Co-delivery of paclitaxel and curcumin by biodegradable polymeric nanoparticles for breast cancer chemotherapy
Graphical abstract
In this study, the PTX-CUR-NPs were developed to co-deliver paclitaxel and curcumin by a self-assembly method using the biodegradable copolymer PCL-PEG-PCL as carriers. The PTX-CUR-NPs showed outstanding therapeutic effect against breast cancer. It may be a potential therapeutic agent in breast cancer chemotherapy.
Introduction
The incidence of cancer is increasing day by day throughout the world. It is predicted that the new cases of cancers would rise from 18.1 million in 2018 to 29.4 million in 2040, leading to death of people of age group <70 in >50% of countries (Palacios-Moreno et al., 2019). Breast cancer is one of the most common types of cancers among women and it is also one of the major causes of mortality in female patients (Fan et al., 2019). Some recent studies indicated that the incidence of breast cancer tends to be younger (Göhler et al., 2017, Sawada et al., 2017). The chemotherapy is considered as the most frequently used conventional treatment strategy for breast cancer. However, the chemotherapy is associated with several disadvantages. For example, chemotherapy could exert toxicity toward normal tissues at optimal doses leading to high systemic toxicity as well as low therapeutic effectiveness (Alemi et al., 2018), which in turn affects the quality life of patients. Additionally, the development of drug resistance is also a serious concern associated with chemotherapeutics. To address these challenges for the treatment of breast cancer, it is urgently required to develop a suitable drug delivery system for the effective delivery of the anticancer drugs to the tumor site, thereby improving their efficacy and bio-safety.
It is well-known that cancer is a complex disease that involves various cell signaling pathways. Therefore, to treat a particular type of cancer, it is highly difficult to select suitable chemotherapeutic drugs that could exert the best therapeutic efficacy with little side effect. It is currently well established that the combination therapy using two or more chemotherapeutic drugs might improve the therapeutic efficacy and reduce their side effects (Gawde et al., 2018). When different chemotherapeutic drugs are combined, each drug employed at optimum doses that would not exhibit intolerable side-effects. The combination of chemotherapeutic medications acts on different molecular targets, thereby increase the possibility of effective eradication of cancer. Genomic studies have earlier confirmed the heterogeneity of tumors (Lawrence et al., 2013). Although the starting cells of cancer are the same, those cells might alter their properties after continuous cell division process. While some of the resulting cells in a tumor may be sensitive toward one chemotherapeutic drug, others might be sensitive toward another one. Moreover, those patients treated a single chemotherapeutic drug are likely to undergo clonal evolution, which causes development of degree of heterogeneity in the treatment process, leading to affecting the response to treatment, therapeutic failure or drug resistance (a). In this context, various research groups have recently focused on combination therapy, which involves combination of two or more drugs at low doses (Do et al., 2018, Liu et al., 2016). The earlier reports demonstrated that the use of combination chemotherapy against various cancers can lead to improvement of the survivability or better response to treatment (Almansour et al., 2017, Kim et al., 2016).
Paclitaxel (PTX), extracted from the bark of Pacific Yew (Taxus brevifolia) is a potent anticancer drug and has been used to treat various types of cancers, including breast, ovarian, cervical, pancreatic, and others (Schwarz et al., 2009). However, the use of PTX has several limitations that hamper its clinical efficacy (Sau et al., 2017). For instance, PTX cannot distinguish cancer cells from normal cells, which usually gives rise to adverse side effects (Lichtman et al., 2012). Further, the poor water solubility of PTX is another problem for its practical clinical application (Yao et al., 2017). Apart from PTX, curcumin (CUR), an anti-inflammatory polyphol derived from Curcuma longa (turmeric), is widely used in traditional Indian medicine for the treatment of cancer as well as respiratory diseases (Zaman et al., 2016). The earlier study demonstrated that CUR could inhibit dynamic instability of microtubules, activate mitotic sites, and induce apoptosis in MCF-7 cells (Banerjee et al., 2010). However, just like PTX, the clinical application of CUR is also limited due to its low solubility and poor bioavailability (Alemi et al., 2018). Considering these limitations and the advantages of combination therapy, it could be a good approach to develop a new drug delivery system to deliver PTX and CUR simultaneously, for the effective treatment of cancers. Fortunately, polymer chemistry and nanotechnology have brought a promising solution for the development of potent drug delivery systems that could exhibit efficient combination therapy. A large number of studies demonstrated that nanoparticles have great advantages for cancer therapy, including sustained release of drugs, targeting of cancer cells, high bioavailability and so on. Meanwhile, polymeric nanoparticles have numerous merits in drug delivery systems (DDSs). For instance, they have a low risk of immunogenicity as well as disease transmission and are highly stable in the systemic circulation (De Souza et al., 2010). Moreover, their hydrophobicity prevents their capture by the reticuloendothelial system, leading to prolong the circulation time in the body system (Mora-Huertas et al., 2010). Additionally, the small-sized polymeric nanoparticles (10–200 nm) are prone toward enhanced permeability and retention (EPR) effect, which is helpful for the accumulation and retention of the nanoparticulate DDS at the tumor tissue, leading to target cancer cells (Zhao et al., 2019). Therefore, polymeric nanoparticles are considered as promising vehicle for the delivery of anticancer drugs.
