Paclitaxel-loaded hyaluronan solid nanoemulsions for enhanced treatment efficacy in ovarian cancer

被引:39
作者
Kim, Joo-Eun [1 ]
Park, Young-Joon [1 ]
机构
[1] Ajou Univ, Coll Pharm, Suwon, South Korea
关键词
paclitaxel; hyaluronan solid nanoemulsion; targeting; MTD; efficacy; NANOSTRUCTURED LIPID CARRIERS; DRUG-DELIVERY; IN-VITRO; TARGETING PACLITAXEL; BREAST-CANCER; NANOPARTICLES; VIVO; THERAPEUTICS; COMPLEXES; CARCINOMA;
D O I
10.2147/IJN.S124158
中图分类号
TB3 [工程材料学];
学科分类号
0805 ; 080502 ;
摘要
Paclitaxel-loaded hyaluronan solid nanoemulsions (PTX-HSNs) were successfully fabricated for the delivery of PTX to improve ovarian cancer treatment via active tumor targeting. PTX-HSNs were fabricated using high-pressure homogenization with a microfluidizer and were lyophilized with D-mannitol. Hyaluronan was coated on the outside of the PTX-HSN sphere. The mean size of the PTX-HSNs was maintained less than 100 nm, with a relatively narrow size distribution. The PTX loading content was 3 mg/mL, and encapsulation efficiency (EE) was close to 100%. In vitro cell affinity studies using SK-OV-3 (cluster of differentiation 44 [CD44(+)]) and OVCAR-3 (CD44(-)) cells showed that PTX-HSN had a targeting capability hundredfold higher than that of PTX-loaded solid nanoemulsions (PTX-SNs) without hyaluronan. Further, the in vitro PTX release by PTX-SNs and PTX-HSNs lasted more than 6 days without showing a release burst, which was more sustained than that of Taxol (R), suggesting a more constant effect on cancer cells at the tumor site than was observed for Taxol. The in vivo toxicity, in vivo antitumor effects, and pharmacokinetics of PTX-HSNs and Taxol were evaluated in nude mice and rats. The maximum tolerated dose (MTD) for PTX-HSNs, PTX-SNs, and Taxol was determined by measuring changes in clinical symptoms after administering 20-50 mg/kg PTX via the caudal vein. The MTD of PTX-HSNs had a dosing capacity greater than 50 mg PTX/kg, which was 2.5-fold higher than that of Taxol when administered as a PTX injection. In vivo, PTX-HSN treatment effectively inhibited tumor growth and showed less toxicity in tumor-transplanted mice compared to that observed for Taxol treatments. The pharmacokinetic parameters of PTX-HSNs were more desirable than those of Taxol. After PTX-HSN treatment, the circulation time of PTX was prolonged and retention of PTX in ovarian tumor tissues increased. Therefore, PTX-HSN is a highly effective nanosystem with a high MTD for delivering PTX to ovarian cancers characterized by CD44 overexpression, enhanced active tumor targeting, and low toxicity.
引用
收藏
页码:645 / 658
页数:14
相关论文
共 36 条
[1]   Hyaluronan as drug carrier. The in vitro efficacy and selectivity of Hyaluronan-Doxorubicin complexes to affect the viability of overexpressing CD44 receptor cells [J].
Battistini, F. D. ;
Flores-Martin, J. ;
Olivera, M. E. ;
Genti-Raimondi, S. ;
Manzo, R. H. .
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2014, 65 :122-129
[2]   Targeting of tumor endothelium by RGD-grafted PLGA-nanoparticles loaded with Paclitaxel [J].
Danhier, Fabienne ;
Vroman, Benoit ;
Lecouturier, Nathalie ;
Crokart, Nathalie ;
Pourcelle, Vincent ;
Freichels, Helene ;
Jerome, Christine ;
Marchand-Brynaert, Jacqueline ;
Feron, Olivier ;
Preat, Veronique .
JOURNAL OF CONTROLLED RELEASE, 2009, 140 (02) :166-173
[3]   Nanoparticle therapeutics: an emerging treatment modality for cancer [J].
Davis, Mark E. ;
Chen, Zhuo ;
Shin, Dong M. .
NATURE REVIEWS DRUG DISCOVERY, 2008, 7 (09) :771-782
[4]   Tumor-specific targeting of an anticancer drug delivery system by LHRH peptide [J].
Dharap, SS ;
Wang, Y ;
Chandna, P ;
Khandare, JJ ;
Qiu, B ;
Gunaseelan, S ;
Sinko, PJ ;
Stein, S ;
Farmanfarmaian, A ;
Minko, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (36) :12962-12967
[5]   The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect [J].
Fang, Jun ;
Nakamura, Hideaki ;
Maeda, Hiroshi .
ADVANCED DRUG DELIVERY REVIEWS, 2011, 63 (03) :136-151
[6]   Hyaluronan Oligomers-HPMA Copolymer Conjugates for Targeting Paclitaxel to CD44-Overexpressing Ovarian Carcinoma [J].
Journo-Gershfeld, Gal ;
Kapp, Dana ;
Shamay, Yosi ;
Kopecek, Jindrich ;
David, Ayelet .
PHARMACEUTICAL RESEARCH, 2012, 29 (04) :1121-1133
[7]   Hyaluronan: Towards novel anti-cancer therapeutics [J].
Karbownik, Michel S. ;
Nowak, Jerzy Z. .
PHARMACOLOGICAL REPORTS, 2013, 65 (05) :1056-1074
[8]  
Kim J. E., 2016, COLLOIDS SURF B
[9]   Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies [J].
Kim, TY ;
Kim, DW ;
Chung, JY ;
Shin, SG ;
Kim, SC ;
Heo, DS ;
Kim, NK ;
Bang, YJ .
CLINICAL CANCER RESEARCH, 2004, 10 (11) :3708-3716
[10]   Stability investigation of hyaluronic acid based nanoemulsion and its potential as transdermal carrier [J].
Kong, Ming ;
Park, Hyun Jin .
CARBOHYDRATE POLYMERS, 2011, 83 (03) :1303-1310