*Review* **Poly(caprolactone)-***b***-poly(ethylene glycol)-Based Polymeric Micelles as Drug Carriers for Efficient Breast Cancer Therapy: A Systematic Review**

**Siti Hajar Ahmad Shariff <sup>1</sup> , Wan Khartini Wan Abdul Khodir <sup>1</sup> , Shafida Abd Hamid <sup>1</sup> , Muhammad Salahuddin Haris <sup>2</sup> and Mohamad Wafiuddin Ismail 1,\***


**Abstract:** Recently, drug delivery systems based on nanoparticles for cancer treatment have become the centre of attention for researchers to design and fabricate drug carriers for anti-cancer drugs due to the lack of tumour-targeting activity in conventional pharmaceuticals. Poly(caprolactone)-*b*poly(ethylene glycol) (PCL-PEG)-based micelles have attracted significant attention as a potential drug carrier intended for human use. Since their first discovery, the Food and Drug Administration (FDA)-approved polymers have been studied extensively for various biomedical applications, specifically cancer therapy. The application of PCL-PEG micelles in different cancer therapies has been recorded in countless research studies for their efficacy as drug cargos. However, systematic studies on the effectiveness of PCL-PEG micelles of specific cancers for pharmaceutical applications are still lacking. As breast cancer is reported as the most prevalent cancer worldwide, we aim to systematically review all available literature that has published research findings on the PCL-PEG-based micelles as drug cargo for therapy. We further discussed the preparation method and the anti-tumour efficacy of the micelles. Using a prearranged search string, Scopus and Science Direct were selected as the databases for the systematic searching strategy. Only eight of the 314 articles met the inclusion requirements and were used for data synthesis. From the review, all studies reported the efficiency of PCL-PEG-based micelles, which act as drug cargo for breast cancer therapy.

**Keywords:** PCL-PEG; polymer micelle; drug cargo; drug delivery; breast cancer

## **1. Introduction**

The statistics from the International Agency for Research on Cancer in 2020 have estimated around 19.3 million new cases and almost 10.0 million deaths worldwide, with female breast cancer as the most commonly diagnosed cancer [1]. The World Health Organization in 2019 reported cancer as the first or second most significant cause of mortality among people before the age of 70 in 112 of 183 countries [2]. According to the National Cancer Institute, some cancer treatments include surgery, chemotherapy, immunotherapy, stem cell transplant, and precision medicine [3]. Among the many treatments, chemotherapy is one of the most commonly used methods for cancer therapy [4].

Nevertheless, several drawbacks have limited the benefits of chemotherapy treatment, such as the poor water solubility of some anti-cancer drugs that lower their efficiency. In addition, anti-cancer drugs also possess a high toxicity that results in severe side effects which cannot be reduced using traditional pharmaceutical dosage forms [5]. While conventional pharmaceutical formulations are lacking in the activity that targets tumours, resulting in only a limited amount of drugs that enter systemic circulation to target the tumour tissues. Consequently, the drug uptake of conventional pharmaceuticals is lowered [6]. As such,

**Citation:** Ahmad Shariff, S.H.; Wan Abdul Khodir, W.K.; Abd Hamid, S.; Haris, M.S.; Ismail, M.W. Poly(caprolactone)-*b*-poly(ethylene glycol)-Based Polymeric Micelles as Drug Carriers for Efficient Breast Cancer Therapy: A Systematic Review. *Polymers* **2022**, *14*, 4847. https://doi.org/10.3390/ polym14224847

Academic Editors: Antonia Ressler and Inga Urlic

Received: 25 August 2022 Accepted: 13 September 2022 Published: 10 November 2022

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drug delivery systems based on nanoparticles for cancer treatment have become the centre of attention for researchers to design and fabricate drug carriers for anti-cancer drugs, such as vesicles, liposomes, nanogels, and polymer micelles [5,7,8]. These nanodrug delivery methods can lower drug toxicity while increasing bioavailability since the drugs are dissolved, adsorbed, and covalently bound to the surface of the nanocarriers. The surface of the carriers can also be modified to direct the drug toward the tumour, minimising drug transport to healthy tissues and increasing treatment safety. The discovery of this cancer-targeting technology based on nanodrug delivery has resurrected the medicinal use of many powerful anti-cancer drugs that previously contained a high toxicity [6,7,9].

