Dual-modal imaging-guided theranostic nanocarriers based on 2-methoxyestradiol and indocyanine green
Graphical abstract
Introduction
New tumor therapies based on nano-drug delivery systems have a promising potential for the diagnosis and treatment of cancer (Xu et al., 2019, Zhang et al., 2017). However, significant challenges remain in developing nanopharmaceuticals that integrate multiple imaging and treatment capabilities into a single nanoplatform (Xu et al., 2017). Nano-scale photonics improves the accuracy and effectiveness of photothermal therapy (PTT) agents combined with nanopharmaceuticals by accurately controlling the conversion of light to other forms of energy for the real-time monitoring of drug delivery and the physical evaluation of tumors, which can be applied to achieve personalized treatment (Kapp et al., 2017, Li et al., 2019). Compared to non-optical methods for diagnosis and treatment, optical technologies have a higher spatial and temporal resolution, and specifically, non-invasive phototherapy technology has attracted widespread attention for its effective tumor destruction and minimal damage to normal tissues (Dissanayake et al., 2017, Chen et al., 2016, Plan Sangnier et al., 2018). PTT is the main phototherapy method used in clinical cancer treatment (Agrawal et al., 2017, Chen et al., 2016, Dai et al., 2019). In PTT, near-infrared (NIR) light radiation is used to excite a photothermic agent, which generates heat that raises the local temperature to induce hyperthermia in the tumor tissue, thereby mediating tumor ablation (Hu et al., 2018, Mura et al., 2018, Nieberler et al., 2017).
It is well known that the longer the wavelength, the stronger the light penetration and the lower the absorption coefficient of NIR light in human tissues (Mura et al., 2013, Pang et al., 2016, Cong et al., 2020). Therefore, NIR light (700–900 nm) with strong tissue penetration, high light energy utilization, low light scattering, and low phototoxicity is the preferred light source in clinical applications (Zhang et al., 2014, Zhang et al., 2017). The new photosensitizer indocyanine green (ICG; Figure S1) has been approved by the US Food and Drug Administration (FDA) as a diagnostic dye (Carr et al., 2018, Choi et al., 2013). Due to its excellent light-to-heat conversion ability in the NIR light region, it is used in light-to-heat tumor treatment regimens (Mura et al., 2013, Iyer et al., 2013, Guan et al., 2017). ICG emits strong fluorescence and photoacoustic (PA) signals in the NIR wavelength region, which can be utilized for integrating the diagnosis and treatment of tumors in vivo, and therefore, ICG is widely used as a probe for the diagnosis and treatment of diseases (Kneidl et al., 2014, Kunjachan et al., 2014). However, as a potential photothermal agent, ICG also has some disadvantages, such as poor stability in aqueous solution, rapid degradation in the body, and lack of tissue targeting. Therefore, improving the stability and tumor specificity of ICG is an urgent medical need.
The development of suitable nanomaterials represents an effective method to circumvent the limitations associated with ICG. Nanoparticles can specifically deliver drugs through enhanced permeation and retention (EPR), which can increase the drug’s effect on tumor target sites (Liu et al., 2017). ICG has been encapsulated into a variety of polymer- and lipid-based nanostructures, including thermosensitive liposomes (TSLs) that are prepared by a heat-induced phase transition process from a solid gel phase to a liquid crystal phase to generate an ideal heat-sensitive carrier (Neumann et al., 2019). Li et al. synthesized “smart” folic acid (FA)-modified polymeric nanocapsules (FA-ICG), which improved the stability of ICG in vivo and achieved targeted photothermal treatment of tumors (Zhang et al., 2018). These research results demonstrated that loading ICG onto nanocarriers has significantly improved the in vivo stability, circulation time, and tumor targeting of this agent. However, due to the uneven heat distribution inside the tumor and the heat resistance of the tumor cells, the use of ICG-TSLs might have limited therapeutic effects (Yan et al., 2016). Interestingly, it has been reported that a combination therapy consisting of different drugs and mechanisms has improved the efficiency of PTT treatment. Specifically, combining PTT with chemotherapy, photodynamic therapy, or sonodynamic therapy can generate a synergistic antitumor effect that significantly improves the antitumor therapy (Hu et al., 2020, Wang et al., 2018).
