αvβ3 Integrin-Targeted Peptide/Peptidomimetic-Drug Conjugates: In-Depth Analysis of the Linker Technology
Alberto Dal Corso, Luca Pignataro, Laura Belvisi1
1Universita degli Studi di Milano, Dipartimento di Chimica, via C. Golgi, 19, I-20133, Milan (Italy). laura.belvisi@unimi.it.
Abstract:
Covalent conjugation of anticancer drugs to targeting carriers (e.g., antibodies or small molecules) capable of selectively binding to tumor-specific antigens, is emerging as a successful strategy to overcome the drawbacks of traditional chemotherapy. Due to its overexpression on blood vessels of human tumors, αvβ3 integrin is one of the most studied receptors of tumor-targeted therapeutics: several peptides and peptidomimetics, bearing the RGD (Arg-Gly-Asp) recognition sequence, have been developed as integrin ligands and linked to different anticancer drugs. The resulting integrin- targeted small molecule-drug conjugates (SMDCs) are able to release the cytotoxic agents upon cleavage of a linker under specific conditions (i.e., hydrolysis, enzymatic action or reduction). Despite the significant efforts made in this field, αvβ3 integrin-targeted SMDCs are still far from the clinic. In this review, we survey this approach with a special focus on the different linkers employed and the reported biological activities in vitro and in vivo.
Insights
Targeted drug delivery using small molecule-drug conjugates (SMDCs) that bind to αvβ3 integrin shows promise for cancer therapy. This review focuses on RGD-containing SMDCs, their linkers, and biological activities, noting challenges for clinical translation.
Area of Science:
- Oncology
- Drug Delivery
- Bioconjugation
Background:
- Traditional chemotherapy faces limitations like systemic toxicity and lack of specificity.
- Tumor-specific antigens, such as αvβ3 integrin, are key targets for novel therapeutic strategies.
- Integrin-targeted therapeutics offer a promising approach to enhance drug efficacy and reduce side effects.
Purpose of the Study:
- To review the development of αvβ3 integrin-targeted small molecule-drug conjugates (SMDCs) for cancer treatment.
- To analyze the various linker technologies employed in SMDC design.
- To summarize the in vitro and in vivo biological activities of these targeted conjugates.
Main Methods:
- Literature review of studies on αvβ3 integrin-targeted SMDCs.
- Analysis of different linker chemistries (hydrolysis, enzymatic, reduction-cleavable).
- Evaluation of reported in vitro and in vivo efficacy and safety data.
Main Results:
- Development of RGD (Arg-Gly-Asp) peptides and peptidomimetics as ligands for αvβ3 integrin.
- Successful conjugation of anticancer drugs to these ligands via diverse linker systems.
- Demonstrated in vitro and in vivo anti-tumor activity, with varying degrees of success.
- Challenges remain in translating these promising SMDCs to clinical application.
Conclusions:
- αvβ3 integrin-targeted SMDCs represent a viable strategy for improving cancer chemotherapy.
- Linker design is critical for controlled drug release and therapeutic efficacy.
- Further research and development are needed to overcome hurdles for clinical implementation.
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