Please cite this article in press as: Rani, S., Gupta, U. Drug Discovery Today  Volume 00, Number 00  April 2020 REVIEWS HPMA-based polymeric conjugates in anticancer therapeutics Sarita Rani Q2 and Umesh Gupta Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan, 305817, India Polymer therapeutics has gained prominence as an attractive structural polymer chemistry applicable in biomedicals. In this review, we discuss the development and capabilities of N-(2-hydroxypropyl) methacrylamide (HPMA) and HPMA–drug conjugates in cancer therapy. The design, architecture, and structural propert Q3 ies of HPMA make it a versatile system for the synthesis of polymeric conjugations for biomedical applications. Research suggests that HPMA could be a possible alternative for polymers such polyethylene glycol (PEG) in biomedical applications. Although numerous clinical trials of HPMA–drug conjugates are ongoing, no product has been successfully brought to market. Thus, further research is required to develop HPMA–drug conjugates as successful cancer therapeutics. Introduction The development of an effective and potent drug therapy is a major goal of dru Q4 g discovery. More than a century ago, Paul Ehrlich coined the term ‘magic bullet’ and deciphered the importance of biorecognition for successful drug delivery. Howe Q5 ver, the effective targeting of drugs and macromolecules to pathogenic cells, specifically the intracellular compartment, remains a significant challenge, particularly against cancers. Research focuses on developing a selective/ targeted delivery vehicle for anticancer effectivity without harming heal Q6 thy cells. At the cellular level, the cell membrane and the inherent compartmentalization of organelles are additional obstacles [1]. To elicit effective therapeutic action, drugs, including macromolecules such as proteins, antibodies, small molecules, and antineoplastic agents, have to be delivered to their specific targets, mainly the cytoplasm or nucleus of cancer cells. However, many chemother- apeutics fail to target tumor cells because of their small size and/or molecular weight, low aqueous solubility, and poor pharmacokinetics (PK). In addition, following intravenous delivery, these agents are rapidly cleared from the circulation. Active and passive targeting are considered to be possible ways to ameliorate this problem to some extent. In active targeting, the polymer is directly conjugated with a ligand moiety, drug, or antibody, whereas in passive targeting, therapeutic carrier enters the tumor vasculature via the enhanced permeation and retention (EPR) effect [2–6]. Targeted delivery by increasing selectivity towards the target and decreasing toxicity can be achieved by carriers including liposomes (e.g., Doxil, Myocet, and Caelyx) [7,8], Reviews  KEYNOTE REVIEW Umesh Gupta was awarded a PhD in pharmaceutical sciences from Dr H.S. Gour University, India and carried out postdoctoral work at South Dakota State University, USA. He is currently an assistant professor in the Department of Pharmacy, Central University of Rajasthan, India. His area of research includes solubilization, nanotechnology, polymer bioconjugation, and dendrimers. He was recently awarded the 2019 American Association of Indian Pharmaceutical Scientists Distinguished Young Educator and Researcher Award. Sarita Rani completed a MSc in pharmaceutical sciences from the Central University of Rajasthan, India under the mentorship of Umesh Gupta. She is currently pursuing her doctoral studies in the Department of Pharmacy, Central University of Rajasthan, as a senior research fellow. She is AICTE- GPAT and WIPO-GCoIP qualified. Her research interests include polymer chemistry and nanoparticulate drug delivery. Corresponding author: Gupta, U. (umeshgupta175@gmail.com), (umeshgupta@curaj.ac.in) 1359-6446/ã 2020 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.drudis.2020.04.007 www.drugdiscoverytoday.com 1