Enhanced antitumor effect of camptothecin loaded in long-circulating polymeric micelles

Kawano, Keiichi; Watanabe, Masato; Yamamoto, Tatsuhiro; Yokoyama, M.; Opanasopit, Praneet; Okano, Teruo; Maitani, Yoshie

doi:10.1016/j.jconrel.2006.03.012

Cited by 101 publications

(61 citation statements)

References 14 publications

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“…Various approaches have been reported in literature in order to reduce these severe systemic toxicities and enhance antitumor effects of CPT. These includes conjugation to synthetic polymers [28][29][30][31], incorporation into liposomes [32,33], microspheres [34,35], nanohybrids [36], and polymeric micelles [37][38][39][40][41].…”

Section: Introductionmentioning

confidence: 99%

Mixed PEG–PE/vitamin E tumor-targeted immunomicelles as carriers for poorly soluble anti-cancer drugs: Improved drug solubilization and enhanced in vitro cytotoxicity

Sawant

Torchilin

2008

European Journal of Pharmaceutics and Biopharmaceutics

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Two poorly soluble, potent anticancer drugs, paclitaxel and camptothecin, were successfully solubilized by mixed micelles of polyethylene glycol-phosphatidyl ethanolamine (PEG-PE) and vitamin E. Drug containing micelles were additionally modified with anti-nucleosome monoclonal antibody 2C5 (mAb 2C5), which can specifically bring micelles to tumor cells in vitro. The optimized micelles had an average size of about 13-to-22 nm and the immuno-modification of micelles did not significantly change it. The solubilization of both drugs by the mixed micelles was more efficient than by micelles made of PEG-PE alone. Solubilization of camptothecin in micelles prevented also the hydrolysis of active lactone form of the drug to inactive carboxylate form. Drug loaded mixed micelles and mAb 2C5-immunomicelles demonstrated significantly higher in vitro cytotoxicity than free drug against various cancer cell lines.

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Section: Introductionmentioning

confidence: 99%

Mixed PEG–PE/vitamin E tumor-targeted immunomicelles as carriers for poorly soluble anti-cancer drugs: Improved drug solubilization and enhanced in vitro cytotoxicity

Sawant

Torchilin

2008

European Journal of Pharmaceutics and Biopharmaceutics

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“…The total drug concentrations in liposomes before centrifugation (liposome A) and in the supernatant after centrifugation (supernatant B) were determined using a F-4010 fluorescence spectrophotometer (Hitachi Electronics, Tokyo, Japan) with the excitation and emission wavelengths of 369 and 437 nm, respectively as described previously. 16) Incorporation efficiency of DB was determined by HPLC (wavelength at 254 nm). A Shimadzu LC-10AT (Shimadzu Co., Ltd., Japan) apparatus equipped with a Shimadzu RF-10AXL fluorescence detector in which the wavelengths were set at 254 nm.…”

Section: Methodsmentioning

confidence: 99%

“…[16][17][18][19] Therefore, the artificial lipids with a phenyl group, DBs were synthesized and added to liposome formulation to obtain stable liposomes incorporating CPT (DBliposome). Basic formulation, HSPC : Ch : OA : CPTϭ7 : 3 : 1 : 1 (molar ratio) was decided as HSPC, Ch and OA since liposomes with OA showed about five-fold higher incorporation efficiency of CPT compared with ones without OA.…”

Section: Preparation and Characterization Of Cpt Incorporated In Lipomentioning

confidence: 99%

“…15) Previously we have reported that the stability of CPT loaded polymeric micelles in vivo was increased by benzyl esterification of hydrophobic segment of block copolymer. [16][17][18] However, long circulation of CPT loaded polymeric micelles in vivo was not achieved yet. Other carriers such as liposomes were examined because release of drugs encapsulated in carriers depended on carriers.…”

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confidence: 99%

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Artificial Lipids Stabilized Camptothecin Incorporated in Liposomes

