3.4.1. Hyaluronic Acid-Based Micelles

HA-based micelles were shown to target CD44 positive breast cancer cells with highaffinity in vitro and in vivo [103]. The hydrophilic HA backbone is modified with hydrophobic groups to form an amphiphilic compound, which can self-assemble into a micelle in an aqueous solution and encapsulate or conjugate drugs After reaching cancer cells, drug release is achieved using various mechanisms, such as through pH dependence or enzyme action [171,172].

HA-conjugated hexadecylamine micelles for the docetaxel delivery to MDA-MB-231 breast cancer cells are examples of a study testing HA-conjugated micelle drug formation [173]. Results showed that HA conjugation of micelles enhanced cellular uptake. Moreover, treating mice bearing xenograft MCF-7 human breast cancer tumors with HAshelled-paclitaxel prodrug micelles resulted in 100% mouse survival and tumor-specific accumulation of the micelles [174].

In pancreatic cancer, the use of HA-engineered nano-micelles loaded with 3,4 difluorobenzylidene curcumin were tested in CD44-positive MiaPaCa-2 and AsPC-1 pancreatic cancer cell lines [175]. The existence of pancreatic cancer stem cells overexpressing CD44 was identified, contributing to a tumor's resistance to chemotherapy [175,176]. Recent studies in vivo continued to prove the success of HA:Sucrose nanoparticles in the delivery of anticancer treatments (such asEF2-Kinase inhibitor) to pancreatic cancer cells, leading to significant inhibition of division and tumor formation [177].

Recognized, HA-based micelles' disadvantages are the limited drug circulation in the blood and the fast uptake by liver endothelial cells [178]. Therefore, the conjugation of HA-micelles with PEG has been tested to improve their blood circulation time. Although PEGylation may affect the micelle interaction with cancer cells HA-receptors [179], the simultaneous use of these two types of micelles showed no significant variances as to their delivery efficiency in vivo [180].
