Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of injectable microspheres for sustained drug delivery to the arterial wall is a major challenge. We demonstrated the possibility of entrapping an antiproliferative agent, taxol, in poly(ethylene glycol) (PEG)-coated biodegradable poly(lactic acid) (PLA) microspheres with a mean diameter of 2-6 microm. A solution of taxol and PLA dissolved in an acetone/dichloromethane mixture was poured into an aqueous solution of PEG [or poly(vinyl alcohol) (PVA] with stirring with a high-speed homogenizer for the formation of microspheres. Taxol recovery in PLA-PEG microspheres was higher (61.2 +/- 2.3%) than with PVA-based (41.6 +/- 1.8%) preparations. An analysis by diffuse reflectance infrared Fourier transform spectroscopy revealed that PEG was incorporated well on the PLA microsphere surface. Scanning electron microscopy revealed that the PEG-coated PLA microspheres were spherical in shape and had a smooth surface texture like those of PVA-based preparations. The amount of drug release was much higher initially (25-30%); this was followed by a constant slow-release profile for a 30-day period of study. This PEG-coated PLA microsphere formulation may have potential for the targeted delivery of antiproliferative agents to treat restenosis.
 ...
PMID:Controlled delivery of taxol from poly(ethylene glycol)-coated poly(lactic acid) microspheres. 1142 3

When SW620 colon cancer-derived metastatic cells were exposed to nanomolar concentrations of Taxol, colchicine or (Z)-3,5,4'-trimethoxystilbene (R3), huge aneuploid, polynuclear cells survived the treatment. These cells released considerable amounts of the matrix metalloproteinase matrilysin (MMP-7), and tissue-type plasminogen activator (tPA) into the surrounding culture medium. MMP-7, and other proteolytic enzymes were highly expressed by these cells. In spite of their enormous size, the polyploid cells exhibited a considerable migratory capacity, as was demonstrated by their migration through an artificial basement membrane. While colchicine and R3-treated cells showed an inverse relationship between drug concentration and invasiveness, treatment with Taxol increased the capacity of the SW620 cells to penetrate through the membrane. The invasive capacity was not correlated with the induction and release of proteolytic enzymes. The idea that expression and release of proteolytic enzymes is a fundamental prerequisite of tumour cell invasiveness is generally accepted. The ability of the cells to respond to chemotactic signalling, and the filamentous structures of the cells, together with several cell adhesion factors, which are the basis of cell migration, are prerequisites of invasiveness. These factors are presumably different in the aneuploid cells produced by Taxol, colchicine and R3, and await scrutiny.
 ...
PMID:Polyploidisation of metastatic colon carcinoma cells by microtubule and tubulin interacting drugs: effect on proteolytic activity and invasiveness. 1537 54

Paclitaxel is one of the best antineoplastic drugs found in nature in the past decades, which has excellent therapeutic effects against a wide spectrum of cancers. Because of its high hydrophobicity, Cremophor EL has to be used as adjuvant in its clinical dosage form (Taxol), which has been found to cause serious side effects. Nanoparticles of biodegradable polymers may provide an ideal solution. In this research, paclitaxel-loaded nanoparticles of poly(D,L-lactide)/methoxy poly(ethylene glycol)-polylactide (PLA/MPEG-PLA) blends of various blend ratio 100/0, 75/25, 50/50, 25/75, and 0/100 were formulated by the nanoprecipitation method for controlled release of paclitaxel. It was found that increasing the proportion of MPEG-PLA component in the blend from 0 to 100% resulted in a progressive decrease of the particle size from 230.6+/-11.1 nm to 74.8+/-14.0 nm. The zeta potential of the drug-loaded nanoparticles was increased accordingly from -19.60+/-1.13 mV to a nearly neutral, that is, -0.33+/-0.28 mV, which indicates the gradual enrichment of PEG segments on the particle surface. The findings were further confirmed by X-Ray Photoelectron Spectroscopy (XPS) analysis. Differential scanning calorimetry (DSC) analysis showed that the glass transition temperature of PLA was significantly decreased from 58.7 to 52.1 degrees C with an increase of MPEG-PLA proportion from 0 to 75%, suggesting the miscibility of PLA and MPEG-PLA. The pure PLA nanoparticles (100/0) exhibited the slowest drug-release rate with 37.3% encapsulated drug released from the nanoparticles for 14 days while the MPEG-PLA nanoparticles (0/100) achieved the fastest drug release with 95.9% drug release in the same period.
 ...
PMID:Nanoparticles of poly(D,L-lactide)/methoxy poly(ethylene glycol)-poly(D,L-lactide) blends for controlled release of paclitaxel. 1659 86

