Page 108 - Demo

accumulation in the tumor site and consequently the efficiency. From thisperspective, aiming to achieve a tumor-targeted therapy, liposomes havebeen functionalized with arginine/glycine/aspartic acid (RGD) moieties tospecifically bind to integrin receptors (e.g., %u03b1v%u03b23) that are specificallyoverexpressed in tumor neovascularization. Such strategy showed thatactive targeting functionalized liposomes significantly increased drugaccumulation in tumor site. Other overexpressed neovascular targetingligands such endothelial-growth facto receptor 1 (VEGFR-1) and receptor 3(VEGFR-3) have been explored for targeted agents%u2019 delivery. In fact, anticancer drug-laden F-56 peptide conjugated nanoparticles (F56 peptide: aspecific CEGGFR-1 ligand), induced nanoparticles internalization byendothelial cells and resulted in prolonged survival rate on mice withcolorectal cancer.From another perspective, abnormal cancer cells have demonstrated theincreased expression of specific receptors (e.g., EGFR, HER2, CD44) orantigens (e.g., Tn, STn) compared to healthy counterparts. Therefore,aiming to increase the therapeutic effect of anti-cancer drugs, hyaluronanbased micelles were designed to target the overexpressed CD44 receptoron the cancer cell membrane. Such strategy showed that MDA-MB-231human breast cancer cells successfully internalized the engineeredpaclitaxel-laden micelles through HA-CD44 interaction and suggested themicelles potential for anti-cancer drugs intracellular delivery. A key advantage of nanocarrier systems is their ability to exhibit acontrolled drug release at tumor site by external stimuli. For that purpose,nanoparticles can be formulated with specific responsiveness to specificcues (e.g., pH, enzymes, oxygen levels, temperature) allowing for asustained release of anti-cancer drugs. One of the major obstacles ofchemotherapy is tumor heterogeneity characterized by the presence ofcancer stem cells (CSCs), that ultimately drives tumorigenesis andchemotherapy failure. Aiming to tackle this, nanotherapeutic strategieshave been explored targeting CSCs using nanoparticles. From thisstandpoint, HA-oxalate nanoparticles were chemically conjugated with achemotherapeutic drug (Camptothecin) and loaded with a CSCdifferentiation-inducing agent, all-trans retinoic acid, to obtain a sequentialrelease. Taking advantage of the hypoxic regions of TME, where CSCs reside,ATRA is released, by a hypoxia-triggered structural alteration, inducing CSCdifferentiation. Then, the rising ROS level promotes the chemotherapeuticdrug release causing CSC decreased stemness and cell death. Overall, several formulations including nanocarriers have alreadyadvanced to clinical applications (e.g., Pazenir, Vyxeos, Onivyde, Abraxane),and a number of others are under clinical trials (e.g., NCT02283320,106Potential of 3D tumor models for nanotherapies pre-clinical screeningVitor M. Gaspar1, Jo%u00e3o F. Mano, et al.