Researchers highly sought polymer micelles in breast cancer treatment due to their flexibility in designing and modifying their structures and compositions [10]. As a result, the development of polymer micelles as breast anti-cancer drug carriers has been ongoing even up to this day. Polymer micelles are usually spherical, nano-sized, amphiphilic copolymers that self-assembled spontaneously in aqueous media to form micelles above the critical micelle concentration (CMC), comprised of hydrophobic and hydrophilic block domains. The hydrophobic core dissolves the hydrophobic drugs, improving their solubility and biostability. At the same time, the hydrophilic outer shell provides micelles with compatibility in the aqueous media and shields the drugs in the core from interactions with the blood components [11].

One of the most commonly used polymeric micelles is based on a polyester-polyether, poly(caprolactone)-*b*-poly(ethylene glycol) (PCL-PEG) block copolymer due to their amphiphilicity, high biocompatibility, controlled biodegradability, and self-assembling ability to produce polymeric micelles in aqueous media [12–15]. Polyester cores were reported to have higher hydrophobic anti-cancer drug loading than polyether [16]. PCL has a very low glass transition temperature, making it suitable for developing drug delivery systems based on nanoparticles, in addition to its biodegradability, biocompatibility, and FDA approval [17]. Compared to other hydrophobic polyesters such as poly(lactic-co-glycolic acid (PLGA) and polylactic acid (PLA), PCL displayed a relatively weak acidic environment, lessening the biological inflammation. Furthermore, PCL is less expensive and more stable in the body than PLGA and degrades rather slowly [18]. PCL is the most promising polyester for the development of novel, commercial medical devices. This capability is related to PCL's unique physicochemical features, relatively harmless biodegradation behaviour, and the ability to fine-tune and make significant chemical alterations [19].

On its own, pure PCL has poor water stability as it easily aggregates. Therefore, the addition of PEG chains is used to address this issue. PEG has been used as a therapeutic agent for a long time as an FDA-approved hydrophilic constituent of polymeric micelles because it can prevent micelle uptake in the reticuloendothelial system (RES), hence lengthening the blood circulation time of the drug in the polymer micelles [20,21]. PEGylation of the hydrophobic PCL results in amphiphilicity properties and a controllable degradation speed and drug release profile, enhancing its biocompatibility and circulation time [17]. Apart from that, the addition of PEG to PCL increased the degree of crystallinity of PCL, resulting in more refined PCL crystals. In fact, even a substantial amount of PEG resulted in a significant decrease in the degradation temperature, crystallinity, time of crystallisation, and an increase in the crystal's average size [22]. The synergistic effects of PCL-PEG copolymers make them attractive in the anti-cancer drug delivery system. Over the years, the application of PCL-PEG-based polymeric micelles in the area of cancer therapeutics has been studied numerous times as drug carriers for various types of cancer, such as breast cancer [23,24], colorectal cancer [25], lung cancer [26], colon cancer [27,28], prostate cancer [29], and others. PCL-PEG based nanoparticles as nanocarriers for chemotherapeutic drugs such as paclitaxel, campothecin, and doxorubicin confirmed increased cellular internalisation, sustained drug release, and lower cytotoxic effects compared to free drugs [30].

These studies focus on the efficacies and capabilities of the amphiphilic polymeric micelles to act as anti-cancer drug cargo. However, there is still a limited number of existing studies that have been reviewed systematically, specifically on breast cancer therapy. Hence, this review was conducted to systematically review past studies in detail. The fundamental question that led to this review is: what is the efficiency of PCL-PEG-based micelles as drug carriers for breast cancer therapy? This study aims to narrow the gap by systematically examining past related studies (2016–2021) to acquire better knowledge on the efficiency of the PCL-PEG-based micelles as drug carriers for breast cancer treatment.

### **2. Methods**

In this section, the reviewers discussed the strategy used to identify papers about poly(caprolactone)-*b*-poly(ethylene glycol)-based polymeric micelles as drug carriers for efficient breast cancer therapy. The method used for this systemic review was PRISMA, which included Scopus and ScienceDirect as resources.

### *2.1. The Review Protocol—PRISMA*

This systematic review uses the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA) guideline. PRISMA is a published standard that guides researchers on how to conduct a systematic literature review. It is widely used in medical research and can identify the inclusion and exclusion criteria of the study [31].

## *2.2. Formulation of the Research Question*

The research question for this review was formulated based on PICO. PICO is a method that helps construct a relevant research question for systematic literature reviews. The four main concepts in PICO are Population or Problem, Intervention or Experimental Variables, Control Variable, and Outcome [32]. Based on the concepts, the researchers outlined four main aspects in the review: PCL-PEG (population), micelle (Intervention/experimental variables), drug carrier (control variable), and breast cancer (outcome), which then guided the formulation of the leading research question: what is the efficiency of the PCL-PEGbased micelles as drug carriers for breast cancer therapy?