Polysorbate 80 (Tween 80) has been widely used as an emulsifier with excellent effects in nanoparticles technology for biomedical applications. This work was thus triggered to synthesize poly(lactide)/Tween 80 copolymers with various copolymer blend ratio, which were synthesized by ring-opening polymerization and characterized by 1H NMR and TGA. Nanoparticles of poly(lactide)/Tween 80 copolymers were prepared by the dialysis method without surfactants/emulsifiers involved. Paclitaxel was chosen as a prototype anticancer drug due to its excellent therapeutic effects against a wide spectrum of cancers. The drug-loaded nanoparticles of poly(lactide)/Tween 80 copolymers were then characterized by various state-of-the-art techniques, including laser light scattering for particles size and size distribution, field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) for surface morphology; laser Doppler anemometry for zeta potential; differential scanning calorimetry (DSC) for the physical status of the drug encapsulated in the polymeric matrix; X-ray photoelectron spectrometer (XPS) for surface chemistry; high performance liquid chromatography (HPLC) for drug encapsulation efficiency; and in vitro drug release kinetics. HT-29 cells and Glioma C6 cells were used as an in vitro model of the GI barrier for oral chemotherapy and a brain cancer model to evaluate in vitro cytotoxicity of the paclitaxel-loaded nanoparticles. The viability of C6 cells was decreased from 37.4 +/- 4.0% for poly(D,L-lactide-co-glycolic acid) (PLGA) nanoparticles to 17.8 +/- 4.2% for PLA-Tween 80-10 and 12.0 +/- 5.4% for PLA-Tween 80-20 copolymer nanoparticles, which was comparable with that for Taxol at the same 50 microg/mL drug concentration.
 ...
PMID:In vitro investigation on poly(lactide)-Tween 80 copolymer nanoparticles fabricated by dialysis method for chemotherapy. 1660 31

Nanoparticles (NPs) of poly(lactide)-Vitamin E TPGS (PLA-TPGS) copolymers were synthesized by a dialysis method in the present study to formulate paclitaxel for oral chemotherapy with Caco-2 cells as an in vitro model of the gastrointestinal (GI) drug barrier. The PLA-TPGS NPs were of size 340nm in diameter with 5.2% drug loading. The drug release kinetics showed a 31% initial burst in the first day, followed by 80% accumulative drug release after 30 days in the PBS buffer at pH 7.4, and the release rate was found lower in simulated gastric and intestinal conditions. The internalization of fluorescent PLA-TPGS NPs by Caco-2 cells was visualized by confocal laser scanning microscopy (CLSM). PLA-TPGS NPs showed significant increase in the cellular uptake by 1.8- and 1.4-fold in comparison with poly(lactide-co-glycolide) (PLGA) NPs cultured with HT-29 and Caco-2 cells, respectively, and the cellular uptake efficiency was found affected by the incubation time and the particle concentration in the culture medium. Investigation on HT-29 and Caco-2 cytotoxicity showed advantages of the PLA-TPGS NP formulation versus Taxol. The IC(50) of the PLA-TPGS NP formulation with HT-29 cells was found 40% lower than of Taxol at the same dose of paclitaxel. The results obtained in this research demonstrated feasibility for the PLA-TPGS NPs to be applied for oral delivery of paclitaxel as well as other anticancer drugs.
 ...
PMID:Self-assembled nanoparticles of poly(lactide)--Vitamin E TPGS copolymers for oral chemotherapy. 1684 44

