Cytotoxic and antiangiogenic paclitaxel solubilized and permeation-enhanced by natural product nanoparticles (original) (raw)
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Development of Lipid-Based Nanoparticles for Enhancing the Oral Bioavailability of Paclitaxel
AAPS PharmSciTech, 2011
The current research work investigates the potential of solid lipid nanoparticles (SLNs) in improving the oral bioavailability of paclitaxel. Paclitaxel-loaded SLNs (PTX-SLNs) were prepared by modified solvent injection method using stearylamine as lipid, soya lecithin and poloxamer 188 as emulsifiers. SLNs were characterized in terms of surface morphology, size and size distribution, surface chemistry and encapsulation efficiency. Pharmacokinetics and bioavailability studies were conducted in male Swiss albino mice after oral administration of PTX-SLNs. SLNs exhibited spherical shape with smooth surface as analyzed by transmission electron microscopy (TEM). The mean particle size of SLNs was 96±4.4 nm with a low polydispersity index of 0.162±0.04 and zeta potential of 39.1±0.8 mV. The drug entrapment efficiency was found to be 75.42±1.5% with a loading capacity of 31.5±2.1% (w/w). Paclitaxel showed a slow and sustained in vitro release profile and followed Higuchi kinetic equations. After oral administration of the PTX-SLNs, drug exposure in plasma and tissues was ten-and twofold higher, respectively, when compared with free paclitaxel solution. PTX-SLNs produced a high mean C max (10,274 ng/ml) compared with that of free paclitaxel solution (3,087 ng/ml). The absorbed drug was found to be distributed in liver, lungs, kidneys, spleen, and brain. The results suggested that PTX-SLNs dispersed in an aqueous environment are promising novel formulations that enhanced the oral bioavailability of hydrophobic drugs, like paclitaxel and were quite safe for oral delivery of paclitaxel as observed by in vivo toxicity studies.
Paclitaxel-loaded PCL–TPGS nanoparticles: In vitro and in vivo performance compared with Abraxane®
Colloids and Surfaces B: Biointerfaces, 2014
The purpose of this work was to develop Cremophor ® EL-free nanoparticles (NPs) loaded with Paclitaxel (PTX) in order to improve the drug i.v. pharmacokinetic profile and to evaluate its activity against commercially available formulations such as Taxol ® and Abraxane ® . PTX-loaded poly(-caprolactone)-alpha tocopheryl polyethylene glycol 1000 succinate (PCL-TPGS) NPs were prepared using three different techniques: (i) by nanoprecipitation (NPr-method), (ii) by emulsion-solvent evaporation homogenized with an Ultra-Turrax ® (UT-method) and (iii) by emulsion-solvent evaporation homogenized with an ultrasonicator (US-method). The NPs prepared by US-method showed the smallest size and the highest drug content. The NPs exhibited a slow and continuous release of PTX. The in vitro anti-tumoral activity was assessed using two human breast cancer cell lines (MCF-7 and MDA-MB-231) with the WTS assay. Cytotoxicity studies with both cell lines showed that PTX-loaded PCL-TPGS NPs exhibited better anti-cancer activity compared to PTX solution and the commercial formulation Abraxane ® at different concentrations. Importantly, in the case of triple negative MDA-MB-231 breast cancer cells, the IC 50 value for PTX-loaded PCL-TPGS NPs was 7.8 times lower than Abraxane ® . Finally, in vivo studies demonstrated that PTX-loaded PCL-TPGS NPs exhibited longer systemic circulation time and slower plasma elimination rate than Taxol ® and Abraxane ® . Therefore, the novel NPs investigated might be an alternative nanotechnological platform for PTX delivery system in cancer chemotherapy.
Paclitaxel Drug Delivery Systems: Focus on Nanocrystals’ Surface Modifications
Polymers, 2022
Paclitaxel (PTX) is a chemotherapeutic agent that belongs to the taxane family and which was approved to treat various kinds of cancers including breast cancer, ovarian cancer, advanced non-small-cell lung cancer, and acquired immunodeficiency syndrome (AIDS)-related Kaposi’s sarcoma. Several delivery systems for PTX have been developed to enhance its solubility and pharmacological properties involving liposomes, nanoparticles, microparticles, micelles, cosolvent methods, and the complexation with cyclodextrins and other materials that are summarized in this article. Specifically, this review discusses deeply the developed paclitaxel nanocrystal formulations. As PTX is a hydrophobic drug with inferior water solubility properties, which are improved a lot by nanocrystal formulation. Based on that, many studies employed nano-crystallization techniques not only to improve the oral delivery of PTX, but IV, intraperitoneal (IP), and local and intertumoral delivery systems were also devel...
