Poly(lactide)-vitamin E derivative/montmorillonite nanoparticle formulations for the oral delivery of Docetaxel

Department of Chemical and Biomolecular Engineering, National University of Singapore, Block E5, 02-11, 4 Engineering Drive 4, Singapore 117576, Singapore.
Biomaterials (Impact Factor: 8.56). 04/2009; 30(19):3297-306. DOI: 10.1016/j.biomaterials.2009.02.045
Source: PubMed


Four systems of nanoparticles of biodegradable polymers were developed in this research for oral delivery of anticancer drugs with Docetaxel used as a model drug, which include the poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs), the poly(lactide)-vitamin E TPGS nanoparticles (PLA-TPGS NPs), the poly(lactic-co-glycolic acid)-montmorillonite nanoparticles (PLGA/MMT NPs) and the poly(lactide)-vitamin E TPGS/montmorillonite nanoparticles (PLA-TPGS/MMT NPs). Vitamin E TPGS stands for d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), which is a water-soluble derivative of natural vitamin E formed by esterification of vitamin E succinate with polyethylene glycol (PEG) 1000. The design was made to take advantages of TPGS in nanoparticle technology such as high emulsification effects and high drug encapsulation efficiency, and those in drug formulation such as high cellular adhesion and adsorption. MMT of similar effects is also a detoxifier, which may cure some side effects caused by the formulated drug. The drug-loaded NPs were prepared by a modified solvent extraction/evaporation method and then characterized for their MMT content, size and size distribution, surface charge and morphology, physical status and encapsulation efficiency of the drug in the NPs, and in vitro drug release profile. Cellular uptake of the coumarin 6-loaded NPs was investigated. In vitro cancer cell viability experiment showed that judged by IC(50), the PLA-TPGS/MMT NP formulation was found 2.89, 3.98, 2.12-fold more effective and the PLA-TPGS NP formulation could be 1.774, 2.58, 1.58-fold more effective than the Taxotere((R)) after 24, 48, 72h treatment, respectively. In vivo PK experiment with SD rats showed that oral administration of the PLA-TPGS/MMT NP formulation and the PLA-TPGS NP formulation could achieve 26.4 and 20.6 times longer half-life respectively than i.v. administration of Taxotere((R)) at the same 10mg/kg dose. One dose oral administration of the NP formulations could realize almost 3 week sustained chemotherapy in comparison of 22h of i.v. administration of Taxotere((R)). The oral bioavailability can be enhanced from 3.59% for Taxotere((R)) to 78% for the PLA-TPGS/MMT NP formulation and 91% for the PLA-TPGS NP formulation respectively. Oral chemotherapy by nanoparticles of biodegradable polymers is feasible.