Methoxy polyethylene glycol-polylactide (MPEG-PLA) nanoparticles (NPs) were prepared by the nanoprecipitation method with particle size of 140+/-21nm in diameter and drug encapsulation efficiency of 87.6+/-3.1%. In vitro cytotoxicity of the drug formulated in the NPs was investigated with MCF-7 cancer cells in close comparison with that of Taxol((R)). The in vitro cytotoxicity with MCF-7 cells showed that the NP formulation could be 33.3, 10.7, 7.7 times more effective than Taxol((R)) after 24, 48, 72h culture at the same drug concentration of 1microg/ml. Confocal laser scanning microscopy (CLSM) visualized cellular internalization of the coumarin 6-loaded MPEG-PLA NPs. The in vitro results were further confirmed by the in vivo pharmacokinetic analysis with SD rats. The total area-under-the-curve (AUC(0-infinity)), which determines the therapeutic effects of a dose, was found to be 29,600+/-1,690ng-h/ml for the NP formulation, which is 3.09 times of 9,570+/-1,480ng-h/l for Taxol((R)) with 10mg/kg dose i.v. injection. The half-life (t(1/2)) of the drug formulated in the NPs was found to be 18.80+/-3.14h, which is 2.75 times of 6.84+/-1.39h for Taxol((R)). The distribution volume at steady state for the drug loaded in the NPs was 7.21+/-2.17l/kg, which was 2.93 times of 2.46+/-1.41l/kg for Taxol((R)). Our proof-of-concept in vitro and in vivo valuation shows that our MPEG-PLA NP formulation could have great advantages versus the original drug in small-molecule drug chemotherapy as well as in various applications in nanomedicine.
 ...
PMID:In vitro and in vivo evaluation of methoxy polyethylene glycol-polylactide (MPEG-PLA) nanoparticles for small-molecule drug chemotherapy. 1757 4

Despite recent advances in cancer therapy, many malignant tumors still lack effective treatment and the prognosis is very poor. Paclitaxel is a potential anticancer drug, but its use is limited by the facts that paclitaxel is a P-gp substrate and its aqueous solubility is poor. In this study, three-step tumor targeting of paclitaxel using biotinylated PLA-PEG nanoparticles and avidin-biotin technology was evaluated in vitro as a way of enhancing delivery of paclitaxel. Paclitaxel was incorporated both in biotinylated (BP) and non-biotinylated (LP) PEG-PLA nanoparticles by the interfacial deposition method. Small (mean size approximately 110 nm), spherical and slightly negatively charged (-10 mV) BP and LP nanoparticles achieving over 90% paclitaxel incorporation were obtained. The successful biotinylation of nanoparticles was confirmed in a novel streptavidin assay. BP nanoparticles were targeted in vitro to brain tumor (glioma) cells (BT4C) by three-step avidin-biotin technology using transferrin as the targeting ligand. The three-step targeting procedure increased the anti-tumoral activity of paclitaxel when compared to the commercial paclitaxel formulation Taxol and non-targeted BP and LP nanoparticles. These results indicate that the efficacy of paclitaxel against tumor cells can be increased by this three-step targeting method.
 ...
PMID:Three-step tumor targeting of paclitaxel using biotinylated PLA-PEG nanoparticles and avidin-biotin technology: Formulation development and in vitro anticancer activity. 1855 75

Antiangiogenic cancer therapy can be achieved through the targeted delivery of antiangiogenic agents to the endothelial cells of tumor neovasculature. In the present study, we developed a drug delivery system (DDS), nanoparticles conjugated with K237-(HTMYYHHYQHHL) peptides for tumor neovasculature targeting drug delivery. Paclitaxel, a chemotherapeutic agent with potent antiangiogenic activity, was used as a prototype drug. We synthesized the aldehyde poly(ethylene glycol)-poly(lactide) (aldehyde-PEG-PLA) block copolymer by ring opening polymerization. The nanoparticles loading paclitaxel (PTX-NP) were fabricated using the O/W emulsion and evaporation technique. K237 ligand, a peptide that can bind to the KDR receptors predominantly expressed on the surface of tumor neovasculature endothelial cells with high affinity and specificity and inhibit the VEGF-KDR angiogenic signal pathway, was conjugated to the aldehyde group of PEG chain using the N-terminal PEGylation technique. The K237 conjugated paclitaxel-loaded nanoparticles (K237-PTX-NP) had a hydrodynamic diameter of 150 nm. The K237 density on nanoparticle surface was 474 and the mean distance between two neighboring PEG chains linked to K237 peptide was 12 nm. The K237 conjugated nanoparticles could be significantly internalized by human umbilical vein endothelial cells (HUVEC) through the K237-KDR interaction, and this facilitated uptake led to the expected enhanced antiangiogenic activity shown by HUVEC proliferation, migration and tube formation compared to cells treated with the commercial formulation Taxol and PTX-NP. The long-circulating property and the K237 ligand of K237-PTX-NP warranted rapid, long-term, and accurate in vivo tumor neovasculature targeting, and thereafter the significant apoptosis of tumor neovasculature endothelial cells and necrosis of tumor tissues of MDA-MB-231 breast tumors implanted in female BLAB/c nude mice. This nanoparticulate DDS offers a new strategy for paclitaxel chemotherapy application and it could also be used to carry other chemotherapeutic drugs, genes, and proteins with antiangiogenic activity for antiangiogenic cancer therapy.
 ...
PMID:Peptide-conjugated biodegradable nanoparticles as a carrier to target paclitaxel to tumor neovasculature. 2005 44