Materials Science and Engineering: C, 2018
Adenocarcinoma is the most lethal gynecologic tumor and treatment usually consists in surgery followed by chemotherapy. However, the chemotherapy benefits are eventually limited due to drug toxicity to normal tissues and cells, which cause several and harsh side effects. Paclitaxel (PCX) is the drug of first choice for ovarian cancer treatment, but it has low aqueous solubility, which reduces its bioavailability. Thus, in the commercial drug, Taxol ® , PCX is solubilized in a mixture of toxic surfactants. The development of drug nanocarriers has been investigated to promote the reduction of toxic effects and increase the safety and therapeutic efficacy of PCX. The aim of this work was the development and characterization of PCX loaded nanoparticles (PNPCX) and evaluation of in vitro efficacy of developed system using adenocarcinoma cell line. The nanocarrier was successfully obtained using nanoprecipitation technique. The results showed that the PNPCX-A had a particle size distribution around 140 nm and polydispersity index smaller than 0.1, with high PCX encapsulation efficiency. The results obtained were suitable for the intravenous administration route and promotion of passive targeting in the tumor microenvironment. The in vitro cytotoxicity assays of SKOV-3 cell line demonstrated that PNPCX-A was able to release PCX and reduce cell viability. The flow cytometry assays first reported that a nanostructured system with such composition (PNPCX-A) presented a time dependent cellular uptake, showing the ability of nanocarrier to be internalized. PNPCX-A present a distinguish potential for ovarian cancer therapy optimization. In vivo studies are needed to confirm the in vitro results and provide additional data regarding safety and efficacy of ovarian cancer treatment.
Self-Assembling PCL-Based Nanoparticles as PTX Solubility Enhancer Excipients
Macromolecular Bioscience, 2018
in this application has been hampered by the heterogeneity of the solid tumor microenvironments in the patients, such as different pore of the vessels, increased interstitial fluid pressure, hypoxia, and sometimes even the complete absence of vasculature. [2] A typical example of lipophilic anticancer drug loaded in NPs in an attempt to improve its therapeutic index is paclitaxel (PTX), one of the most important chemotherapeutic drugs developed so far for the treatment of a large number of cancers, such as ovarian, lung, and breast cancers. [3] PTX, isolated for the first time from the bark of the Taxus brevifolia, is a very poor water-soluble white crystalline powder that requires to be formulated with polyoxyethylated castor oil (Cremophor EL) and dehydrated ethanol (50/50 v/v) in order to be administrated. [4] However, Cremophor EL is a surfactant well-known to cause adverse effects, such as hypersensitivity reactions and peripheral neuropathy. [5] Among all the nanocarriers developed to encapsulate PTX eliminating this toxic compound, polycaprolactone (PCL) and poly(lacticco-glycolic acid) (PLGA)-based NPs have shown good profile of biocompatibility, biodegradability, and efficacy. [6] A formulation based on PLGA micelles named Genexol is, together with Abraxane, a PTX albumin-bound NP formulation, one of the currently approved PTX alternatives to the more toxic Cremophor EL-based Taxol. [7,8] The improvement in the toxicological profile, however, is probably due to different effects of the NPs, such as the removal of toxic excipients, an increased solubility, or a different rate of binding to plasma proteins. As long as the NPs play only the role of a solubility enhancer excipient, they should be able to load the drug with the highest efficiency possible and degrade into biocompatible and easy removable compounds. In the fabrication of the NPs, a significant amount of the lipophilic drug is lost during the loading and dialysis and this can cause an additional increase in the cost of a less toxic formulation. Recently, we developed a novel type of PCL-based NPs for the drug delivery of different lipophilic therapeutics including PTX and demonstrated the in vivo antitumor activity. [9] These NPs are made via a two-step process that consists in i) the synthesis of a PCL macromonomer (Figure 1, HEMA-CL 5) via ring-opening polymerization (ROP) and ii) the emulsion Drug Delivery
Journal of Advanced Zoology, 2023
The effectiveness of paclitaxel as a cancer treatment is widely recognized. However, its solubility issue can be addressed by blending it with ethanol and Cremophor EL, a product marketed under the trade name Taxol. Nevertheless, to enhance the anticancer efficacy of Cremophor EL and reduce adverse effects, alternative delivery methods and strategies must be explored. The objective of this work was to synthesize PLGA nanoparticles (PNF) loaded with paclitaxel and evaluate a number of characteristics, including in vitro drug release, drug loading, polydispersity index, zeta potential, and particle size. Finding the best formulation, PNF4, based on its in vitro drug release properties, was the main goal of the study. The surface morphology of PNF4 was then investigated by means of scanning and transmission electron microscopy after that (SEM and TEM). The delivery method follows the Korsmeyer-Peppas model, according to analysis of the in vitro drug release kinetics, indicating a "Fickian diffusion" mechanism. Furthermore, the in vitro cytotoxicity assessment demonstrated that the PNF4 formulation exhibited superior cytotoxicity compared to free paclitaxel.
