC nanoparticles were less cytotoxic to B16F10 melanoma cells than free paclitaxel formulated in Cremophor EL. Injection of PTX-HGC nanoparticles into the tail vein of tumor-bearing mice prevented increases in tumor volume for 8 days. Finally, PTX was less toxic to the tumor-bearing mice when formulated in HGC nanoparticles than when formulated with Cremophor EL.
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PMID:Hydrophobically modified glycol chitosan nanoparticles as carriers for paclitaxel. 1645 88

Breast cancer remains the most common malignancy in women of developed countries. Taxanes are cornerstones in the treatment of breast cancer. Nanoparticle albumin-bound paclitaxel (ABI-007, Abraxane) is a novel taxane that obviates the need of using a toxic solvent such as Cremophor EL leading to a safer administration without standard premedication. Several factors such as the presence of albumin receptors in cell surface, the increased need of nutrients such as albumin by tumor cells and the lack of sequestering Cremophor micelles lead to increased intratumoral concentration of this new taxane. Recent trials have shown that ABI-007 is not only well tolerated but, compared with conventional paclitaxel, is associated with superior response rate, longer time to tumor progression and prolonged survival as second-line therapy in patients with metastatic breast cancer.
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PMID:Nanoparticle albumin-bound paclitaxel (ABI-007): a newer taxane alternative in breast cancer. 1655 53

Recently, we developed a novel implantable drug delivery system which can provide sustained intraperitoneal (i.p.) delivery of paclitaxel (PTX). As the impact of local sustained delivery on the development of multidrug resistance (MDR) is unknown, the objective of this study was to determine the impact of this drug delivery system on the in vivo expression of MDR1/P-glycoprotein (PGP) in a human ovarian xenograft tumor model. As compared to controls, intermittent i.p. dosing with PTX formulated in Cremophor EL (PTX(CrEL)) induced a two-fold increase in mRNA levels of MDR1 after a 14-day dosing period. On the other hand, sustained i.p. delivery of PTX with the implant system (PTX(film)) did not significantly affect MDR1 expression. Immunodetection of PGP in isolated xenografts supported the mRNA data. Histological analysis by H&E staining demonstrated a dose-dependent increase in tumor necrosis in the PTX(film) treated animals. Further, in vitro studies in human ovarian carcinoma cells also demonstrated a significant induction in the efflux activity of PGP with intermittent dosing schedules to PTX(CrEL) whereas this was not seen in cells dosed with PTX(film). Our findings suggest that sustained i.p. administration with PTX(film) attenuates development of MDR, suggesting that sustained, localized delivery of chemotherapeutic agents may improve current treatment strategies for ovarian cancer.
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PMID:Impact of intraperitoneal, sustained delivery of paclitaxel on the expression of P-glycoprotein in ovarian tumors. 1711 77

9-Nitrocamptothecin (9-NC) is an orally administered topoisomerase-I inhibitor for the treatment of pancreatic carcinoma, but its oral absorption and bioavailability are poor. The main objective of this study was to develop optimal 9-nitrocamptothecin (9-NC) microemulsion prepared by self-microemulsifying drug delivery system (SMEDDS). Two SMEDDS formulations of 9-NC prepared from a mixture of ethyl oleate, Tween-80 (T-form) or Cremophor EL (C-form), and PEG-400/ethanol were formed as microemulsions under dilution with aqueous phase. The resulting microemulsions were evaluated in vitro and in vivo, including the kinetics and antitumor effects in SKOV-3 human ovarian cancer xenograft in nude mice. Following 1:10 aqueous dilution of optimal 9-NC SMEDDS, the droplet sizes of resulting microemulsions were (30.8+/-4.6)nm and (39.8+/-8.2)nm for SMEDDS T-form and C-form, respectively, and the zeta potential values were -(4.3+/-0.5)mV and -(5.7+/-0.5)mV, respectively. In SKOV-3 cells, the growth inhibition (IC50) of various 9-NC formulations was greatest with SMEDDS T-form (3.5+/-0.7 nM) followed by SMEDDS C-form (4.6+/-0.4 nM), 9-NC solution (6.6+/-1.4 nM) and 9-NC suspension (26.0+/-2.9 nM) (P<0.01). It was indicated that the area under the plasma concentration-time curve (AUC0-->8h) values of various formulations of 9-NC after oral administration ranked as the following sequence: SMEDDS T-form (360.12+/-19.44 ngh/ml) approximately SMEDDS C-form (351.71+/-33.66 ngh/ml) >9-NC solution (241.21+/-24.67 ngh/ml)>9-NC suspension (161.24+/-24.31 ngh/ml). The 9-NC SMEDDS formulations also produced significantly more tumor shrinkage (P<0.01) when compared to 9-NC suspension in nude mice bearing human ovarian cancer xenografts. The results suggest that SMEDDS is a promising drug delivery system to increase the oral bioavailability and antitumor effects of 9-NC and may be applied to other lipophilic drugs. 9-NC SMEDDS represents a novel 9-NC therapy for cancer patients.
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PMID:Self-microemulsifying drug delivery system (SMEDDS) improves anticancer effect of oral 9-nitrocamptothecin on human cancer xenografts in nude mice. 1843 9

