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      Preparation, characterization, and in vitro/vivo studies of oleanolic acid-loaded lactoferrin nanoparticles

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          Oleanolic acid (OA), a pentacyclic triterpene, is used to safely and economically treat hepatopathy. However, OA, a Biopharmaceutics Classification System IV category drug, has low bioavailability owing to low solubility (<1 μg/mL) and biomembrane permeability. We developed a novel OA nanoparticle (OA-NP)-loaded lactoferrin (Lf) nanodelivery system with enhanced in vitro OA dissolution and improved oral absorption and bioavailability. The OA-NPs were prepared using NP albumin-bound technology and characterized using dynamic light scattering, scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, and in vitro dissolution test. The in vivo pharmacokinetics was investigated in Sprague Dawley rats using liquid chromatography-tandem mass spectrometry. OA-NPs (OA:Lf =1:6, w/w%) exhibited spherical morphology, 202.2±8.3 nm particle size, +(27.1±0.32) mV ζ potential, 92.59%±3.24% encapsulation efficiency, and desirable in vitro release profiles. An effective in vivo bioavailability (340.59%) was achieved compared to the free drug following oral administration to rats. The Lf novel nanodelivery vehicle enhanced the dissolution rate, intestinal absorption, and bioavailability of OA. These results demonstrate that Lf NPs are a new strategy for improving oral absorption and bioavailability of poorly soluble and poorly absorbed drugs.

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          Most cited references 43

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          Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.

          ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast congruent with ovary > prostate > colon. The LD(50) and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007.
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            Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation.

             C Keck,  H. Müller (2005)
            For many new chemical entities (NCE) of very low solubility oral bioavailability enhancement by micronisation is not sufficient, the next step taken was nanonisation. The production of drug nanocrystals by bottom up techniques (precipitation) is briefly described, main focus is given on particle diminution by high pressure homogenisation. Homogenisation can be performed in water (DissoCubes) or alternatively in non-aqueous media or water-reduced media (Nanopure). There is also a combination process of precipitation followed by a second high energy step, e.g. homogenisation (NANOEDGE). The result is a suspension of drug nanocrystals in a liquid, the so-called nanosuspension. Presented are the physical background of the diminution process, effects of production parameters (power density, number of homogenisation cycles) on crystal size, clinical batch production and scaling up of the production. As an important point the transfer of the liquid nanosuspensions to patient convenient oral dosage forms such as tablets and capsules is described.
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              CYP716A subfamily members are multifunctional oxidases in triterpenoid biosynthesis.

               Kazuki Saito,  E Ono,  H Seki (2011)
              Triterpenoids are a diverse group of secondary metabolites that are associated with a variety of biological activities. Oleanolic acid, ursolic acid and betulinic acid are common triterpenoids in plants with diverse biological activities, including antifungal, antibacterial, anti-human immunodeficiency virus (HIV) and/or antitumor activities. In the present study, using the gene co-expression analysis tool of Medicago truncatula, we found a strong correlation between CYP716A12 and β-amyrin synthase (bAS), which encodes the enzyme responsible for the initial cyclization of 2,3-oxidosqualene to β-amyrin (the basic structural backbone of most triterpenoid saponins). Through an in vitro assay, we identified CYP716A12 as a β-amyrin 28-oxidase able to modify β-amyrin to oleanolic acid (through erythrodiol and, possibly, oleanolic aldehyde). We also confirmed its activity in vivo, by expressing CYP716A12 in transgenic yeast that endogenously produce β-amyrin. In addition, CYP716A12 was evaluated for its potential α-amyrin- and lupeol-oxidizing activities. Interestingly, CYP716A12 was able to generate ursolic acid (through uvaol and, possibly, ursolic aldehyde) and betulinic acid (through betulin). Hence, CYP716A12 was characterized as a multifunctional enzyme with β-amyrin 28-oxidase, α-amyrin 28-oxidase and lupeol 28-oxidase activities. We also identified homologs of CYP716A12 in grape (CYP716A15 and CYP716A17) that are involved in triterpenoid biosynthesis, which indicates the highly conserved functionality of the CYP716A subfamily among plants. These findings will be useful in the heterologous production of pharmacologically and industrially important triterpenoids, including oleanolic acid, ursolic acid and betulinic acid.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                09 May 2017
                : 11
                : 1417-1427
                [1 ]Department of Pharmaceutics, China Pharmaceutical University, Nanjing
                [2 ]Department of Pharmaceutics, ZheJiang Pharmaceutical College, Ningbo
                [3 ]Department of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, People’s Republic of China
                Author notes
                Correspondence: Jianping Zhou, Department of Pharmaceutics, China Pharmaceutical University, #24 Tong Jia Xiang, Nanjing 210009, People’s Republic of China, Tel +86 139 5199 0456, Fax +86 258 327 1102, Email zhoujianp60@ 123456163.com
                Zhiying Zhao, College of Traditional Chinese Pharmacy, China Pharmaceutical University, #24 Tong Jia Xiang, Nanjing 210009, People’s Republic of China, Tel +86 135 1512 1868, Fax +86 258 530 1528, Email zhaozhiying608@ 123456126.com
                © 2017 Xia et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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