European Journal of Pharmaceutics and Biopharmaceutics, 2012
The aim of this work was to study the potential of pegylated poly(anhydride) nanoparticles as carriers for the oral delivery of paclitaxel (PTX). Paclitaxel is an anticancer drug, ascribed to the class IV of the Biopharmaceutical Classification system, characterised for its low aqueous solubility and to act as a substrate of the P-glycoprotein and cytochrome P450. For the pegylation of nanoparticles, three different poly(ethylene glycol) (PEG) were used: PEG 2000 (PTX-NP2), PEG 6000 (PTX-NP6) and PEG 10000 (PTX-NP10). The transport and permeability of paclitaxel through the jejunum mucosa of rats was determined in Ussing chambers whereas its oral bioavailability was studied in rats. The loading of PTX in pegylated nanoparticles increased between 3 and 7times the intestinal permeability of paclitaxel through the jejunum compared with the commercial formulation Taxol®. Interestingly, the permeability of PTX was significantly higher for PTX-NP2 and PTX-NP6 than for PTX-NP10. In the in vivo studies similar results were obtained. When PTX-NP2 and PTX-NP6 were administered to rats by the oral route, sustained and therapeutic plasma levels of paclitaxel for at least 48-h were observed. The relative oral bioavailability of paclitaxel delivered in nanoparticles was calculated to be 70% for PTX-NP2, 40% for PTX-NP6 and 16% in case of PTX-NP10. All of these observations would be related with both the bioadhesive properties of these carriers and the inhibitory effect of PEG on the activity of both P-gp and P450 cytochrome.
Efficacy and In Vitro Cytotoxicity of Nanostructured Lipid Carriers for Paclitaxel Delivery
Paclitaxel (PTX) is an anticancer drug having poor aqueous solubility and low bioavailability. Formulation of PTX into Nanostructure lipid carriers (NLC) could be a potential way to enhance PTX aqueous solubility and bioavailability hence increases efficacy and decreases side effects. Eight PTX-NLC formulae were prepared using homogenization-ultrasonication technique. Characterization of the nanoparticles was done by transmission electron microscopy and by measurement of particle size, poly dispersibility index and zeta potential. Encapsulation efficiency, drug loading, and In Vitro release were measured. Particle size ranged between 172.8 ± 0.8 to 378.2 ± 1.8 nm and zeta potential between-18.6 ± 0.4 to-28.1 ± 1.2 mV. High EE and DL were obtained due to incorporation of liquid lipid and the In Vitro release showed prolonged time dependent release compared to Taxol ®. NLC-3 had the best results among the eight prepared formulae. In Vitro cytotoxicity of NLC-3 was evaluated on MCF-7 cell line and compared to pure PTX powder and Taxol ®. These findings show that NLC is a potential carrier to improve efficacy and enhance PTX delivery.
Nanomedicine, 2014
Aim: The authors report a novel approach for enhancing the oral absorption of paclitaxel (PTX) by encapsulation in poly(anhydride) nanoparticles (NPs) containing cyclodextrins and poly(ethylene glycol). Materials & methods: Formulations were prepared using the solvent displacement method. Subsequently, pharmacokinetics and organ distribution assays were evaluated after oral administration into C57BL/6J mice. In addition, antitumor efficacy studies were performed in a subcutaneous tumor model of Lewis lung carcinoma. Results: PTX-loaded NPs displayed sizes between 190–300 nm. Oral NPs achieved drug plasma levels for at least 24 h, with an oral bioavailability of 55–80%. Organ distribution studies revealed that PTX, orally administered in NPs, underwent a similar distribution to intravenous Taxol® (Bristol-Myers Squibb, NJ, USA). For in vivo antitumor assays, oral strategy maintained a slower tumor growth than intravenous Taxol. Conclusion: PTX orally administered in poly(anhydride) N...