Paclitaxel (PTX) is an antitumor agent for the treatment of various human cancers. Cremophor EL and ethanol are used to formulate PTX in commercial injection solutions, because of its poor solubility in water. However, these agents cause severe allergic reaction upon intravenous administration. The aim of this study is to synthesize water-soluble macromolecular prodrugs of PTX for enhancing the therapeutic efficacy. Poly(vinyl alcohol) (PVA, 80 kDa), water-soluble synthetic polymer, was used as a drug carrier which is safe and stable in the body. The 2'-hydroxyl group of PTX was reacted with succinic anhydride and then carboxylic group of the succinyl spacer was coupled to PVA via ethylene diamine spacer, resulting the water-soluble prodrug of poly(vinyl alcohol)-paclitaxel conjugate (PVA-SPTX). The solubility of PTX was greatly enhanced by the conjugation to PVA. The release of PTX from the conjugate was accelerated at the neutral to basic conditions in in vitro release experiment. [125 I]-labeled PVA-SPTX was retained in the blood circulation for several days and was gradually distributed into the tumorous tissue after intravenous injection to the tumor-bearing mice. PVA-SPTX inhibited the growth of sarcoma 180 cells subcutaneously inoculated in mice. It was suggested that the water-solubility of PTX was markedly enhanced by the conjugation to PVA, and PVA-SPTX effectively delivered PTX to the tumorous tissue due to the enhanced permeability and retention (EPR) effect.
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PMID:Synthesis and evaluation of water-soluble poly(vinyl alcohol)-paclitaxel conjugate as a macromolecular prodrug. 1845 27

Previously, we identified angiogenic vessel-homing peptide Ala-Pro-Arg-Pro-Gly (APRPG), and showed that APRPG-modified liposomes could selectively target to tumor neovasculature. Here, we designed an APRPG-modified liposome encapsulating SU5416, an angiogenesis inhibitor, to overcome the solubility problem, and to enhance the antiangiogenic activity of SU5416. Liposomal SU5416 appeared to have the appropriate characteristics, such as particle size and stability in serum. It showed a significantly lower hemoglobin release than SU5416 dissolved in a Cremophor EL-containing solvent. Compared with peptide-unmodified liposomal SU5416, the APRPG-modified liposomal SU5416 significantly suppressed tumor growth and with no remarkable side effects. Thus, targeted delivery of antiangiogenic drugs with tumor vasculature-targeted liposomes may be useful for antiangiogenic cancer therapy.
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PMID:Antiangiogenic cancer therapy using tumor vasculature-targeted liposomes encapsulating 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one, SU5416. 1855 91

Polyethylene glycol-polybenzyl-L-glutamate copolymer (PEG-PBLG) was synthesized and paclitaxel-loaded core-shell type nano-micelles with amphiphilic copolymer PEG-PBLG was prepared by the dialysis method. The drug loading content and entrapment efficiency were determined by HPLC. The average size and its distribution were determined by dynamic light scattering method. The paclitaxel release rate in vitro from micelles was measured by HPLC. The cell cytotoxicity in vitro was observed with MTT assay. The anti-tumor activity of paclitaxel-loaded micelles were evaluated in tumor-inhibiting test of nude mice using human liver cancer HepG-2. The results indicated that paclitaxel could be entrapped in PEG-PBLG copolymer micelles and its size was in the range of 80-265 nm which increased with an increase in molecular weight of PBLG in copolymer; in vitro the paclitaxel could be released sustainably from the micelles. In high concentration of paclitaxel (>20 microg x mL(-1)) the paclitaxel-loaded PEG-PBLG micelles displayed much less cell cytotoxicity than paclitaxel injections with Cremophor EL (P<0.05); the tumor inhibiting activity of paclitaxel-loaded PEG-PBLG micelles was similar to that of paclitaxel injections with Cremophor EL in the same paclitaxel concentration. It was concluded that the paclitaxel-loaded PEG-PBLG micelles had more uniform size and size distribution, excellent drug sustainable-release behavior, less cytotoxicity, good anti-tumor activity similar to paclitaxel injections with Cremophor EL. So paclitaxel-loaded PEG-PBLG micelles would be a novel paclitaxel preparation in clinic for the treatment of tumor.
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PMID:[Preparation and properties of self-assemble paclitaxel-loaded core-shell type nano-micelles]. 1866 5

Intraperitoneal chemotherapy prolongs survival of ovarian cancer patients, but its utility is limited by treatment-related complications and inadequate drug penetration in larger tumors. Previous intraperitoneal therapy used the paclitaxel/Cremophor EL (polyethoxylated castor oil) formulation designed for intravenous use. The present report describes the development of paclitaxel-loaded microparticles designed for intraperitoneal treatment (referred to as tumor-penetrating microparticles or TPM). Evaluation of TPM was performed using intraperitoneal metastatic, human ovarian SKOV3 xenograft tumor models in mice. TPM were retained in the peritoneal cavity and adhered to tumor surface. TPM consisted of two biocompatible and biodegradable polymeric components with different drug release rates; one component released the drug load rapidly to induce tumor priming, whereas the second component provided sustained drug release. Tumor priming, by expanding interstitial space, promoted transport and penetration of particulates in tumors. These combined features resulted in the following advantages over paclitaxel/Cremophor EL: greater tumor targeting (16-times higher and more sustained concentration in omental tumors), lower toxicity to intestinal crypts and less body weight loss, greater therapeutic efficacy (longer survival and higher cure rate), and greater convenience (less frequent dosing). TPM may overcome the toxicities and compliance-related problems that have limited the utility of intraperitoneal therapy.
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PMID:Tumor-penetrating microparticles for intraperitoneal therapy of ovarian cancer. 1878 Aug 31


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