Poly(N-vinylpyrrolidone)-block-poly(D,L-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs:: in vitro and in vivo evaluation

被引:208
作者
Le Garrec, D
Gori, S
Luo, L
Lessard, D
Smith, DC
Yessine, MA
Ranger, M
Leroux, JC
机构
[1] Univ Montreal, Fac Pharm, Canada Res Chair Drug Delivery, Montreal, PQ H3C 3J7, Canada
[2] Labopharm Inc, Laval, PQ H7V 4B4, Canada
基金
加拿大自然科学与工程研究理事会;
关键词
polymeric micelles; taxanes; maximum tolerated dose; pharmacokinetics; in vivo antitumor activity;
D O I
10.1016/j.jconrel.2004.06.018
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The majority of novel anticancer drugs developed to date are intended for parenteral administration. Paradoxically, most of these drugs are water-insoluble, delaying their clinical development. A common approach to confering water solubility to drugs is to use amphiphilic, solubilizing agents, such as polyethoxylated castor oil (e.g., Cremophor(R) EL, CrmEL). However, these vehicles are themselves associated with a number of pharmacokinetic and pharmaceutical concerns. The present work is aimed at evaluating a novel polymeric solubilizer for anticancer drugs, i.e., poly(N-vinylpyrrolidone)-block-poly(D,L-lactide) (PVP-b-PDLLA). This copolymer self-assembles in water to yield polymeric micelles (PM) that efficiently solubilize anticancer drugs, such as paclitaxel (PTX), docetaxel (DCTX), teniposide (TEN) and etoposide (ETO). A PM-PTX formulation was evaluated, both, in vitro on three different cancer cell lines and in vivo for its safety, pharmacokinetics, biodistribution and antitumor activity. In vitro, cytotoxicity studies revealed that the drug-loaded PM formulation was equipotent to the commercial PTX formulation (Taxol(R)). In the absence of drug, PVP-b-PDLLA with 37% DLLA content was less cytotoxic than CrmEL. In vivo, acute toxicity was assessed in mice after a single injection of escalating dose levels of formulated PTX PM-PTX was well tolerated and the maximum tolerated dose (MTD) was not reached even at 100 mg/kg, whereas the MTD of Taxol(R) was established at 20 mg/kg. At 60 mg/kg, PM-PTX demonstrated greater in vivo antitumor activity than Taxol(R) injected at its MTD. Finally, it was shown in mice and rabbits that the areas under the plasma concentration-time curves were inversely related to PM drug loading. (C) 2004 Elsevier B.V. All rights reserved.
引用
收藏
页码:83 / 101
页数:19
相关论文
共 69 条
[41]  
PRATTEN MK, 1985, MAKROMOL CHEM, V186, P725
[42]   CELL ADHESION TO POLYMERIC MATERIALS - IMPLICATIONS WITH RESPECT TO BIOCOMPATIBILITY [J].
RATNER, BD ;
HORBETT, T ;
HOFFMAN, AS ;
HAUSCHKA, SD .
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH, 1975, 9 (05) :407-422
[43]   Use of a cholesterol-rich emulsion that binds to low-density lipoprotein receptors as a vehicle for paclitaxel [J].
Rodrigues, DG ;
Covolan, CC ;
Coradi, ST ;
Barboza, R ;
Maranhao, RC .
JOURNAL OF PHARMACY AND PHARMACOLOGY, 2002, 54 (06) :765-772
[44]  
ROSE WC, 1995, TAXOL SCI APPL PHARM, V8, P209
[45]   Micellar nanocontainers distribute to defined cytoplasmic organelles [J].
Savic, R ;
Luo, LB ;
Eisenberg, A ;
Maysinger, D .
SCIENCE, 2003, 300 (5619) :615-618
[46]  
SHARMA A, 1993, CANCER RES, V53, P5877
[47]   REVERSED-PHASE HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHIC DETERMINATION OF TAXOL IN MOUSE PLASMA [J].
SHARMA, A ;
CONWAY, WD ;
STRAUBINGER, RM .
JOURNAL OF CHROMATOGRAPHY B-BIOMEDICAL APPLICATIONS, 1994, 655 (02) :315-319
[48]  
Sharma D, 1996, ONCOL RES, V8, P281
[49]   Core-cross-linked polymeric micelles as paclitaxel carriers [J].
Shuai, XT ;
Merdan, T ;
Schaper, AK ;
Xi, F ;
Kissel, T .
BIOCONJUGATE CHEMISTRY, 2004, 15 (03) :441-448
[50]  
SONG D, 1995, J CHROMATOGR B, V663, P337