Oncolytic adenovirus loaded with L-carnosine as novel strategy to enhance the anti-tumor activity

Oncolytic viruses are able to specifically replicate, infect and kill only cancer cells. Their combination with chemotherapeutic drugs have shown promising results due to the synergistic action of virus and drugs; the combinatorial therapy is considered a potential clinically relevant approach for cancer. In the present study we optimized a strategy to absorb peptides on the viral capsid, based on electrostatic interaction and used this strategy to deliver an active anti-tumor drug. We used L-carnosine, a naturally occurring histidine dipeptide with a significant anti-proliferative activity. An ad-hoc modified, positively charged L-carnosine was combined with the capsid of an oncolytic adenovirus to generate an electrostatic virus-carnosine complex. This complex showed enhanced anti tumor efficacy in vitro and in vivo in different tumor models. In HCT116 colorectal and A549 lung cancer cells the complex showed higher transduction ratio and infectious titer compared to an uncoated oncolytic adenovirus. The in vivo efficacy of the complex was tested in lung and colon cancer xenograft models, showing a significant reduction in tumor growth. Importantly, we investigated the molecular mechanisms underlying the effects of complex on tumor growth reduction. We found that complex induces apoptosis in both cells lines, by using two different mechanisms, enhancing viral replication and affecting the expression of Hsp27. Our system could be used in future studies also for delivery of other bioactive drugs.

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