Maitani

Katayama

Kawano

et al. 2008

Biological & Pharmaceutical Bulletin

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Camptothecin (CPT) is a naturally occurring cytotoxic alkaloid isolated from the Chinese plant Camptotheca accuminate.1) CPT and some of its analogs have shown a broad spectrum of antitumor activity against many solid tumors in xenografts including colorectal cancer. 2,3) CPT inhibits the enzyme DNA topoisomerase I, initially by noncovalent binding and subsequently by stabilization of the complex through a nucleophilic attack by the enzyme at the acyl position of the CPT lactone ring. 4)Of significant importance for pharmaceutical formulation is that, while only the lactone form of CPT is biologically active, this form exhibits poor aqueous solubility. The lactone of CPT is converted to carboxylate in a pH-dependent equilibrium.5) To overcome the aforementioned solubility problems and hydrolytic processes of CPT, several approaches have been investigated. Numerous attempts have been made to prepare water-soluble CPT analogs. The majority of these analogs were less potent in assays both in vitro and in vivo than the parent drug. In addition to the synthesis of new derivatives and pro-drug products, 6-10) the development of adequate drug carriers is gaining increasing attention. There are many reports about effective formulation and utilization of CPT in cancer therapy by using drug delivery technologies such as liposomes, 11,12) microemulsions, 12) microspheres, 13,14) and inclusion complexes with cyclodextrins. 15) Previously we have reported that the stability of CPT loaded polymeric micelles in vivo was increased by benzyl esterification of hydrophobic segment of block copolymer. [16][17][18] However, long circulation of CPT loaded polymeric micelles in vivo was not achieved yet. Other carriers such as liposomes were examined because release of drugs encapsulated in carriers depended on carriers. The designed amphipathic compounds are called artificial lipid, which has similar properties with phospholipid to form vesicles. Therefore, artificial lipid with a phenyl group, e.g., 3,5-bis(dodecyloxy)benzoic acid, was synthesized and added to the liposome formulation. The PEGylated liposomes incorporating CPT were stable in vivo. 19) However, there was not enough information about interaction between CPT and artificial lipid molecules in liposomes.To develop the therapeutic utilization of CPT, it is necessary to prepare liposomes with high incorporation efficiency and stability of CPT. This study demonstrated that incorporation of 5 mol% of 3,4,5-tris(dodecyloxy)benzoic acid increased incorporation efficiency and stability of CPT in liposomes. MATERIALS AND METHODSMaterials (S)-(ϩ)-Camptothecin (CPT), cholesterol (Ch), high performance liquid chromatography (HPLC) grade methanol and tetrahydrofuran (THF) were purchased from Wako Pure Chemicals (Tokyo, Japan). Hydrogenated soybean phosphatidylcholine (HSPC, Ͼ90% phosphatidylcholine), and oleic acid (OA) were purchased from NOF Corporation (Tokyo, Japan). 4-n-Dodecyloxy benzoic acid (M12B) was purchased from Tokyo Chemical Industry (Tokyo, Japan). 3,5-Bis(dodecyloxy)...

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“…Camptothecin (CPT) loaded in polymeric micelles showed enhanced tumor inhibitory activity. The micelles prolonged the drug's blood circulation time and increased accumulation in tumors compared with free CPT [10] . FG020326, an imidazole derivative, is a highly potent, efficacious MDR modulator in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

FG020326-loaded nanoparticle with PEG and PDLLA improved pharmacodynamics of reversing multidrug resistance in vitro and in vivo

Deng

Yang

Liang

et al. 2007

Acta Pharmacologica Sinica

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Aim: FG020326, a novel imidazole derivative, is a potent multidrug-resistance (MDR) modulator in vitro and in vivo. However, FG020326 is insoluble. PEDLLA-FG020326 is a FG020326-loaded nanoparticle formed with diblock copolymers of poly (ethylene glycol)-block-poly (D,L-lactic acid) (PEG:PDLLA, PEDLLA) that can solubilize FG020326. This work was intended to evaluate the pharmacodynamics of PEDLLA-FG020326 on reversing MDR in vitro and in vivo. Methods: Cytotoxicity was determined by tetrazolium assay. The intracellular accumulation and efflux of doxorubicin (Dox) were detected by fluorescence spectrophotometry. The function of P-glycoprotein was examined by Rhodamine 123 (Rh123) accumulation detected by flow cytometry. The KBv200 cell xenograft model was established to investigate the effect of PEDLLA-FG020326 on reversing MDR in vivo. Results: PEDLLA-FG020326 and FG020326 exhibited 56.4-and 35.9-fold activity in reversing KBv200 cells to vincristine (VCR) resistance, respectively and 14.98-and 7.64-fold to Dox resistance, respectively. PEDLLA-FG020326 was much stronger than FG020326, resulting in the increase of Dox and Rh123 accumulation and the decrease of intracellular Dox extrusion in KBv200 cells. Importantly, PEDLLA-FG020326 exhibited more powerful activity than FG020326 in enhancing the effect of VCR against KBv200 cell xenografts in nude mice, but did not appear more toxic. Conclusion: The pharmacodynamics of FG020326 was improved by incorporating it into a micellar nanoparticle formed with PEG-block-PDLLA copolymers.

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Enhanced antitumor effect of camptothecin loaded in long-circulating polymeric micelles

Cited by 101 publications

References 14 publications

Mixed PEG–PE/vitamin E tumor-targeted immunomicelles as carriers for poorly soluble anti-cancer drugs: Improved drug solubilization and enhanced in vitro cytotoxicity

Mixed PEG–PE/vitamin E tumor-targeted immunomicelles as carriers for poorly soluble anti-cancer drugs: Improved drug solubilization and enhanced in vitro cytotoxicity

Artificial Lipids Stabilized Camptothecin Incorporated in Liposomes

FG020326-loaded nanoparticle with PEG and PDLLA improved pharmacodynamics of reversing multidrug resistance in vitro and in vivo

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