Peptide Targeted Drug Delivery To Non-Small Cell Lung Cancer
Gray, Bethany Powell
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Non-small cell lung cancer (NSCLC) is a notoriously deadly disease. The integrin alpha(v)beta(6) is emerging as a viable target for NSCLC; it is expressed in more than half of NSCLC patient tumor samples and only rarely expressed in normal tissue. Importantly, alpha(v)beta(6) is turned on early in the disease progression of NSCLC, indicating that it may be a good biomarker for early cancer detection and treatment. The phage display selected H2009.1 peptide exhibits high affinity for alpha(v)beta(6), specifically binding and internalizing into alpha(v)beta(6)-expressing cells. Tumor targeting therapies that specifically deliver drugs to the tumor, reducing accumulation and toxicity in non-target tissues, are a promising niche of cancer therapeutics, and the H2009.1 peptide is anticipated to have great utility as a targeting ligand for the delivery of therapeutics to alpha(v)beta(6)-positive NSCLC tumors. To examine the ability of the H2009.1 peptide to specifically deliver drugs to NSCLC cells, it was used as a targeting ligand for three different drug platforms: liposomal doxorubicin and direct drug conjugates of both doxorubicin and paclitaxel. Conjugation of the H2009.1 peptide to all three of these drug platforms led to alpha(v)beta(6)-specific targeting and toxicity in vitro. In vitro studies determined the ideal construct for H2009.1 peptide targeting of liposomal doxorubicin. Liposomes displaying the higher affinity multivalent H2009.1 tetrameric peptide demonstrated higher specificity and greater toxicity towards alpha(v)beta(6)-expressing cells than liposomes displaying the lower affinity monomeric H2009.1 peptide. All H2009.1 peptide liposomal doxorubicin formulations exhibited greater toxicity towards alpha(v)beta(6)-expressing cells than control non-targeted liposomes. Both the H2009.1-doxorubicin and paclitaxel conjugates demonstrated alpha(v)beta(6)-specific toxicity in vitro, although they were less toxic than the respective free drugs and exerted their effects on a later time frame. Neither H2009.1 peptide-targeted liposomal doxorubicin nor the H2009.1 direct drug conjugates improved in vivo efficacy compared to the non-targeted drugs. The liposomes suffered from poor tumor penetration and the in vitro studies with the drug conjugates suggest that they suffered from poor intracellular drug release. These results highlight the complexity of drug delivery and targeting in vivo and provide a basis for the design of optimized H2009.1 targeting therapies.