The use of glioblastoma-targeted drug delivery system facilitates efficient delivery of chemotherapeutic agents to malignant gliomas in the central nervous system while minimizing high systemic doses associated with debilitating toxicities. To employ the high binding affinity of a cyclic RGD peptide (c(RGDyK), cyclic Arginine-Glycine-Aspartic acid-D-Tyrosine-Lysine) with integrin alpha(v)beta(3) over-expressed on tumor neovasculature and U87MG glioblastoma cells, we prepared paclitaxel-loaded c(RGDyK)-Poly(ethylene glycol)-block-poly(lactic acid) micelle (c(RGDyK)-PEG-PLA-PTX). In vitro physicochemical characterization of these novel micelles showed satisfactory encapsulated efficiency, loading capacity and size distribution. In vitro cytotoxicity studies proved that the presence of c(RGDyK) enhanced the anti-glioblastoma cell cytotoxic efficacy by 2.5 folds. The binding affinity of c(RGDyK)-PEG-PLA micelle with U87MG cells was also investigated. The competitive binding IC(50) value of c(RGDyK)-PEG-PLA micelle was 26.30 nM, even lower than that of c(RGDyK) (56.23 nM). In U87MG glioblastoma-bearing nude mice model, biodistribution of (125)I-radiolabeled c(RGDyK)-PEG-PLA or DiR encapsulated micelles and anti-glioblastoma pharmacological effect was investigated after intravenous administration. c(RGDyK)-PEG-PLA micelle accumulated in the subcutaneous and intracranial tumor tissue, and when loaded with PTX (c(RGDyK)-PEG-PLA-PTX), exhibited the strongest tumor growth inhibition among the studied paclitaxel formulations. The anti-glioblastoma effect of c(RGDyK)-PEG-PLA-PTX micelle was also reflected in the median survival time of mice bearing intracranial U87MG tumor xenografts where the median survival time of c(RGDyK)-PEG-PLA-PTX micelle-treated mice (48 days) was significantly longer than that of mice treated with PEG-PLA-PTX micelle (41.5 days), Taxol (38.5 days) or saline (34 days). Therefore, our results suggested that c(RGDyK)-PEG-PLA micelle may be a potential drug delivery system in the treatment of integrin alpha(v)beta(3) over-expressed glioblastoma.
 ...
PMID:Cyclic RGD conjugated poly(ethylene glycol)-co-poly(lactic acid) micelle enhances paclitaxel anti-glioblastoma effect. 2005 23

The clinical dosage formulation of Paclitaxel and Docetaxel, Taxol and Taxotere, while having high efficacy, can cause serious side effects due to the adjuvant used. We have developed a system of nanoparticles (NPs) of biodegradable copolymer, poly(lactic acid)-d- -tocopheryl polyethylene glycol 1000 succinate (PLA-TPGS), for Docetaxel formulation to achieve enhanced, sustainable and controlled chemotherapeutic effectiveness and reduce the undesirable side actions. Docetaxel-loaded PLA-TPGS NPs were synthesized with desired size and physicochemical and pharmaceutical properties. In vitro studies using MCF-7 cancer cells have demonstrated the cellular uptake and lack of cytotoxicity of the NP formulation. In vivo pharmacokinetics and biodistribution analysis have shown that one dose of the NP formulation of Docetaxel can achieve a 360-h effective chemotherapy with 3.44-fold higher therapeutic effect and 4.42- fold lower side effect than that of Taxotere at the same dose of 10 mg/kg, as indicated by the larger area-under-the-curve and better biodistribution.
 ...
PMID:Nanomedicine: enhancement of chemotherapeutical efficacy of docetaxel by using a biodegradable nanoparticle formulation. 2061 52


1 2 3 Next >>