Conjugates of Cryptophycin and RGD or isoDGR Peptidomimetics for Targeted Drug Delivery

Abstract

RGD‐cryptophycin and isoDGR‐cryptophycin conjugates were synthetized by combining peptidomimetic integrin ligands and cryptophycin, a highly potent tubulin‐binding antimitotic agent across lysosomally cleavable Val‐Ala or uncleavable linkers. The conjugates were able to effectively inhibit binding of biotinylated vitronectin to integrin αvβ3, showing a binding affinity in the same range as that of the free ligands. The antiproliferative activity of the novel conjugates was evaluated on human melanoma cells M21 and M21‐L with different expression levels of integrin αvβ3, showing nanomolar potency of all four compounds against both cell lines. Conjugates containing uncleavable linker show reduced activity compared to the corresponding cleavable conjugates, indicating efficient intracellular drug release in the case of cryptophycin‐based SMDCs. However, no significant correlation between the in vitro biological activity of the conjugates and the integrin αvβ3 expression level was observed, which is presumably due to a non‐integrin‐mediated uptake. This reveals the complexity of effective and selective αvβ3 integrin‐mediated drug delivery.

Cyanobacteria as Natural Therapeutics and Pharmaceutical Potential: Role in Antitumor Activity and as Nanovectors

“…Cryptophycins are promising drug candidates as their activity is not negatively affected by P-glycoprotein (a drug efflux system commonly found in multidrug-resistant tumor cell lines). Recently, cryptophycin conjugates with antibodies and peptides were developed for targeted drug delivery in cancer therapy [ 44 ]. The antiproliferative activities of RGD-cryptophycin and iso-DGR-cryptophycin conjugates were evaluated against human melanoma cells M21 and M21-L.…”

Molecular Delivery of Cytotoxic Agents via Integrin Activation

“…Subsequently, Borbély et al [ 94 ] employed Criyptophycin-55 glycinate for the conjugation with cyclo[DKP-RGD] peptidomimetic for integrin targeted delivery ( Figure 22 ).…”

Integrin-Targeting Dye-Doped PEG-Shell/Silica-Core Nanoparticles Mimicking the Proapoptotic Smac/DIABLO Protein

“…Finally, the tumor-targeting precision of drugs [25,26], NPs [27,28], polymers [29], biomaterials [30], or nanostructured materials [20,31,32] can be strongly improved by conjugation with peptide ligands addressing integrin receptors overexpressed by cancer cells [20,33,34]. The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression, and metastatization of solid tumors, making them an appealing target for cancer therapy [35].…”