In the present study, we have synthesized the tri-block copolymer poly (ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) and used this to develop a biodegradable nanoparticulate DDS PTX-CUR-NPs for the effective co-delivery of PTX and CUR (Fig. 1A). PCEC is a linear polyester polymer, which consists of a hydrophobic PCL block and a hydrophilic PEG block. We have chosen PCEC polymeric NPs for the development of DDS due to their various advantages including low toxicity, good biocompatibility, biodegradability, amphiphilic property as well as ease to produce (Zhang et al., 2012). We have speculated that by employing PCEC as nano carrier, the water solubility of PTX and CUR could be improved and their therapeutic effect against tumor would be enhanced.
To date, several researchers investigated the anti-tumor efficacy of PTX and CUR co-loaded nanoparticles on different cancers such as pancreatic cancer, cervical carcinoma and glioma (Cui et al., 2016, Do et al., 2018; Jamal-Hanjani et al., 2015). However, most of these studies were focused on in vitro assessment, and only few demonstrated about in vivo evaluation. Herein, we have demonstrated that PTX and CUR co-loaded biodegradable nanoparticulate DDS significantly inhibited the proliferation of MCF-7 breast cancer cells than the control experiments. Moreover, the intravenous administration of the DDS to BALB/c nude mouse xenografted with MCF-7 cells exhibited significant tumor growth inhibition while reducing side effects as compared to the control groups.
Section snippets
Materials, cells, and animals
Paclitaxel (PTX; ≥98%) was purchased from Chengdu Manchester Biotechnology Co., Ltd. (Chengdu, China). Curcumin (CUR; ≥98%) was obtained from Aladdin Reagent Co. Ltd. Poly (ethylene glycol) (PEG, Mn = 2000) and ε-caprolactone (ε-CL) were purchased from Alfa Aesar (USA). Stannous octoate [Sn(Oct)2], and MTT were procured from Sigma (St. Louis, MO). Dimethyl sulfoxide (DMSO) (BIOFLU, New Zealand), acetonitrile and methyl alcohol (HPLC grade) were obtained from Kelong Co. Ltd. (Chengdu, China).
Preparation and characterization of SLN
In this study, the tri-block PCEC copolymer was synthesized by molten ring-open copolymerization. The spectra of FT-IR (Fig. S1) and 1H NMR (Fig. S2) (see the supplementary material) confirmed the information of the chemical of structure of the PCEC copolymer. PTX-CUR-NPs with different mass ratios of PTX/CUR (2:1, 1:1, 1:2 wt/wt) were synthesized through self-assembly as shown in Fig. 1A. The particle size, DL, and EE of PTX-CUR-NPs were thoroughly characterized and presented in Table 1.
Among
Discussion
Breast cancer is one of the most widespread malignant tumors that threaten health and life of women throughout the world (Ma et al., 2019). To date, chemotherapy can improve survival rate of breast cancer patients and remains an essential treatment strategy for breast cancer. Of late, researchers have introduced advanced therapeutic treatment strategies by combining two or more drugs, as combination of multiple drugs are believed to be more effective than a single drug, while reducing their
Conclusion
In the present study, we have developed the PCEC nanoparticles for the efficient co-delivery PTX and CUR. The synthesized nanoparticles exhibited small size, spherical morphology and narrow particle size distribution, which are suitable for intravenous injection. In vitro drug release study demonstrated that PTX and CUR could release in sustained manner from the DDS PTX-CUR-NPs. Further, the administration of PTX-CUR-NPs to MCF-7 cells exhibited dose-dependent toxicity with enhanced cellular
CRediT authorship contribution statement
Kang Xiong: Writing - original draft, Data curation. Yan Zhang: Funding acquisition, Methodology. Qian Wen: Data curation. Jia Luo: Investigation. Yun Lu: Visualization, Investigation. ZhouXue Wu: Data curation. BiQiong Wang: Data curation. Yue Chen: Methodology. Ling Zhao: Methodology. ShaoZhi Fu: Project administration, Conceptualization, Funding acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This study was supported by the Open Project Program of Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, the Union Project of Luzhou Municipal People's Government-Southwest Medical University (2018LZXNYD-ZK06), the project from the Affiliated hospital of Southwest Medical University (2017-PT-28), the Youth Fund Project of Southwest Medical University (2016-ZRQN-116, 2019-ZQN-169).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Yan Zhang and Kang Xiong contributed equally to this work.