Malignant melanoma is the deadliest type of skin cancer. It is associated with high malignancy, early metastasis, and high mortality (Wang et al., 2017). Early diagnosis and early treatment are critical. Surgical resection is now mostly used when the disease is limited, but it is associated with a poor prognosis in the most advanced patients. Among potential treatment options, 2-methoxyestradiol (2-ME; Figure S2) is an endogenous metabolite with antitumor effects and good biological safety (Sheng et al., 2018). However, its bioavailability is extremely low due to poor water solubility and a short half-life, limiting its use as an anticancer drug.
To improve treatment efficacy, agents have been developed that exploit the EPR effect for relatively large nanoparticles to passively target the tumor microenvironment (Xu et al., 2019, Zhang et al., 2019). However, the amount of drug that can enter the tumor microenvironment is limited and may not be enough for successful treatment (Niidome et al., 2006). Thus, there is a need to design drug delivery systems that ensure the active targeting of antitumor agents (Zhang et al., 2017). Our project was focused on developing a single nanocarrier that encapsulated both ICG and 2-ME. The combination of PTT and chemotherapy guided by NIR fluorescence/photoacoustic imaging was predicted to enhance the antitumor properties (Pang et al., 2016). The multifunctional drug delivery system is shown in the Graphical Abstract. The cRGDyk cyclic peptide is grafted onto the outer surface of the TSL as the targeting agent, and 2-ME and ICG are loaded into the hydrophobic cavity of the TSL as therapeutic agents. The antitumor mechanism of cRGDyk-mediated targeting of 2-ME and ICG-TSLs (cRGDyk-2-ME@ICG-TSLs) includes the following aspects: (1) the agent formulation selectively translocates to tumor sites and enters the tumor cells via the EPR effect and active targeting; (2) the cRGDyk-2-ME@ICG-TSL is designed as a diagnostic and therapeutic probe to track tumor areas, which is essential for focusing the laser beam on the tumor area to achieve satisfactory antitumor properties by efficiently converting the NIR light energy into heat; (3) under NIR laser radiation, the activated ICG is expected to produce hyperthermia, thereby exerting the PTT effect and triggering the release of 2-ME from the TSL; (4) the released 2-ME will function as a chemotherapeutic agent, and, in combination with the PTT effect produced by ICG, it can potentially generate a synergistic antitumor effect and efficiently block tumor cell proliferation.
Section snippets
Materials
Indocyanine green (ICG, 98% purity) was purchased from Dalian Meilun Biological Co., Ltd. (China). 2-Methoxyestradiol (2-ME, 99% purity) was provided internally by researchers at Zhengzhou University School of Pharmacy (China). 1,2-Distearoylsn-glycero-3-phosphoethanolamine-N-[(polyethyleneglycol)-2K] (DSPE-PEG2K), phospholipid polyethylene glycol-RGD peptide (cRGDyk-DSPE-PEG2K), dipalmitoylphosphatidylcholine (DPPC), and cholesterol (Chol) were purchased from Xian Ruixi Biological Technology
Characterization of cRGDyk-2-ME@ICG-TSLs
Three TSL formulations, cRGDyk-ICG-TSLs, cRGDyk-2-ME-TSLs, and cRGDyk-2-ME@ICG-TSLs, were prepared via lipid hydration and purified by extrusion. Table 1 lists critical TSL characteristics such as particle size (shown in Fig. 1a), polydispersity index, EE, and drug loading. The TSL zeta potential values (Fig. 1b) ranged between − 12.4 and − 17.4 mV, indicating that the preparation was very stable and did not have a tendency toward vesicle aggregation and fusion (Pang et al., 2016). The TEM
Discussion
In this study, we successfully combined temperature-controlled drug release with NIR fluorescence and photoacoustic dual-modality imaging to create a multifunctional antitumor drug carrier, cRGDyk-2-ME@ICG-TSL, for use with PTT and chemotherapy. This system has several advantages. First, 2-ME and ICG were incorporated into TSLs with relatively high packaging efficiency to overcome the disadvantages of free reagents. Second, the PTT effect of ICG enhanced the release of 2-ME loaded into TSLs,
CRediT authorship contribution statement
Nan Zhang: Conceptualization. Yue Xu: Methodology, Software, Data curation, Writing - original draft. Xiangying Xin: Writing - review & editing, Resources. Pengchao Huo: Investigation, Supervision. Yan Zhang: Investigation. Hui Chen: Investigation. Nannan Feng: Resources. Quanling Feng: Project administration, Funding acquisition. Zhenzhong Zhang: Project administration, 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
I would particularly like to express my gratitude to Simin Wu. In the process of writing the manuscript, I am very grateful to her for completing some work, including the modification of the manuscript picture. At the same time, I also want to thank my family as well as friends for their help and support.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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