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Synthesis and biological evaluation of RGD conjugated with Ketoprofen/Naproxen and radiolabeled with [Tc] via N4(GGAG) for αβ integrin-targeted drug delivery

DARU, Journal of Pharmaceutical Sciences, ISSN: 2008-2231, Vol: 28, Issue: 1, Page: 87-96
2020
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Background: Integrins are interesting targets in oncology. RGD sequence has high affinity for αβ integrin receptors. Diagnostic/therapeutic agents can be selectively delivered into cancer cells overexpressing αβ integrin by using RGD as a carrier. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown anticancer properties in in vitro and in vivo studies. The anti-cancer properties of NSAIDs occur though COX-2 inhibition. Regarding the anti-cancer properties of NSAIDs and overexpression of COX-2 enzyme in cancer cells, targeted delivery of NSAIDs into cancer cells to maximize their efficiency and minimize their side effects may gain increased clinical interest. Objectives: In this study, RGD was conjugated to ketoprofen/Naproxen to selectively transfer these non-selective COX inhibitors into cancer cells. Methods: Keto/Nap-RGD-N4 peptides were synthesized based on solid phase fmoc peptide synthesis. Radiolabeling with [Tc] via N4 (GGAG) ligand was done for biological evaluation. Affinity and specificity of Keto/Nap-RGD-N4 to integrin was determined using A2780, OVCAR-3, SKOV-3 and HT-1080 cell lines. Percentage of Intenalization was measured in A2780 cells. Biodistriburion was studied in normal and tumor model mice. Results: Radiolabeled compounds showed high affinity to cells expressing αβ integrin in comparison to cells not expressing αβ. The affinity to A2780 was significantly higher than OVCAR-3 cells. The %internalization into A2780 cells was quite low. Compounds showed more than 50% inhibition on A2780 and OVCAR-3 cells, less than 10% on MCF-7 and HT-1080 cells and no cytotoxicity on fibroblast cells after 48 h incubation. Although uptake of radiolabeled compounds in tumor was high at 1 h post-injection, the tumor/blood ratio was less than 1.5 which made SPECT imaging impossible. Conclusion: Provided that NSAID drugs are conjugated to RGD, there will be a selective delivery to target tissues as well as synergetic anti-tumor effects which reduce systemic doses and toxicity. [Figure not available: see fulltext.]

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