Development of a highly stable and targetable nanoliposomal formulation of topotecan

被引:86
作者
Drummond, Daryl C. [1 ]
Noble, Charles O. [1 ]
Guo, Zexiong [2 ]
Hayes, Mark E. [1 ]
Connolly-Ingram, Ceirin [1 ]
Gabriel, Bianca S. [1 ]
Hann, Byron [3 ]
Liu, Bin [3 ]
Park, John W. [3 ]
Hong, Keelung [1 ]
Benz, Christopher C. [3 ,4 ]
Marks, James D. [3 ]
Kirpotin, Dmitri B. [1 ]
机构
[1] Hermes Biosci Inc, San Francisco, CA 94080 USA
[2] Jinan Univ, Affiliated Hosp 1, Guangzhou 510630, Guangdong, Peoples R China
[3] Univ Calif San Francisco, San Francisco, CA 94143 USA
[4] Buck Inst Age Res, Novato, CA 94945 USA
关键词
Liposomes; Topotecan; ErbB2; Antibody targeting; Nanoparticles; CONVECTION-ENHANCED DELIVERY; TOPOISOMERASE-I INHIBITORS; LIPOSOMAL ENCAPSULATION; THERAPEUTIC-EFFICACY; XENOGRAFT; PHARMACOKINETICS; IRINOTECAN; TUMOR; DRUG; IMMUNOLIPOSOMES;
D O I
10.1016/j.jconrel.2009.08.006
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Topotecan (TPT), a highly active anticancer camptothecin drug, would benefit from nanocarrier-mediated site-specific and intracellular delivery because of a labile lactone ring whose hydrolysis inactivates the drug, poor cellular uptake resulting from both lactone hydrolysis and a titratable phenol hydroxyl, and the schedule-dependency of its efficacy due to its mechanism of action. We have encapsulated topotecan in liposomes using transmembrane gradients of triethylammonium salts of polyphosphate (Pn) or sucroseoctasulfate (SOS). Circulation lifetimes were prolonged, and the rate of drug release in vivo depended on the drug load (T-1/2 = 5.4 h vs. 11.2 h for 124 and 260 g TPT/mol PL, respectively) and the nature of intraliposomal drug complexing agent used to stabilize the nanoliposome formulation (T-1/2 = 11.2 h vs. 27.3 h for Pn and SOS, respectively). Anti-EGFR and anti-HER2-immunoliposomal formulations dramatically increased uptake of topotecan compared to nontargeted nanoliposomal topotecan and poorly permeable free topotecan in receptor-overexpressing cancer cell lines, with a corresponding increase in cytotoxicity in multiple breast cancer cell lines and improved antitumor activity against HER2-overexpressing human breast cancer (BT474) xenografts. We conclude that stabilization of topotecan in nanoliposomes significantly improves the targetability and pharmacokinetic profile of topotecan, allowing for highly active formulations against solid tumors and immunotargeting to cancer-overexpressing cell surface receptors. (C) 2009 Elsevier B.V. All rights reserved.
引用
收藏
页码:13 / 21
页数:9
相关论文
共 50 条
[1]   An evaluation of transmembrane ion gradient-mediated encapsulation of topotecan within liposomes [J].
Abraham, SA ;
Edwards, K ;
Karlsson, G ;
Hudon, N ;
Mayer, LD ;
Bally, MB .
JOURNAL OF CONTROLLED RELEASE, 2004, 96 (03) :449-461
[2]  
Allen Theresa M., 2006, Anti-Cancer Agents in Medicinal Chemistry, V6, P513, DOI 10.2174/187152006778699121
[3]   Hematologic safety and tolerability of topotecan in recurrent ovarian cancer and small cell lung cancer: An integrated analysis [J].
Armstrong, DK ;
Spriggs, D ;
Levin, J ;
Poulin, R ;
Lane, S .
ONCOLOGIST, 2005, 10 (09) :686-694
[4]  
BARTLETT GR, 1959, J BIOL CHEM, V234, P468
[5]   ESTROGEN-DEPENDENT, TAMOXIFEN-RESISTANT TUMORIGENIC GROWTH OF MCF-7 CELLS TRANSFECTED WITH HER2/NEU [J].
BENZ, CC ;
SCOTT, GK ;
SARUP, JC ;
JOHNSON, RM ;
TRIPATHY, D ;
CORONADO, E ;
SHEPARD, HM ;
OSBORNE, CK .
BREAST CANCER RESEARCH AND TREATMENT, 1992, 24 (02) :85-95
[6]  
BLIGH EG, 1959, CAN J BIOCHEM PHYS, V37, P911
[7]  
Brave M, 2006, ONCOLOGY-NY, V20, P1401
[8]   STABILIZATION OF TOPOTECAN IN LOW PH LIPOSOMES COMPOSED OF DISTEAROYLPHOSPHATIDYLCHOLINE [J].
BURKE, TG ;
GAO, X .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1994, 83 (07) :967-969
[9]  
DENNIS MJ, 1997, SEMIN ONCOL S5, V24
[10]   Improved Pharmacokinetics and Efficacy of a Highly Stable Nanoliposomal Vinorelbine [J].
Drummond, Daryl C. ;
Noble, Charles O. ;
Guo, Zexiong ;
Hayes, Mark E. ;
Park, John W. ;
Ou, Ching-Ju ;
Tseng, Yun-Long ;
Hong, Keelung ;
Kirpotin, Dmitri B. .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2009, 328 (01) :321-330