Polymeric Micelles for Breast Cancer Therapy: Recent Updates, Clinical Translation and Regulatory Considerations

Abstract

With the growing burden of cancer, parallel advancements in anticancer nanotechnological solutions have been witnessed. Among the different types of cancers, breast cancer accounts for approximately 25% and leads to 15% of deaths. Nanomedicine and its allied fields of material science have revolutionized the science of medicine in the 21st century. Novel treatments have paved the way for improved drug delivery systems that have better efficacy and reduced adverse effects. A variety of nanoformulations using lipids, polymers, inorganic, and peptide-based nanomedicines with various functionalities are being synthesized. Thus, elaborate knowledge of these intelligent nanomedicines for highly promising drug delivery systems is of prime importance. Polymeric micelles (PMs) are generally easy to prepare with good solubilization properties; hence, they appear to be an attractive alternative over the other nanosystems. Although an overall perspective of PM systems has been presented in recent reviews, a brief discussion has been provided on PMs for breast cancer. This review provides a discussion of the state-of-the-art PMs together with the most recent advances in this field. Furthermore, special emphasis is placed on regulatory guidelines, clinical translation potential, and future aspects of the use of PMs in breast cancer treatment. The recent developments in micelle formulations look promising, with regulatory guidelines that are now more clearly defined; hence, we anticipate early clinical translation in the near future.

Keywords: bioavailability; breast cancer; clinical translation; drug delivery; polymeric micelles; regulatory affairs.

Figure 1

TEM image of blank micelles and doxorubicin (DTX)-loaded PM. The PM composition consists of poly(ethylene glycol)-poly(caprolactone) (PEG-PCL) (molecular weight: 3900 Da) with a two-block ratio of 1:1. Reproduced from [40] Originally published by and used with permission from Dove Medical Press Ltd.

Figure 2

Schematic representation of the mechanisms of polymeric micelles. All mechanisms either work in a standalone manner or are mutually influenced by various conditions; unimer*, single unit of amphiphilic block; * Triggering stimuli represent various strategies, such as temperature, pH, enzymes, and magnetism. Note: EPR, enhanced permeability and retention; CMC, critical micellar concentration. Reprinted from [37] CC BY 4.0 License.

Figure 3

pH-sensitive micelles loaded with methotrexate (MTX) disassemble to release MTX in the presence of an acidic tumor microenvironment. A diblock copolymer of poly(monomethoxy ethylene glycol)-b-poly(ε-caprolactone) (mPEG-PCL) was used in the preparation, and the release was triggered by the sensitivity of the ester linkages to acidic pH. Reproduced from [60] CC-BY License.

Figure 4

Temperature/photosensitive micelles entrapping drugs that are released in the presence of NIR. Note: drug delivery systems (DDSs); near-infrared (NIR), (650–950 nm); photothermal therapy (PTT); photodynamic therapy (PDT); reactive oxygen species (ROS); reproduced from [62] CC-BY License.

Figure 5

Schematic diagram showing the generation of redox-sensitive micelles made up of polyphosphoesters (PPEs): (A) mPEG₄₅-b-P(DssEEP₁₂-co-EEP₆) and mPEG₄₅-b-P(DssEEP₁₅-co-EEP₂₀). Note: N2-(2-(dodecyldisulfanyl)ethoxy)-1,3,2-dioxaphospholane 2-oxide (DssEEP). (B) Methoxy polyethylene glycol (mPEG) loaded with doxorubicin (DOX) is released in the presence of a GSH-rich milieu in the tumor microenvironment. Multidrug resistance (MDR), glutathione (GSH). Reproduced with permission from [64]. Copyright © 2015, American Chemical Society.

Figure 6

Various strategies in micellar tumor targeting to deliver therapeutic cargoes.

Figure 7

Chemical structures and schematic diagrams of PMs and respective drug candidates in the clinical trials, polymers used in the preparation (subscript represents molecular weights in Daltons) and drug molecule names are presented: (A) Genexol-PM block copolymer of poly(ethylene glycol)₂₀₀₀-b-poly(D,L-lactide)₁₇₅₀ and paclitaxel (PTX); (B) NK105 block copolymer of PEG₁₂₀₀₀-b-poly (4-phenyl-1-butanoate-L-aspartamide)₈₀₀₀ and paclitaxel (PTX); (C) Nanoxel-PM block copolymer of poly(ethylene glycol)₂₀₀₀-b-poly(Lactide)₁₇₆₅ and docetaxel; (D) Docecal XR-17 (N-all-trans retinoyl cysteine methyl ester sodium salt and N-13-cis retinoyl cysteine methyl ester sodium salt) and docetaxel; (E) NK012 block copolymer of poly(ethylene glycol)₁₂₀₀₀-b-poly(l-glutamic acid) and docetaxel modified and reprinted from [104] with permission from Elsevier, © 2022 Published by Elsevier B.V. on behalf of the Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Figure 7

Chemical structures and schematic diagrams of PMs and respective drug candidates in the clinical trials, polymers used in the preparation (subscript represents molecular weights in Daltons) and drug molecule names are presented: (A) Genexol-PM block copolymer of poly(ethylene glycol)₂₀₀₀-b-poly(D,L-lactide)₁₇₅₀ and paclitaxel (PTX); (B) NK105 block copolymer of PEG₁₂₀₀₀-b-poly (4-phenyl-1-butanoate-L-aspartamide)₈₀₀₀ and paclitaxel (PTX); (C) Nanoxel-PM block copolymer of poly(ethylene glycol)₂₀₀₀-b-poly(Lactide)₁₇₆₅ and docetaxel; (D) Docecal XR-17 (N-all-trans retinoyl cysteine methyl ester sodium salt and N-13-cis retinoyl cysteine methyl ester sodium salt) and docetaxel; (E) NK012 block copolymer of poly(ethylene glycol)₁₂₀₀₀-b-poly(l-glutamic acid) and docetaxel modified and reprinted from [104] with permission from Elsevier, © 2022 Published by Elsevier B.V. on behalf of the Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Figure 8

The Common Technical Document (Reference: [114]). The eCTD has five modules: 1. Administrative information and prescribing information. This is a country specific regional module, i.e., different for each region or country; 2. Common technical document summaries. This is a common module in all regions; 3. Quality; 4. Nonclinical study reports; 5. Clinical study reports. Image source: https://www.ich.org/page/ctd © International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, https://www.ich.org/page/legal-mentions (accessed on 1 August 2022).

Figure 9

Steps and principles involved in the successful clinical translation of polymeric micelles. QbD, Quality by Design; CQAs, critical quality attributes; CPPs, critical process parameters; AI, artificial intelligence; HTS, high-throughput screening.