Deep‐Penetrating Triple‐Responsive Prodrug Nanosensitizer Actuates Efficient Chemoradiotherapy in Pancreatic Ductal Adenocarcinoma Models

Abstract

Chemoradiotherapy (CRT) is the most accepted treatment for locally advanced pancreatic ductal adenocarcinoma (PDAC) and can significantly improve the R0 resection rate. However, there are few long‐term survivors after CRT. Although some polymer nanoparticles have shown potential in alleviating the dose‐limiting toxicity and assisting the chemotherapy of PDAC, there are few efficient nanosensitizers (NS) available for CRT of this malignancy, especially in the context of its hypoxic nature. Herein, based on the biological features of PDAC, a γ‐glutamyl transpeptidase (GGT)/glutathione (GSH)/hypoxia triple‐responsive prodrug NS to overcome the biological barrier and microenvironmental limitations confronted by CRT in PDAC is developed. Due to triple‐responsiveness, deep tumor penetration, GSH/hypoxia‐responsive drug release/activation, and hypoxia‐induced chemoradio‐sensitization can be simultaneously achieved with this NS. As a result, tumor shrinkage after CRT with this NS can be observed in both subcutaneous and orthotopic PDAC models, foreshadowing its potential in clinical neoadjuvant CRT.

Prodrug Nanosensitizer Overcomes the Radiation Resistance of Hypoxic Tumor

“…Composite nanodroplets formed by phospholipids conjugated with cisplatin prodrug and perfluoro-15-crown-5 can bring oxygen to hypoxic tumors and cause severe DNA damage during RT . As a typical member of the electron-affinic nitroimidazoles family, metronidazole (MN) is not only an efficient hypoxic radiosensitizer but also an important component of the hypoxia-responsive drug vehicle due to the bioreduction-induced hydrophobicity–hydrophilicity transition, ,, as confirmed by our previous works. , …”

“…38 As a typical member of the electron-affinic nitroimidazoles family, 39 metronidazole (MN) is not only an efficient hypoxic radiosensitizer 40 but also an important component of the hypoxia-responsive drug vehicle due to the bioreduction-induced hydrophobicity−hydrophilicity transition, 39,41,42 as confirmed by our previous works. 24,25 Despite the advances in hypoxia-directed drug delivery systems, the tumor hypoxia heterogeneity may also hinder their application. Due to the uncontrolled proliferation of cancer cells and hypervascularity of some solid tumors, the hypoxic region is often located at 100−200 μm away from vessels, significantly restricting the activation of hypoxiadirected drugs.…”

“…The basic principle of radiation therapy (RT), one of the most widely used clinical therapies against malignant tumors, is the direct or indirect interaction between the internal materials of cancer cells and high-energy radiation. , The primary effector of ionizing radiation is DNA molecules, and the therapeutic effects are exerted by forming single-strand DNA breakage (SSB) or double-strand DNA breakage (DSB). , These damages further interfere with DNA–protein transcription and translation, resulting in termination of cell proliferation and causing necrosis or apoptosis. − The degree of radiation-induced damage to tumor cells depends highly on the available oxygen, which stabilizes the DNA damage and prevents DNA repair. , However, the hypoxic characteristic of tumor microenvironment may strengthen the radioresistance of cancer cells and eventually cause the failure of RT. , In addition to reoxygenating the tumor microenvironment by oxygen carriers or oxygen generators to alleviate the innate radioresistance, , an alternative way is to sensitize the RT efficiency by some exogeneous molecules, called radiosensitizers. , A variety of substances, such as endogenous radioprotective substances inhibitors, cell cycle arresting agents, DNA repair suppressors, and thymine analogues, have been used to enhance the therapeutic efficiency of RT. , The combinations of RT with some chemotherapeutics (doxorubicin, cisplatin, paclitaxel, etc. ), known as chemoradiotherapy (CRT), has been shown to be vital options for many kinds of clinical cancers. − Except for some clinically available chemotherapeutics, gambogic acid (GA), a naturally occurring heat shock protein (HSP) inhibitor and cytotoxic drug, has also been reported to synergize with RT by producing reactive oxygen species (ROS) and inhibiting the AKT/mTOR signaling pathway. , However, the poor aqueous solubility (less than 0.5 μg/mL) and toxic side effects of GA limit its bioavailability in clinical application . Furthermore, free GA treatment can also cause the senescence of cancer-associated fibroblasts, which subsequently intensifies drug resistance and proliferation of cancer cells through paracrine pathways .…”

Cancer nanomedicine in preoperative therapeutics: Nanotechnology-enabled neoadjuvant chemotherapy, radiotherapy, immunotherapy, and phototherapy

“…Also, some pre-clinical research was preformed simultaneously to broaden the application of nanoparticles in neoadjuvant radiotherapy, especially preoperative chemoradiotherapy (CRT), mainly relying on the superiority of nanomedicine to deliver drugs to the tumor [ [75] , [76] , [77] ]. For example, to overcome the stromal and hypoxic tumor microenvironment and preoperative radioresistance in pancreatic ductal adenocarcinoma (PDAC) and increase the R0 resection rate and long-term survivor after CRT, Xiao Hu et al developed a γ-glutamyl transpeptidase (GGT)/glutathione (GSH)/hypoxia triple-responsive prodrug nanosensitizers SS CMG NPs [ 78 ] ( Fig. 4 ).…”

“…4 Deep-penetrating triple-responsive prodrug nanosensitizer Actuates Efficient CRT in PDAC a. Efficient PDAC tumor accumulation, b. GGT-triggered tumor penetration, c. The potential mechanism of GSH/hypoxia dual-responsive drug release and hypoxic chemo-radio sensitization, and d. Representative in vivo bioluminescence images of orthotopic PDAC models treated as indicated [ 78 ]. Copyright 2022, John Wiley and Sons.…”