Targeting endothelium and its dynamic caveolae for tissue-specific transcytosis in vivo:: A pathway to overcome cell barriers to drug and gene delivery

被引:155
作者
McIntosh, DP
Tan, XY
Oh, P
Schnitzer, JE
机构
[1] Sidney Kimmel Canc Ctr, San Diego, CA 92121 USA
[2] Harvard Univ, Sch Med, Beth Israel Hosp, Dept Pathol, Boston, MA 02215 USA
关键词
D O I
10.1073/pnas.251662398
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Site-directed pharmacodelivery is a desirable but elusive goal. Endothelium and epithelium create formidable barriers to endogenous molecules as well as targeted therapies in vivo. Caveolae provide a possible, yet unproven, transcellular pathway to overcome such barriers. By using an antibody- and subfractionation-based strategy, we generated a monoclonal antibody specific for lung caveolae (TX3.833) that targets rat lungs after i.v. injection (up to 89% of dose in 30 min). Unlike control antibodies (nonbinding or to lipid rafts), TX3.833 targets lung caveolae that bud to form free vesicles for selective and quantal transendothelial transport to underlying tissue cells in vivo. Rapid sequential transcytosis can occur to the alveolar air space via epithelial caveolae. Conjugation to TX3.833 increases drug delivery to the lung up to 172-fold and achieves rapid, localized bioefficacy. We conclude that: (i) molecular heterogeneity of the endothelium and its caveolae permits vascular targeting to achieve theoretical expectations of tissue-specific pathway for overcoming key cell barriers to many drug and gene therapies in vivo.
引用
收藏
页码:1996 / 2001
页数:6
相关论文
共 38 条
[1]   Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model [J].
Arap, W ;
Pasqualini, R ;
Ruoslahti, E .
SCIENCE, 1998, 279 (5349) :377-380
[2]  
BUNDGAARD M, 1983, FED PROC, V42, P2425
[3]   ENDOTHELIAL PLASMALEMMAL VESICLES AS ELEMENTS IN A SYSTEM OF BRANCHING INVAGINATIONS FROM THE CELL-SURFACE [J].
BUNDGAARD, M ;
FROKJAERJENSEN, J ;
CRONE, C .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1979, 76 (12) :6439-6442
[4]   VASCULAR TARGETING - A NEW APPROACH TO THE THERAPY OF SOLID TUMORS [J].
BURROWS, FJ ;
THORPE, PE .
PHARMACOLOGY & THERAPEUTICS, 1994, 64 (01) :155-174
[5]   Immunotargeting of glucose oxidase to endothelium in vivo causes oxidative vascular injury in the lungs [J].
Christofidou-Solomidou, M ;
Pietra, GG ;
Solomides, CC ;
Arguiris, E ;
Harshaw, D ;
Fitzgerald, GA ;
Albelda, SM ;
Muzykantov, VR .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 2000, 278 (04) :L794-L805
[6]  
CUMBER AJ, 1985, METHOD ENZYMOL, V112, P207
[7]  
DENEKAMP J, 1984, PROG APPLIED MICROCI, V4, P28
[8]  
DVORAK HF, 1991, CANCER CELL-MON REV, V3, P77
[9]   Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin [J].
Feng, D ;
Nagy, JA ;
Hipp, J ;
Dvorak, HF ;
Dvorak, AM .
JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 183 (05) :1981-1986
[10]  
FRAKER PJ, 1978, BIOCHEM BIOPH RES CO, V80, P849, DOI 10.1016/0006-291X(78)91322-0