Cancers 2023, 15, 4. https://doi.org/10.3390/cancers15010004 www.mdpi.com/journal/cancers Review Smart Polymeric Micelles for Anticancer Hydrophobic Drugs Andy Guzmán Rodríguez 1 , Marquiza Sablón Carrazana 2 , Chrislayne Rodríguez Tanty 2 , Martijn J. A. Malessy 3 , Gastón Fuentes 1,4, * and Luis J. Cruz 1, * 1 Translational Nanomedicine and Imaging Group, Department of Radiology, K2-24g room, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands 2 Cuban Center of Neurosciences, La Habana 11600, Cuba 3 Department of Neurosurgery, J-11-R-84 room, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands 4 Biomaterials Center, University of Havana, La Habana 10400, Cuba * Correspondence: gastonfe@biomat.uh.cu (G.F.); l.j.cruz_ricondo@lumc.nl (L.J.C.) Simple Summary: Cancer has been a lethal and high-incidence disease for many years and its cure is characterized by invasive methods and with notable side effects. Nanotechnology has come to shorten the gap in the search for the holy grail of a cure for cancer. This work aims to contribute, from the exposure of the different nanocarriers that can be used as vehicles for the transport of anticancer drugs, to the knowledge of the new routes to reach the final goal, which is none other than to reduce the incidence of this lethal disease to very low levels in humans. Abstract: Cancer has become one of the deadliest diseases in our society. Surgery accompanied by subsequent chemotherapy is the treatment most used to prolong or save the patient’s life. Still, it carries secondary risks such as infections and thrombosis and causes cytotoxic effects in healthy tissues. Using nanocarriers such as smart polymer micelles is a promising alternative to avoid or minimize these problems. These nanostructured systems will be able to encapsulate hydrophilic and hydrophobic drugs through modified copolymers with various functional groups such as car- boxyls, amines, hydroxyls, etc. The release of the drug occurs due to the structural degradation of these copolymers when they are subjected to endogenous (pH, redox reactions, and enzymatic ac- tivity) and exogenous (temperature, ultrasound, light, magnetic and electric field) stimuli. We did a systematic review of the efficacy of smart polymeric micelles as nanocarriers for anticancer drugs (doxorubicin, paclitaxel, docetaxel, lapatinib, cisplatin, adriamycin, and curcumin). For this reason, we evaluate the influence of the synthesis methods and the physicochemical properties of these systems that subsequently allow an effective encapsulation and release of the drug. On the other hand, we demonstrate how computational chemistry will enable us to guide and optimize the de- sign of these micelles to carry out better experimental work. Keywords: smart polymeric micelles; anticancer hydrophobic drugs; nanocarriers; smart drug- delivery systems; gold nanoparticles 1. Introduction Cancer is one of the leading causes of death worldwide. Surgery accompanied by subsequent chemotherapy is the most widely used treatment to lengthen or save the pa- tient’s life. Surgery inherently bears secondary risks, such as infection and thrombosis. Chemotherapeutic compounds may be ineffective due to low water solubility, low tumor targeting, and low cellular uptake, and they may cause cytotoxic effects on healthy tissues [1]. In cancer treatment, nanocarrier systems have great potential to help or replace tradi- tional chemotherapy. Controlled drug delivery by nanoparticles is crucial but has always been a significant challenge in developing new effective cancer therapies and diagnostics. The nanocarriers most used for these purposes are carbon nanotubes [2], dendrimer [3], Citation: Guzmán Rodríguez, A.; Sablón Carrazana, M.; Rodríguez Tanty, C.; Malessy, M.J.A.; Fuentes, G.; Cruz, L.J. Smart Polymeric Micelles for Anticancer Hydrophobic Drugs. Cancers 2023, 15, 4. https://doi.org/10.3390/ cancers15010004 Academic Editor: Michael Hausmann Received: 24 November 2022 Revised: 15 December 2022 Accepted: 16 December 2022 Published: 20 December 2022 Copyright: © 2022 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https://creativecommons.org/licen- ses/by/4.0/).