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    • "Oral 58 chemotherapy can maintain a sustained moderate plasma concen- 59 tration of the drug to achieve a prolonged exposure of cancerous 60 cells to the drug as well as to avoid high peak above the mean ther- 61 apeutic concentration. resulting in much better efficacy and fewer 62 side effects than the current intermittent parenteral chemotherapy 63 could do (Feng et al., 2009). "
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    ABSTRACT: The aim of study was to formulate PLGA nanoparticles (NPs) of Gemcitabine HCl for enhanced oral bioavailability via absorption through M cells of Peyer's patches. Commercially, the drug is available as i.v. infusion due to its short half life (8-17 min), rapid metabolism and limited tumour uptake. The NPs were prepared by multiple solvent emulsification method. Optimized formulation had particle size (PS) of 166.4 ± 2.42 nm, and entrapment of 56.48 ± 3.63%. TEM images revealed discrete spherical structures of NPs. DSC and FTIR studies confirmed absence of interaction between drug and polymer. In vitro and ex vivo studies demonstrated sustained release from the NPs. The enhanced absorption and uptake of NPs in Caco-2 cells and in vivo absorption in intestinal tissue after oral delivery in rats was confirmed by confocal microscopy. Transport studies in Caco-2 cells confirmed 6.37 fold permeability for NPs. In vitro antiproliferative studies confirmed marked cytotoxicity of NPs on K562 leukemia cell lines. In vivo pharmacokinetic studies in rats showed 21.47 folds bioavailability enhancement from NPs. Hence, orally delivered Gemcitabine HCl loaded NPs have the potential for improving its bioavailability and avoiding side effects associated with iv infusions as well as enhancing patient compliance.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 05/2014; 60. DOI:10.1016/j.ejps.2014.04.014 · 3.35 Impact Factor
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    • "It also has capability to adsorb dietary toxins, microbial toxins associated with gastrointestinal turbulences, hydrogen ions in acidosis and metabolic toxins such as steroidal metabolites associated with pregnancy [14]. Na + -MMT has also been proved to be safe by preclinical , biochemical and histological studies in animal [15]. "
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    ABSTRACT: This work evaluates cationic intercalation of Capecitabine (Xeloda), an antineoplastic agent in interlayer gallery of Na+-MMT, which was further compounded with Poly (L-Lactide) to form microcomposite spheres, for oral chemotherapy of breast cancer. The XRD, TGA, SEM, TEM and FT-IR analysis indicated the CAP intercalated in interlayer of MMT and stabilized in the longitudinal monolayer mode by electrostatic interface. No significant alteration in fundamental active properties of CAP was found in the MMT efficacy and data from in vitro study showed controlled drug release pattern >72 h. The efficacy of CAP-MMT hybrid/MPs was also confirmed on Human neuroblastoma cell line (IMR32) by in vitro cell culture experiments evaluating cell cytotoxic and oxidative stress marker indices which showed that intercalated drug and MPs, were as effective as pristine drug. In vivo pharmacokinetics of CAP-MMT hybrids in rats was examined and plasma CAP levels were evaluated. Our findings suggest that CAP-MMT hybrids and MPs can be of considerable value in chemotherapy of malignant neoplastic disease with reduced side effects and clearly demonstrated that MMT not only plays a role as a delivery matrix for drug but also facilitates significant increase in the delivery proficiency.
    Composites Science and Technology 01/2014; 90:193–201. DOI:10.1016/j.compscitech.2013.11.003 · 3.57 Impact Factor
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    • "Hence, the vast majority of patients prefer oral administration of drugs [6] [7] [8] [9] [10] [11]. Despite the advantages of oral delivery, there are several life-saving drugs, such as anti-cancer drugs, docetaxel, doxorubicin and widely used drugs such as insulin, that are not suitable for oral administration as those drugs are not absorbed or very poorly absorbed orally [12] [13]. The low oral bioavailability of such drugs is due to their large molecular weight and solubility. "
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    ABSTRACT: Oral delivery is the preferred route to deliver therapeutics via nanoparticles due to ease of administration and patient acceptance. Here, we report on the findings of the absorption pathway of taurocholic acid (TCA)-linked heparin and docetaxel (DTX) conjugate, which we refer to as HDTA. We studied the oral absorption of HDTA using a Caco-2 cell transport system and an animal model. We have also used other absorption enhancers, such as ethylene glycol tetraacetic acid (EGTA), or inhibitors, such as sodium azide, to compare the relative permeability of HDTA conjugates. In vivo comparative studies were conducted using free TCA as a pre-administration and exhibited the maximum absorption site of the organ after oral administration of HDTA conjugates. HDTA was found to be absorbed mainly in the ileum and Caco-2 cell monolayer through passive diffusion and bile acid transporters. High fluorescence intensity of HDTA in mice came from the ileum, and it was eliminated from the body through colon. This novel formulation could be further investigated by clinical trials to find the prospect of oral anti-cancer drug delivery through anti-angiogenic treatment strategies.
    Journal of Controlled Release 01/2014; 177(1). DOI:10.1016/j.jconrel.2013.12.034 · 7.71 Impact Factor
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