Near-Infrared Light Irradiation Induced Mild Hyperthermia Enhances Glutathione Depletion and DNA Interstrand Cross-Link Formation for Efficient Chemotherapy

Abstract

DNA alkylating agents generally kill tumor cells by covalently binding with DNA to form interstrand or intrastrand cross-links. However, in the case of cisplatin, only a few DNA adducts (<1%) are highly toxic irreparable interstrand cross-links. Furthermore, cisplatin is rapidly detoxified by high levels of intracellular thiols such as glutathione (GSH). Since the discovery of its mechanism of action, people have been looking for ways to directly and efficiently remove intracellular GSH and increase interstrand cross-links to improve drug efficacy and overcome resistance, but there has been little breakthrough. Herein, we hypothesized that the anticancer efficiency of cisplatin can be enhanced through iodo-thiol click chemistry mediated GSH depletion and increased formation of DNA interstrand cross-links via mild hyperthermia triggered by near-infrared (NIR) light. This was achieved by preparing an amphiphilic polymer with platinum(IV) (Pt(IV)) prodrugs and pendant iodine atoms (iodides). The polymer was further used to encapsulate IR780 and assembled into Pt−I−IR780 nanoparticles. Induction of mild hyperthermia (43 °C) at the tumor site by NIR light irradiation had three effects: (1) it accelerated the GSH-mediated reduction of Pt(IV) in the polymer main chain to platinum(II) (Pt(II)); (2) it boosted the iodo-thiol substitution click reaction between GSH and iodide, thereby attenuating the GSH-mediated detoxification of cisplatin; (3) it increased the proportion of highly toxic and irreparable Pt-DNA interstrand cross-links. Therefore, we find that mild hyperthermia induced via NIR irradiation can enhance the killing of cancer cells and reduce the tumor burden, thus delivering efficient chemotherapy.

Radiation-Associated Angiosarcoma of the Breast and Chest Wall Treated with Thermography-Controlled, Contactless wIRA-Hyperthermia and Hypofractionated Re-Irradiation

“…To address this challenge, modified fractionation schedules such as hyperfractionation [20] or hypofractionation are used, with the latter combined with concurrent hyperthermia (HT) as a radiosensitizer [21,22]. Radiosensitizing effects of HT include (a) an improved oxygenation as a consequence of increased blood flow at times of re-RT [23,24], (b) depletion of glutathione levels [25], and (c) inhibition of DNA repair [26]. In addition, there is evidence that mild HT (39 • C-43 • C) can activate anti-tumor immune responses (e.g., [27]).…”

Low-Temperature Photothermal Therapy: Strategies and Applications

“…In addition, due to the reduced phototoxicity and enhanced stability of some chemodrugs at moderate temperatures, decreasing the temperature used to kill tumors by controlling light intensity, blocking HSPs, or interfering with other thermoresistance-related signal pathways makes the combined use of chemotherapy and mild PTT an appealing choice for cancer treatments. Furthermore, the administration of chemodrugs can compensate for the insufficient heat damage, thus realizing low-temperature PTT [ 159 – 177 ]. For instance, Sherlock et al fabricated an ultrasmall nanocrystal (FeCo/GC) containing a single crystalline iron-cobalt core surrounded by a single- or few-layer graphitic carbon (GC) shell, which could serve as a PTA and an MRI contrast agent [ 159 ].…”

“…In addition to the weakly acidic pH of TME, the overexpression of GSH in cancer cells can be also used to achieve stimuli-responsive drug release. Recently, a NP based on the DNA alkylating agent cisplatin was prepared by using an amphiphilic polymer containing a platinum(IV) (Pt(IV)) prodrug and pendant iodides [ 177 ]. On the one hand, the Pt(IV) on the main chain of the polymer could be reduced by GSH to obtain cisplatin and result in the breakage of the polymer.…”

“…(d) Scheme showing the significantly elevated cancer treatment efficiency of Pt-I-IR780 NPs (compared with cisplatin) achieved via low-temperature PTT-enhanced chemotherapy. (c, d) Reprinted with permission from Reference [ 177 ]. Copyright 2020, American Chemical Society.…”

Stimuli Responsive Nitric Oxide-Based Nanomedicine for Synergistic Therapy

“…Globally, cancer is one of the most serious diseases threatening human health. Despite the rapid advances made in diagnosis and treatment technologies, it remains a great challenge due to the heterogeneity and complexity of tumors themselves [1][2][3][4]. Therefore, basic and clinical studies for effective cancer treatment are still in desperate need in order to improve the health of human beings [5][6][7][8].…”