Zwitterionic Polymer Coating of Sulfur Dioxide‐Releasing Nanosystem Augments Tumor Accumulation and Treatment Efficacy

Abstract

Multiple drug resistance (MDR) exhibited by cancer cells and low intratumor accumulation of chemotherapeutics are the main obstacles in cancer chemotherapy. Herein, the preparation of a redox‐responsive sulfur dioxide (SO2)‐releasing nanosystem, with high SO2‐loading capacity, aimed at improving the treatment efficacy of cancers exhibiting MDR is described. The multifunctional nanomedicine (MON‐DN@PCBMA‐DOX) is designed and constructed by coating mesoporous organosilica nanoparticles with a zwitterionic polymer, poly(carboxybetaine methacrylate) (PCBMA), which can concurrently load SO2 prodrug molecules (DN, 2,4‐dinitrobenzenesulfonylchloride) and chemotherapeutics (DOX, doxorubicin). The generated SO2 molecules can sensitize cells to chemotherapy and overcome the MDR by downregulating the expression of P‐glycoprotein. Furthermore, the PCBMA coating prolongs the blood circulation time of the inner core, leading to an increased intratumor accumulation of the nanomedicine. Owing to the prolonged blood circulation, enhanced tumor accumulation, and SO2 sensitization of cells to chemotherapy, the nanomedicine exhibits excellent tumor suppression with a tumor inhibition rate of 94.8%, and might provide a new platform for cancer therapy.

A sulfur dioxide polymer prodrug showing combined effect with doxorubicin in combating subcutaneous and metastatic melanoma

“…PDDN showed effective anti-tumor activity, which indicated that the SO 2 -releasing polymer prodrug was efficient in tumor-killing. The anti-tumor mechanism of SO 2 may be ascribed to the oxidative properties of SO 2 as well as its ability to increase intracellular ROS, which induced the death of the tumor cells [ [25] , [26] , [27] , [28] , [29] ]. At an equivalent drug concentration, the order of the cytotoxicity of the tested formulations was as follows: PDDN-DOX ＞ DOX ＞ PDDN.…”

“…Gas therapy refers to the use of gas molecules, such as hydrogen (H 2 ), hydrogen sulfide (H 2 S) and nitric oxide (NO), for treating diseases, which has been recognized as a promising “green treatment” for cancer therapy [ [22] , [23] , [24] , [25] , [26] ]. As a member of the gases family, sulfur dioxide (SO 2 ) has attracted much attention in inhibiting tumor growth in recent years [ [27] , [28] , [29] , [30] , [31] , [32] ]. To achieve controlled and targeted drug release, various stimuli-activated SO 2 -releasing nanoplatforms have been prepared for enhanced cancer treatment.…”

“…For instance, our group developed a glutathione (GSH)-responsive SO 2 polymer prodrug nanovehicle for combating drug-resistance in breast cancer treatment or enhancing the photodynamic therapy via simultaneous depletion of GSH and elevation of reactive oxygen species (ROS) in tumor cells [ 27 , 28 ]. Furthermore, Yang et al prepared a redox-responsive SO 2 -releasing nanoparticle coated with a zwitterionic polymer to achieve increased drug accumulation at the tumor site and subsequently improve cancer treatment [ 29 ]. In addition, light-trigged and pH-triggered SO 2 -releasing nanoplatforms have also been reported for precise gas or gas-assisted therapy of cancer [ [30] , [31] , [32] ].…”

Strategies for engineering advanced nanomedicines for gas therapy of cancer

“…The disulphide-linking shell was decomposed under GSH stimulation in HCC cells, causing release of NPQ ( O 2 -(2,4-dinitro-5-{[2-(β-d-galactopyranosyl olean-12-en-28-oate-3-yl)-oxy-2-oxoethyl] piperazine-1-yl}phenyl) 1-(methylethanolamino)diazen-1-ium-1,2-dilate) which subsequently decomposed into NO under catalysis of GSTπ. We developed mesoporous organosilica nanoparticles (MON) with a disulphide framework to load 2,4-dinitrobenzenesulphonylchloride (DN, a SO 2 prodrug) for GSH-responsive carrier degradation and SO 2 release [ 35 ]. Chen et al .…”

BSA-Stabilized Mesoporous Organosilica Nanoparticles Reversed Chemotherapy Resistance of Anaplastic Thyroid Cancer by Increasing Drug Uptake and Reducing Cellular Efflux

“…Nowadays, mesoporous nanoparticles have attracted extensive interest because their high loading capacity is suitable for drug loading and delivery (Yao et al, 2017;Teng et al, 2018;Chen et al, 2019Chen et al, , 2020. Among these mesoporous materials, considerable attention has been paid to mesoporous organosilica nanocapsules (MONPs) since their excellent biocompatibility, large surface area, adjustable pore volume, and easily modified surface (Tao et al, 2018;Teng et al, 2018;Yao et al, 2020). MONPs are synthesized using organic group-bridged siloxanes as silicon sources, which is different from pure Si-O-Si groups of inorganic mesoporous silica nanoparticles (MSNs) (Chen et al, 2013;Teng et al, 2014b;Croissant et al, 2015).…”