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New ‘portal’ identified for drug delivery

by ecancer reporter Janet Fricker

In a study published in Nature Medicine US scientists have identified a cellular portal at the blood tumour interface in rodents that enables active pumping of antibodies and agents from the blood directly into solid tumours.

The discovery, say the authors, opens the possibility for new treatments and imaging strategies to rapidly reach tumours at low doses.

“A much-needed and long-awaited portal or door has been identified to exist. This door may create new hope that the theoretical impact of targeted molecular medicine envisioned decades ago may someday be realised,” write the authors.

The current passive transvascular delivery paradigm for tumours is inefficient and frequently delivers insufficient tumour penetration for both imaging and therapeutic agents to achieve effective local concentrations.

The consequence is that patients do not benefit from the full impact of treatments and furthermore experience off-target effects.

More recently targeting strategies have shifted the focus to accessible targets on luminal endothelial cell (EC) surfaces to facilitate tissue specific delivery.

Many organs, it has been shown, have specialised plasmalemmal vesicles, known as caveolae, that exist in the tumour endothelium for trafficking agents into cells.

In the current study, Jan Schnitzer and colleagues from the Proteogenomics Research Institute for Systems Medicine, San Diego, integrated proteomic and imaging technologies in order to investigate transendothelial trafficking of caveolae.

First they showed that a post-translationally modified form of annexin A1 (AnnA1) was selectively concentrated in both human and rodent tumour caveolae.

Next the team developed a specific AnnA1 antibody to target this membrane binding protein, allowing the caveolae to rapidly pump antibody into tumours against a concentration gradient.

Intravital microscopy of caveolae-immunotargeted fluorophores, even at low intravenous doses, showed rapid and robust pumping across the endothelium into mammary, prostate and lung tumours.

Within one hour the fluorescence signal in tumours, the team were able to show, exceeded peak levels in blood.

Tumour uptake with other antibodies was found to be over 100 fold less.

“Perhaps the most important discovery here is not the target nor the antibody but rather a tangible active transendothelial pathway into diseased tissue,” wrote the authors.

Imaging agents, they add, could immune target tumour caveolae to be pumped across the endothelium and concentrate inside solid tumours.

Reference

P Oh, J Testa, P Borgstrom, et al. In vivo proteomic imaging analysis of caveolae reveals pumping system to penetrate solid tumours. Nature Medicine. published online 17 August 2014.

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