Overcoming Limitations in Nanoparticle Drug Delivery: Triggered, Intravascular Release to Improve Drug Penetration into Tumors

被引:372
作者
Manzoor, Ashley A. [1 ,2 ]
Lindner, Lars H. [4 ,5 ,6 ]
Landon, Chelsea D. [1 ]
Park, Ji-Young [1 ]
Simnick, Andrew J. [3 ]
Dreher, Matthew R. [7 ]
Das, Shiva [1 ,2 ]
Hanna, Gabi [1 ]
Park, Won [1 ]
Chilkoti, Ashutosh [3 ]
Koning, Gerben A. [4 ]
ten Hagen, Timo L. M. [4 ]
Needham, David [3 ]
Dewhirst, Mark W. [1 ,2 ,3 ]
机构
[1] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27710 USA
[2] Duke Univ, Med Phys Program, Durham, NC USA
[3] Duke Univ, Dept Biomed Engn, Durham, NC USA
[4] Erasmus MC, Dept Surg, Sect Surg Oncol, Lab Expt Surg Oncol, Rotterdam, Netherlands
[5] Univ Munich, Univ Hosp Grosshadern, Dept Internal Med 3, Munich, Germany
[6] German Res Ctr Environm Hlth, CCG Hyperthermia, Helmholtz Zentrum Munchen, Munich, Germany
[7] NIH, Ctr Clin, Bethesda, MD 20892 USA
关键词
TEMPERATURE-SENSITIVE LIPOSOMES; THERMOSENSITIVE LIPOSOMES; LOCAL HYPERTHERMIA; SELECTIVE DELIVERY; BLOOD-VESSELS; IN-VITRO; DOXORUBICIN; EFFICACY; EXTRAVASATION; PERMEABILITY;
D O I
10.1158/0008-5472.CAN-12-1683
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Traditionally, the goal of nanoparticle-based chemotherapy has been to decrease normal tissue toxicity by improving drug specificity to tumors. The enhanced permeability and retention effect can permit passive accumulation into tumor interstitium. However, suboptimal delivery is achieved with most nanoparticles because of heterogeneities of vascular permeability, which limits nanoparticle penetration. Furthermore, slow drug release limits bioavailability. We developed a fast drug-releasing liposome triggered by local heat that has already shown substantial antitumor efficacy and is in human trials. Here, we show that thermally sensitive liposomes (Dox-TSL) release doxorubicin inside the tumor vasculature. Real-time confocal imaging of doxorubicin delivery to murine tumors in window chambers and histologic analysis of flank tumors illustrates that intravascular drug release increases free drug in the interstitial space. This increases both the time that tumor cells are exposed to maximum drug levels and the drug penetration distance, compared with free drug or traditional pegylated liposomes. These improvements in drug bioavailability establish a new paradigm in drug delivery: rapidly triggered drug release in the tumor bloodstream. Cancer Res; 72(21); 5566-75. (C)2012 AACR.
引用
收藏
页码:5566 / 5575
页数:10
相关论文
共 49 条
[1]   Liposomal drug formulations - Rationale for development and what we can expect for the future [J].
Allen, TM .
DRUGS, 1998, 56 (05) :747-756
[2]   Direct visualization of heterogeneous extravascular distribution of trastuzumab in human epidermal growth factor receptor type 2 overexpressing xenografts [J].
Baker, Jennifer H. E. ;
Lindquist, Kirstin E. ;
Huxham, LynseyA. ;
Kyle, Alastair H. ;
Sy, Jonathan T. ;
Minchinton, Andrew I. .
CLINICAL CANCER RESEARCH, 2008, 14 (07) :2171-2179
[3]   Effects of fluctuating oxygenation on tirapazamine efficacy:: Theoretical predictions [J].
Cardenas-Navia, L. Isabel ;
Secomb, Timothy W. ;
Dewhirst, Mark W. .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2007, 67 (02) :581-586
[4]  
Celsion, 2000, STUD THERMODOX COMB
[5]  
Celsion, 2000, PHAS 1 2 STUD THERMO
[6]  
Celsion, 2000, PHAS 3 STUD THERMODO
[7]  
Dewhirst MW, 1997, SEMIN ONCOL, V24, P616
[8]   Polymersomes: Tough vesicles made from diblock copolymers [J].
Discher, BM ;
Won, YY ;
Ege, DS ;
Lee, JCM ;
Bates, FS ;
Discher, DE ;
Hammer, DA .
SCIENCE, 1999, 284 (5417) :1143-1146
[9]   Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers [J].
Dreher, MR ;
Liu, WG ;
Michelich, CR ;
Dewhirst, MW ;
Yuan, F ;
Chilkoti, A .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2006, 98 (05) :335-344
[10]  
DVORAK HF, 1988, AM J PATHOL, V133, P95