Regular Article
Assembly of multifunction dyes and heat shock protein 90 inhibitor coupled to bovine serum albumin in nanoparticles for multimodal photodynamic/photothermal/chemo-therapy

https://doi.org/10.1016/j.jcis.2021.01.052Get rights and content

Abstract

The proangiogenic protein, survivin, is a client protein for heat shock protein 90 (Hsp-90), whose overexpression is induced by photodynamic therapy (PDT), leading to the inhibition of capase-9 and the blockage of apoptosis. The overexpression of Hsp-90 in cancer cells can rapidly acquire thermoresistance during photothermal therapy (PTT), leading to insufficient apoptosis, increased cell viability, and tumor recurrence. A potential approach to block the PTT-induced overexpression of Hsp-90 and the overexpression of survivin is developed by using an Hsp-90 inhibitor and anticancer agent, namely, geldanamycin (GM). These inhibitors also develop a mild-temperature PTT strategy to reach synergistic PDT and PTT efficiency. Thus, Cy7–SQ is designed by a covalent disulfide linkage between a photothermal agent (i.e., canine dye 7 [Cy7]) and a photosensitizer (i.e., squaraine dye [SQ]) for the improved photostability and thermal stability of Cy7 and SQ. The cleavage of the Cy7–SQ linkage by glutathione in a tumor microenvironment increases the efficiency of synergistic PDT and PTT. In the current study, bovine serum albumin (BSA)/Cy7–SQ/GM nanoparticles are developed through the self-assembly of BSA, Cy7–SQ, and GM to accelerate the apoptosis of cancer cells via near-infrared (NIR) laser irradiation, thus realizing Hsp-90-regulated synergistic PDT/PTT combined with chemotherapy.

Introduction

Photodynamic therapy (PDT) has emerged as a promising therapeutic modality for cancer [1], [2]. However, PDT can induce the expression of survivin, a protein inhibitor of apoptosis, in murine and human cancer/tumor cells. As a client protein for heat shock protein 90 (Hsp-90), survivin blocks apoptosis by inhibiting caspase-9 and causes resistance to irradiation, thereby decreasing PDT efficiency [3], [4], [5]. The overexpression of Hsp-90 in cancer cells can rapidly acquire thermoresistance during photothermal therapy (PTT), leading to reduced apoptosis, high cell viability, and tumor recurrence [6].

To improve PDT, studies have mainly concentrated in solving the reactive oxygen species (ROS) scarce capacity of photosensitizer (e.g., to solve the tumor hypoxic and design a new type of photosensitizer to enhance the ROS production rate) [7], [8], [9], [10], [11], [12]. To overcome thermoresistance, PTT is required to exceed over 50 °C, which can induce complete cell necrosis and cause heat damage to the surrounding normal tissues or organs [13], [14], [15]. Sole modal therapy still suffers from low bioavailability, and system and organ toxicity [16]. A promising approach is the combination of PDT and PTT therapy due to its high efficiency and low risk of recurrence [17], [18]. In previous studies [17], [18], [19], the combination of PDT and PTT has been studied to reach an enhanced effect. However, the undesirable overexpression of Hsp-90 and survivin could impair the final therapeutic efficiency. According to the literature, an Hsp-90 inhibitor can inhibit the overexpression of survivin and enhance the efficiency of PDT [3], [4], [5], whereas thermoresistance, which may develop a low-temperature PTT (~43 °C), can be avoided [20].

Therefore, geldanamycin (GM) is used as a natural inhibitor of Hsp-90 to retard the PTT-induced overexpression of Hsp-90 and survivin by blocking client protein binding [21]. GM also exhibits potential antitumor activity in more than 60 cell lines [22], thus resulting in the development of a mild-temperature PTT strategy to attain synergistic PDT and PTT efficiency combined with chemotherapy. Scheme 1 illustrates the self-assembly of bovine serum albumin/canine dye 7–squaraine dye/geldanamycin (BSA/Cy7–SQ/GM) nanoparticles (NPs) for Hsp-90-regulated synergistic PDT/PTT combined with chemotherapy.

Hence, a multifunctional near-infrared (NIR) agent (i.e., Cy7–SQ) is designed by using a photothermal agent (i.e., Cy7) and a photosensitizer (i.e., SQ) (Scheme 1) because the low intensity of NIR (650–900 nm) radiation expresses minimum invasion and deep penetration in skin tissues [23]. Moreover, the typical photostability and thermostability of Cy7 and SQ are enhanced as they are covalently linked through a disulfide bond of soft carbon chains, leading to the formation of an intramolecular dimer due to electrostatic interaction. Consequently, photothermal response is reduced due to the hypsochromic shift of the absorption wavelength. However, the cleavage of the disulfide bond could occur through glutathione (GSH) in a tumor microenvironment, causing the separation of the corresponding photosensitizer and photothermal agent [24]. This separation could generate ROS and heat under different light irradiation for efficient synergistic PDT and PTT.

Section snippets

Materials and methods

Bovine serum albumin (BSA, chromatographically purified), 3-[4,5-dimethylthialzol-2-yl]-2,5-diphenyltetrazolium bromide (MTT, 98%), 1,3-diphenylisobenzofuran (DPBF, 97%) and 2,7-dichlorodihydrofluorescein diacetate (DCFH–DA, 97%) were obtained from Sigma–Aldrich. Cysteine, homocysteine and glutathione were obtained from Thermal Biotechnology Co., Ltd. (Xi’an, China). Dialysis bag (molecular weight 8–14 KD) was purchased from Soleboro Biotechnology Co., Ltd. (Beijing, China). Other chemicals were

Results and discussion

The synthetic route and characteristics of Cy7–SQ are shown in Fig. S1-9 (ESI†). Cy7–SQ, GM, and BSA were self-assembled into stable NPs (BSA/Cy7–SQ/GM) by simply mixing in PBS (Scheme 1). First, the number of Cy7–SQ binding to the BSA was obtained by determining the absorbance spectra when Cy7–SQ was titrated with different concentrations of BSA (Fig. S10). The absorbance spectra revealed that the interaction between BSA and Cy7–SQ is at a molar ratio (BSA:Cy7–SQ) of 1:0.6. Then, the

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 work was financially supported by the National Natural Science Foundation of China (No. U1803283, 21878249, 22078049), the Project of Science and Technology of Social Development in Shaanxi Province (2018JM2008) and the study on the key technique improvement of Xinjiang Licorice planting and quality control of Xinjiang Production & Construction Corps (2018AB012).

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