Critical Reviews™ in Therapeutic Drug Carrier Systems, 36(1): 1–58 (2019) 0743-4863/19/$35.00 ©2019 Begell House, Inc. www.begellhouse.com 1 Polymeric Mixed Micelles: Improving the Anticancer Effcacy of Single-Copolymer Micelles Arehalli S. Manjappa, a,* Popat S. Kumbhar, a Ajit B. Patil, a John I. Disouza, a & Vandana B. Patravale b a Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur, Maharashtra, India; b Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai, Maharashtra, India *Address all correspondence to: Dr. Arehalli S. Manjappa, Assistant Professor, Department of Pharmaceutics, Tatyasaheb Kore College of Pharmacy, Warananagar, Tal: Panhala, Dist: Kolhapur, Maharashtra, India, 416113; Tel.: (02328) 223526; Fax: (02328) 223501, E-mail: manju_as82@yahoo.co.in ABSTRACT: Mixed micelles self-assembled from two or more dissimilar block copolymers provide a direct and convenient approach to improved drug delivery. The present review is focused on mixed micelles (prepared from block copolymers only) for various drug delivery applications along with their merits over single-copolymer micelles. Presented are the physi- cochemical properties of mixed and single-copolymer micelles, various stimuli-responsive mixed micelles for the treatment of cancer, interesting combinations of multifunctional mixed micelles along with their in vitro and in vivo performance, and the potential of mixed micelles as a gene delivery system. Finally, the performance of mixed micelles in preclinical and clini- cal testing is explained. In addition, the interaction of mixed micelles with cancer cells and the biosafety of mixed micelles are summarized. The in vitro and in vivo performance presented here clearly reveals that the mixed-micelle approach has a wider scope than that of the single- copolymer micelle approach and directs researchers to focus on this approach to delivery of drugs/gene/biologics for various applications. KEY WORDS: mixed micelles, single-copolymer micelles, block copolymers, drug delivery, gene delivery ABBREVIATIONS: 17-AAG, 17-allyamino-17-demethoxygeldanamycin; apoB, apolipoprotein B; AUC, area under the curve; BDMC, bisdemethoxy curcumin; BHS-I, baohuoside I; BPD, benzoporphyrin deriva- tives; BPDMA, benzoporphyrin derivative monoacid A-ring; BPDMB, benzoporphyrin derivative mono- acid B-ring; BSA, bovine serum albumin; CMC, critical micelle concentration; CPT, camptothecin; CUR, curcumin; DIR, 1,1′-dDioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine; DLC, drug-loading capacity; DNA, deoxyribonucleic acid; DOX, doxorubicin; DTT, dithiothreitol; DTX, docetaxel; EE, entrapment efciency; EFV, efavirenz; FDA, Food And Drug Administration; FPF, Pluronic P123/F127 mixed mi- celles decorated with folic acid; GAG, glycosaminoglycan; GalNAc, N-acetylgalactosamine; GEJ, gas- troesophageal junction; GI tract, gastrointestinal tract; Glu, glucosamine; GSH, glutathione; i.v., intrave- nous; IC 50 , median inhibition concentration; ITT, intent-to-treat; JGN, juglon; MDR, multidrug resistant; MMs, mixed micelles; MPMs, mixed polyplex micelles; MPS, mean particle size; MRT, mean residential time; MTX, methotrexate; MYR, myricetin; NCL, niclosamide NiPAAM, N-isopropylacrylamide; ORN, oridonin; PAT, parthenolide; PBS, phosphate bufer saline; PDI, polydispersity index; PDMAEMA, poly((dimethylamino)ethylene methacrylate); pDNA, plasmid DNA; PDPA, poly(2 (diisopropylamino)eth-