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Polymeric Nanocarriers: a Transformation in Doxorubicin Therapies

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Polymeric Nanocarriers: a Transformation in Doxorubicin Therapies materials Review Polymeric Nanocarriers: A Transformation in Doxorubicin Therapies Kamila Butowska 1, Anna Woziwodzka 1, Agnieszka Borowik 1,2 and Jacek Piosik 1,* 1 Laboratory of Biophysics, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gda´nsk,Poland; [email protected] (K.B.); [email protected] (A.W.); [email protected] (A.B.) 2 Aging and Metabolism Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, OK 73104, USA * Correspondence: [email protected]; Tel.: +48-58-523-6311 Abstract: Doxorubicin, a member of the anthracycline family, is a common anticancer agent often used as a first line treatment for the wide spectrum of cancers. Doxorubicin-based chemotherapy, although effective, is associated with serious side effects, such as irreversible cardiotoxicity or nephro- toxicity. Those often life-threatening adverse risks, responsible for the elongation of the patients’ recuperation period and increasing medical expenses, have prompted the need for creating novel and safer drug delivery systems. Among many proposed concepts, polymeric nanocarriers are shown to be a promising approach, allowing for controlled and selective drug delivery, simultaneously enhancing its activity towards cancerous cells and reducing toxic effects on healthy tissues. This article is a chronological examination of the history of the work progress on polymeric nanostruc- tures, designed as efficient doxorubicin nanocarriers, with the emphasis on the main achievements of 2010–2020. Numerous publications have been reviewed to provide an essential summation of the nanopolymer types and their essential properties, mechanisms towards efficient drug delivery, as Citation: Butowska, K.; well as active targeting stimuli-responsive strategies that are currently utilized in the doxorubicin Woziwodzka, A.; Borowik, A.; Piosik, transportation field. J. Polymeric Nanocarriers: A Transformation in Doxorubicin Keywords: doxorubicin; drug delivery; polymers; targeted therapy; anticancer treatment; con- Therapies. Materials 2021, 14, 2135. trolled release https://doi.org/10.3390/ma14092135 Academic Editor: Eun-Kyung Lim 1. Introduction Received: 1 March 2021 1.1. Doxorubicin and Other Anthracyclines Accepted: 20 April 2021 Anthracyclines, including doxorubicin (DOX), daunorubicin, and epirubicin, are Published: 22 April 2021 among the most active antitumor compounds with the widest spectrum of activity in human cancers such as carcinomas, sarcomas, and hematological malignancies. They are Publisher’s Note: MDPI stays neutral widely used (alone or in combination with other cytotoxic agents) in clinical practice for with regard to jurisdictional claims in published maps and institutional affil- the treatment of lung, breast, ovarian, and urinary bladder cancers, as well as multiple iations. myeloma, soft tissue sarcoma, osteosarcoma, leukemias, and Hodgkin’s lymphoma. DOX was initially obtained from Streptomyces peucetius actinobacteria isolated from a soil sam- ple, identified, and developed in the 1960s [1,2]. Although DOX was granted marketing authorization nearly five decades ago, it is present on the current World Health Organiza- tion Model List of Essential Medicines, listing the most efficient, safe, and cost–effective Copyright: © 2021 by the authors. medicines needed in the healthcare system [3]. Licensee MDPI, Basel, Switzerland. Apart from its high efficacy in monotherapy (especially in treatment of metastatic This article is an open access article distributed under the terms and breast cancer), several combination therapies including DOX were also developed. The conditions of the Creative Commons combination of DOX with cyclophosphamide, vincristine, and prednisone is used for Attribution (CC BY) license (https:// treatment of diffuse large cell non-Hodgkin’s lymphomas [4]. The combination of DOX creativecommons.org/licenses/by/ with bleomycin, vincristine, and dacarbazine is beneficial and well tolerated in patients 4.0/). with Hodgkin’s lymphoma [4]. Several combination regimens consisting of DOX are used Materials 2021, 14, 2135. https://doi.org/10.3390/ma14092135 https://www.mdpi.com/journal/materials Materials 2021, 14, x FOR PEER REVIEW 2 of 20 Materials 2021, 14, 2135 with Hodgkin’s lymphoma [4]. Several combination regimens consisting2 of 19of DOX are used for treatment of breast cancer (DOX with cyclophosphamide and/or taxotere, DOX with cyclophosphamide and fluorouracil). for treatment of breast cancer (DOX with cyclophosphamide and/or taxotere, DOX with cyclophosphamideStructurally, and DOX fluorouracil). is a glycoside of anthracyclinone. It contains an anthraquinone