### *2.3. Resources*

Two electronic databases were used as sources for this study: Scopus and ScienceDirect. These databases are relevant and provide high-impact factor publication [33]. The researchers analysed the titles and abstracts of the published articles according to the inclusion criteria in this study.

### *2.4. Systematic Searching Strategies*

The systematic search process for selecting relevant articles for this review was done in three stages: identification, screening, and eligibility.

### 2.4.1. Identification

In the first stage, the keywords were identified and expanded by looking for similar or relevant terms in dictionaries, thesauruses, and previous research. To make the search process more accessible and to limit the results to relevant articles, a combination of symbols and coding, such as field codes, Boolean operators (AND, OR), wildcards, and truncation, were used to connect the keywords. The search strings were developed and used on Scopus and ScienceDirect after all keywords were determined (Table 1). Different search strings were used between Scopus and ScienceDirect due to some of the characters not being accepted as keywords.


**Table 1.** The search strings.

### 2.4.2. Screening

A total of 314 articles were automatically screened using the sorting function available in the databases by selecting the predefined inclusion and exclusion criteria (Table 2). The first criterion decided was the article category, with the researchers agreeing to focus solely on research articles because they are classified as primary sources and provide actual data [31,34]. As a result, publications other than research articles were excluded from the current evaluation, including systematic reviews, review papers, meta-analyses, meta-syntheses, proceedings, books, book chapters, and book series. Aside from that, the current study solely looked at articles written in English. Therefore, publications in other languages were not considered. Moreover, articles' acceptable timeline to be included in the review was six years (2016–2021). There were 240 publications removed from the study because they did not fit the criteria. Five articles were identified to be duplicated during the screening process and thus were removed. The remaining 69 articles were found and prepared for the next step in the process: eligibility.

**Table 2.** The inclusion and exclusion criteria.


### 2.4.3. Eligibility

The researchers manually examined the remaining 69 articles to ensure they were fit to be included in the present study to achieve the study's objectives by thoroughly reading the articles' titles and abstracts. A total of 61 articles were excluded because the articles focus on other types of cancers rather than breast cancer, other types of copolymers rather than PCL-PEG copolymers, and polymersomes and nanoparticles rather than micelles. As a result, eight articles were selected for the next process: quality appraisal.

### *2.5. Quality Appraisal*

Quality appraisal was conducted to assess the quality of the articles' content. Two authours independently examined eight papers and categorised them as high, medium, or poor quality based on the pre-set criteria. The criteria were developed in response to the systematic review's research questions. Mutual agreement between authours was practiced during the rating process to eliminate bias. As a result, data abstraction and analysis were carried out in eight papers.

### *2.6. Data Abstraction and Analysis*

The data abstraction was done in response to the formulated research question that had been developed. Any data from the reviewed researchers that could be used to answer the research question was retrieved and tabulated. Thematic analysis was then used to find the themes and sub-themes from the abstracted data based on patterns, similarities, and linkages. The creation of topics was the initial step in the thematic analysis. The researchers attempted to find the patterns that appeared to connect the abstracted data from all eight pieces of study in this step. Any related or comparable data was organised, and five themes were eventually produced. The researchers repeated the process for each new theme, yielding six sub-themes in all (Table 3). The researchers reviewed the data's accuracy and discussed any anomalies in the resulting themes and sub-themes with one another to verify the data's relevance and reliability. The researchers then named the five themes: synthesis and characterisation of PCL-PEG, preparation of micelles, characterisation of micelles, drug delivery study, and anti-tumour efficacy (Table 3).

**Table 3.** The themes and sub-themes.


## **3. Results**

### *3.1. Selected Articles' Background*

Eight selected articles were successfully obtained for the current review (Figure 1). Five themes were developed based on the thematic analysis: synthesis and characterisation of PCL-PEG, preparation of micelles, characterisation of micelles, drug release study, and anti-tumour efficacy. Six sub-themes resulted from further study of the themes. From the eight selected papers, one was published in 2016 [35], four were published in 2017 [36–39], two were published in 2018 [40,41], and one was published in 2019 [42].

**Figure 1.** The flow diagram of the systematic literature review (adapted from Mohamed Shaffril et al. [31]).
