Targeting endothelial caveolae enhances antibody penetration into solid tumors and lungs
Authors: Jan E. Schnitzer
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

SY04-2 

Targeting in vivo imaging agents as well as drugs and gene therapies to specific tissues of the body has been a highly desirable but elusive goal of molecular medicine. Because these agents usually are designed for specific cell types, such as tumor cells, residing deep within the tissue, they may benefit greatly from improved delivery and penetration into specific tissues by overcoming key barriers normally preventing entry into critical tissue compartments where they can be effective. Vascular targeting seeks to facilitate tissue-specific delivery upon intravenous injection by targeting the inherently accessible endothelial cell surface of blood vessels feeding the target tissue, rather than relatively inaccessible targets on cells inside the tissue. Caveolae are specialized omega-shaped invaginations that can bud from the endothelial cell surface, potentially to transcytose select molecular cargo from the circulating blood. Thus, they provide opportunity as a pathway for transporting caveolae-targeted agents across the normally restrictive blood vessel wall to reach underlying tissue cells, the usual end targets of functional imaging and pharmacotherapies. Although both caveolar and vascular targeting are hypothetically promising new strategies for tissue-specific imaging and pharmacodelivery, they so far remain theoretical and not yet understood or fully realized. They both require systematic testing to determine the rapidity, exclusivity, and extent of targeting possible in vivo. How effectively and fast caveolae can transcytose in vivo is unknown, yet critical for tissue penetration. We have mapped the proteome of caveolae as they exist in vascular endothelium of lung and solid tumors. Our differential analysis so far reveals multiple target candidates selectively expressed in solid tumors and lungs in vivo . By using specific monoclonal antibodies and current state-of-the-art dynamic live imaging techniques, we demonstrate not only rapid tissue-specific vascular targeting in vivo but, perhaps more importantly, for the first time, the transendothelial transport in vivo of antibodies targeting caveolae within seconds (normal lung) and minutes (solid tumors) after intravenous injection. Key advantages of dynamic live imaging vs. classic static imaging techniques become quite apparent. We find that caveolae appear to function as an active pump transporting its specific molecular cargo, even against a concentration gradient, to accumulate concentrated in the tissue interstitium. This ability facilitates specific delivery, accumulation, and penetration into the tissue beyond that seen for antibodies to vascular proteins not concentrated in caveolae. Antibodies to caveolar antigens show more rapid and much greater penetration into, and even accumulation throughout, various solid tumors. This unprecedented speed in immunotargeting and caveolar transcytosis in vivo not only underscores the physiological function for caveolae in transvascular exchange and capillary permeability but also encourages the practical utility of targeting caveolae as a worthwhile strategy to enhance molecular and functional imaging as well as drug and gene delivery in vivo.