chromophoreStructurally, placed DOX is within a glycoside a planar of anthracyclinone. aromatic system It contains of four an cycles, anthraquinone bound by a glycosidic chromophorebond to daunosamine placed within a planar(Figure aromatic 1). Anthraquinone system of four cycles, groups bound bycan a glycosidic participate in redox bondreactions, to daunosamine contributing (Figure to1). th Anthraquinonee generation groups of reactive can participate chemical in redox species, reactions, which might be contributing to the generation of reactive chemical species, which might be associated with anthracyclineassociated with cardiotoxicity anthracycline [5]. cardiotoxicity [5]. Figure 1. Chemical structure of doxorubicin. Figure 1. Chemical structure of doxorubicin. 1.2. Doxorubicin Mechanism of Action 1.2. DoxorubicinTo date, several Mechanism distinct mechanisms of Action of DOX action are discussed (Figure2). The first andTo primarydate, several one includes distinct the mech interactionanisms of DOXof DOX with action mammalian are discussed topoisomerase (Figure 2). The first II, stabilization of enzyme–DNA complex, and resulting inhibition of single- and double- strandand primary DNA breaks one includes re-ligation the during interaction the DNA of replication DOX with process mammalian [6]. This leadstopoisomerase to II, sta- irreversiblebilization DNAof enzyme–DNA damage and cell complex, death. Importantly, and result thising mode inhibition of DOX actionof single- is specific and double-strand forDNA proliferating breaks re-ligation (e.g., cancer) during cells which, the mitotically–active, DNA replication are predominantlyprocess [6]. This affected leads by to irreversible topoisomeraseDNA damage II–induced and cell DNA death. breaks Importantly, [7]. Such a mechanism this mode of of action DOX was action confirmed is specific in for prolif- in vitro studies on cell lines with mutated or downregulated topoisomerase II, in which resistanceerating (e.g., to DOX cancer) was reported cells which, [8–10]. mitotically–active, Intercalation of DOX are into predominantly DNA double–helix affected is by topoi- well–evidencedsomerase II–induced and widely DNA accepted, breaks and [7]. 50TCA Such was a reported mechanism as a consensus of action sequence was confirmed in in forvitro the studies highest DOXon cell affinity lines [ 11with]. Nevertheless, mutated or the downregulated actual role of DOX topoisomerase intercalation to II, in which re- DNAsistance in topoisomerase to DOX was II–mediatedreported [8–10]. DNA damageIntercalation remains of unknown. DOX into Topoisomerase DNA double–helix is well– II–relatedevidenced DNA and breaks widely are accepted, reported at and DOX 5′ concentrationsTCA was reported which fallas a below consensus the DOX- sequence for the DNA association constant, along with the fact that selected anthracycline analogs do not intercalatehighest DOX into DNA affinity but still [11]. exert Nevertheless, cytotoxic activity, the might actual suggest role that of DOX intercalation intercalation to DNA in totopoisomerase DNA is not essential II–mediated for its interference DNA damage with topoisomerase remains IIunknown. [12,13]. Topoisomerase II–related DNAIntercalation breaks are of reported DOX into DNA,at DOX although concentratio possibly notns which involved fall in targetingbelow the topoiso- DOX-DNA associ- meraseation constant, II, has an impactalong onwith several the vitalfact intracellularthat selected processes. anthracycline It can affect analogs the activity do not intercalate of enzymes involved in DNA replication and transcription, such as helicases, DNA, or RNAinto DNA polymerases but still [14 ,exert15]. Topological cytotoxic DNA activity, changes might following suggest DOX that intercalation DOX intercalation were to DNA alsois not reported essential to be for associated its interference with increased with topoisomerase nucleosome turnover II [12,13]. around promoters, whichIntercalation affected levels ofof gene DOX expression into DNA, [16]. DOX-relatedalthough po removalssibly ofnot nucleosomes involved at in open targeting topoiso- chromatinmerase II, regions, has an which impact alters on epigenetic several regulationvital intracellular of transcription processes. and contributes It can affect to the activity reduced DNA repair of DOX–induced double–strand breaks, was recently reported [17]. of enzymes involved in DNA replication and transcription, such as helicases, DNA, or Apart from its well–established topoisomerase II–mediated cytotoxicity, DOX, while undergoingRNA polymerases intracellular [14,15]. oxidation Topological and reduction DNA cycles, changes leads to the following generation DOX of reactive intercalation were oxygenalso reported species. Thisto be exposes associated nuclear
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