Chapter 8: Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101
Published:14 Apr 2016
I. Gritli, E. Garmey, S. Eliasof, A. Tellez, M. E. Davis, and Y. Yun, in Nanomedicines: Design, Delivery and Detection, ed. M. Braddock, The Royal Society of Chemistry, 2016, ch. 8, pp. 199-232.
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CRLX101 (formerly IT-101) is a novel cyclodextrin-based polymer that self-assembles into nanoparticles. CRLX101 is covalently conjugated to the hydrophobic topoisomerase 1 (TOP1)-inhibitor camptothecin (CPT) resulting in stabilized structure and increased water solubility. Extensive preclinical studies of CRLX101 demonstrated delayed renal clearance and a prolonged plasma half-life. The nanoparticle passively accumulates in tumour tissue through the enhanced permeability and retention effect and slowly releases active CPT leading to enhanced TOP1 inhibition, potential hypoxia inducible factor-1α (HIF-1α) effect, cancer stem cell targeting, and increased antitumour activity against multiple human tumour xenografts. More than 200 human cancer patients have been treated with CRLX101 in phase I/IIa and phase II clinical trials. In this chapter we explore a wide range of anti-cancer nanotherapeutic strategies to inhibit TOP1, HIF-1α and cancer stem cells. Moreover, we discuss the therapeutic value of combining HIF-1α inhibition with antiangiogenics. Finally, we return to CRLX101 and cover in detail the latest preclinical and clinical evaluations and discuss future directions.