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      Enzymatic synthesis and in vitro evaluation of folate-functionalized liposomes

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          Abstract

          In this study, folate–poly(ethylene glycol) 3400–cholesterol conjugates (FA–PEG–Chol) were enzymatically synthesized in one step and incorporated into liposomes to prepare folate (FA)-functionalized liposomes for targeted drug delivery. The FA-functionalized liposomes loaded with betulinic acid (BA) (FA-L-BA) were prepared by thin lipid film method. The FA-L-BA was characterized by their morphology, particle size, zeta potential, encapsulation efficiency (EE), stability, cell cytotoxicity and cellular uptake. The average size of FA-L-BA was 222±8 nm. The spherical particles exhibited a negative electrical charge of −20.12±1.45 mV and high EE of 91.61%±1.16%. The liposomes were taken up selectively by HepG2 cells. FA-L-BA showed enhanced cytotoxicity (50% inhibitory concentration [IC 50] =63.07±2.22 μg/mL) compared to nontargeted control normal liposomes loaded with BA (L-BA; IC 50 =93.14±2.19 μg/mL) in HepG2 cells in vitro. In addition, FA-functionalized liposomes loaded with Ir-1 (FA-L-Ir-1) showed significantly higher cellular uptake in HepG2 cells compared to nontargeted control normal liposomes loaded with Ir-1 (L-Ir-1). This novel approach for the liposomes surface modified with FA by a one-step enzymatic amidation was expected to provide potential application as a drug carrier for active targeted delivery to tumor cells.

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          Most cited references 27

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          Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes.

          Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, approved by the FDA for the treatment of ovarian and breast cancers. Due to its low solubility in water, it is clinically administered dissolved in Cremophor EL, (polyethoxylated castor oil) and ethanol, which cause serious side effects. Inclusion of paclitaxel in liposomal formulations has proved to be a good approach to eliminating this vehicle and improving the drug's antitumor efficacy. We prepared different conventional and PEGylated liposomes containing paclitaxel and determined encapsulation efficiency, physical stability and drug leakage in human plasma. The best conventional liposome formulation was composed of ePC/PG 9:1, while for PEGylated liposomes the best composition was ePC/PG/CHOL/PEG(5000)-DPPE 9:1:2:0.7. PEGylated liposomes were found to be less stable during storage than the corresponding conventional liposomes and to have lower drug release in human plasma at 37 degrees C. In vitro cytotoxic activities were evaluated on HT-29 human colon adenocarcinoma and MeWo melanoma cell lines. After 2 and 48 h, conventional liposomes had the same cytotoxicity as free paclitaxel, while PEGylated liposomes were as active as free drug, only after 48 h. Pharmacokinetics and biodistribution were evaluated in Balb/c mice after i.v. injection of paclitaxel, formulated in Cremophor EL or in conventional or in PEGylated liposomes. Encapsulation of paclitaxel in conventional liposomes produced marked differences over the free drug pharmacokinetics. PEGylated liposomes were long-circulating liposomes, with an increased t(1/2) beta 48.6 h, against t(1/2) beta 9.27 h of conventional liposomes. Biodistribution studies showed a considerable decrease in drug uptake in MPS-containing organs (liver and spleen) at 0.5 and 3 h after injection with PEGylated compared to conventional liposomes.
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            Solubility studies of oleanolic acid and betulinic acid in aqueous solutions and plant extracts of Viscum album L.

            Mistletoe (Viscum album L.) contains the triterpene acids oleanolic acid (OA) and betulinic acid (BA), which were found to have anti-tumour properties. In this study, the solubilities of OA and BA were studied in water (up to 0.02 microg/mL in each case) and in alkaline solutions of 10 mM trisodium phosphate (pH 11.5; OA: 77.2 microg/mL; BA: 40.1 microg/mL). Furthermore, triterpene acids were quantified in aqueous mistletoe extracts (pH 7.3; drug to extract ratio 1:25). OA (1.1 microg/mL) and BA (0.9 microg/mL) were extracted with a yield of less than 5%. Preparing plant extracts with basic pH values resulted in a triterpene acid content of 9.3 microg/mL OA and 5.2 microg/mL BA (pH 12.1), reaching neither the solubility limits nor a complete extraction of the plant material. The triterpene acid content of neutral plant extracts above the solubility limit could be due to interactions with biocolloids. Interaction studies were performed by gel permeation chromatography. Different mechanisms of the dissolution at pH 7.3 and pH 10.2 are discussed.
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              On the development of new biocatalytic processes for practical pharmaceutical synthesis.

              Biocatalysis has established itself as a scalable and green technology for the production of a broad range of pharmaceutical APIs and intermediates. The number and scope of biocatalysts employed on large scale to deliver cost-advantaged and quality-advantaged processes to important substances continue to expand. This review discusses the recent developments in the field, including examples of processes leveraging hydrolases, reductases, transaminases, oxidases and other biocatalysts, focused on the preparation of important investigational and launched therapeutics. Biocatalysts recently discovered, and in some cases rediscovered, for the interesting chemistry they enable are likely to further substantiate the expansion of the biocatalysis field. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                20 June 2017
                : 11
                : 1839-1847
                Affiliations
                Department of Pharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
                Author notes
                Correspondence: Bohong Guo, Department of Pharmaceutics, Guangdong Pharmaceutical University, 280 Wai Huan Dong Lu, Guangzhou Higher Education Mega Center, Guangzhou 510006, China, Tel +86 20 3935 2117, Fax +86 20 3935 2129, Email guobohong@ 123456gdpu.edu.cn
                Article
                dddt-11-1839
                10.2147/DDDT.S132841
                5484511
                © 2017 Guo 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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                Original Research

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