It is becoming generally accepted that the failure of cancer treatments can be due to a small sub-population of slow growing, invasive and drug resistant cells known as cancer stem cells (CSCs). In a wide variety of cancer indications, the transmembrane receptor of CD44 is used as a phenotypic marker of cancer stem cells where the increased expression of CD44 correlates with the lack of tumour response to current chemotherapeutic drugs which ultimately translates into shorter survival survival periods for cancer patients. Collectively these observations provided the rationale to develop a range of CD44-targeted anti-cancer therapies that would be able to eradicate CD44-expressing tumour cells and ultimately cancer stem cells.
As the primary ligand for CD44 is hyaluronan (HA), a range of HA-derivatised cytotoxic drugs were developed which use HA as the CD44-recognition moiety. The drug delivery platform utilizes the large volumetric domain of HA to entrain small chemotherapeutic drugs within the 3-dimensional milieu resulting in the formation of a nanoparticle with a gyration radius of 100nm. The HA-derivatised cytotoxic drugs demonstrate a dual-action mechanism of action where after intravenous administration the HA-cytotoxic accumulates in the microvascular of the tumour, forming a microembolism that increases drug retention at the tumour site and allows for rapid intracellular uptake of the drug complex via the activated CD44 lysosomal/endosomal pathway. Preclinical development of eight and the clinical development of three of these CD44-targeted anti-cancer drugs has been undertaken and has demonstrated that such formulations are safe and efficacious. This presentation follows the preclinical and clinical development of this technology where mechanisms associated with; i) the mode of molecular interaction between CD44 and the chemotherapeutic drugs, ii) ability of the HA-moiety to act as a targeted transport vehicle for anti-cancer agents, iii) effect of HA on the therapeutic index of chemotherapeutic drugs iv) the clinical safety and efficacy of these HA-based anti-cancer agents and vi) the regulatory approach which has enabled an accelerated development pathway are discussed.