REVIEW An outlook on procedures of conjugating folate to (co) polymers and drugs for effective cancer targeting Prashant S. Kharkar 1 | Govind Soni 2 | Vaibhavi Rathod 3 | Saritha Shetty 3 | M. K. Gupta 2 | Khushwant S. Yadav 3 1 Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, India 2 Oriental College of Pharmacy and Research, Oriental University, Indore, India 3 Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai, India Correspondence Khushwant S. Yadav, Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai 400 056, India. Email: khush.yadav@gmail.com, khushwant. yadav@nmims.edu Abstract Folate receptors (FRs) are expressed in vast majority of cancers. Selective targeting of the FRs is, therefore, one of the most popular and sought-after strategies for improving the efficacy of cancer therapeutics. Variety of approaches involving folate conjugation to several well-known and novel, nontoxic, biodegradable, and biocompatible (co)poly- mers have been attempted and successfully applied to a large number of nanoparticulate drug delivery systems (micelles, liposomes, nanoparticles, quantum dots, mesoporous silica-based materials, and others) in the last decade-and-a-half. Standard and novel syn- thetic approaches were utilized for the conjugation, followed by the formulation of the drug delivery modality. In most of the cases, the targeted system lived up to its reputa- tion, validating its usefulness in targeted cancer therapeutics. The present review sum- marizes the progress and state-of-the-art synthetic methodologies for folate conjugation to (co)polymers, drugs, and nucleic acids. The limitations of the FR targeting are dis- cussed in brief to give the reader the other side of the story. Finally, the information on marketed folic acid conjugates highlight their industrial applications. KEYWORDS FA-chitosan, FA-PLGA, folate, folate receptor, folic acid, nucleic acids, targeting 1 | INTRODUCTION Anticancer drugs kill or destroy rapidly dividing cells. Although chemo- therapy is effective to some extent, a major drawback of being non- specific. Other limitations of conventional chemotherapy include, but not limited to, low therapeutic indices of the drugs, evident toxicity, and fair chances of multidrug resistance (MDR) in the prolonged treat- ment (Allen & Cullis, 2004). Moreover, when these chemotherapeutic drugs are conventionally administered, the doses other than impacting the healthy cells are also possibly responsible for impairment of many other vital organs (Pérez-Herrero & Fernández-Medarde, 2015). Tumor-targeted drug delivery systems are of profound interest in anticancer therapeutics as they not only improve the safety and effi- cacy of the drug but also reduced the debilitating toxic effects associ- ated with the chemotherapy (Peer et al., 2007). Such actively targeted drug delivery systems are able to deliver the right cytotoxic cargo preferentially to the cancer cells (Limeres, Moretton, Bernabeu, Chiappetta, & Cuestas, 2019). They are beneficial in reducing some of the critical issues associated with the conventional drugs like bypassing the biological barriers, and overcoming the drug resistance to a greater extent. Targeted therapies minimize the toxic effects on to the healthy cells and specifically kill the cancer cells (Bertrand, Wu, Xu, Kamaly, & Farokhzad, 2014; Leamon & Low, 2001; Pethe & Yadav, 2019; Soni & Yadav, 2017; Sudimack & Lee, 2000; Yadav, Saxena, & Soni, 2017). For the active targeting, there has to be appro- priate receptor inside the body. Substantial presence of such recep- tors, that is, higher expression, is mandatory for good targeting ability (Soni & Yadav, 2015; Yadav et al., 2011; Yadav, Mishra, Deshpande, & Pethe, 2019). The folate receptor (FR), overexpressed in many types of cancers, is one of the most commonly known bio- markers amenable for targeted delivery (Farran et al., 2019; Ledermann, Canevari, & Thigpen, 2015). Targeting the FR is one of Received: 31 December 2019 Revised: 28 April 2020 Accepted: 7 May 2020 DOI: 10.1002/ddr.21698 Drug Dev Res. 2020;1–14. wileyonlinelibrary.com/journal/ddr © 2020 Wiley Periodicals, Inc. 1