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γ-Ray-Triggered Drug Release of Reactive Oxygen Species-Sensitive Nanomedicine for Enhanced Concurrent Chemoradiation Therapy.

ABSTRACT: Radiotherapy (RT) combined with chemotherapy remains a dominant therapeutic manner in clinical tumor treatment, which is irreplaceable in a short term. To seek an intrinsic connection of combined chemoradiation therapy and maximize the antitumor efficacy, we developed a reactive oxygen species (ROS)-sensitive nanomicelle drug delivery system based on a self-assembled amphiphilic polymer, hyaluronic acid-graft-poly-(propylene sulfide) (HA-PPS). A chemical radiosensitizer, doxorubicin (DOX), was encapsulated into the core of HA-PPS nanomicelles, constituting the DOX-loaded nanomicelles (HA-PPS@DOX NMs) with a spherical structure of around 205.10 ± 11.33 nm diameter with a narrow polydispersity index (PDI) of 0.135 ± 0.01. When combined with RT, the ROS-sensitive HA-PPS@DOX NMs disintegrated and released great drug cargos, which further enhanced cytotoxicity. Meanwhile, as a radiosensitizer, the released DOX sensitized cancer cells to radiotherapy, which has been confirmed by an enhanced sensitizer enhancement ratio (SER) value of 1.78 contributing to the increased cytotoxicity of concurrent chemoradiation tumor therapy, as evidenced by the improvement of half maximal inhibitory concentration (IC₅₀ value) of DOX from 2.316 to 0.8235 μg/mL. Moreover, in vivo studies revealed that HA-PPS@DOX NMs exhibited prolonged circulation time and improved tumor accumulation. Particularly, the released DOX triggered by radiation strengthened radiotherapy sensitization in return. Consequently, these superiorities of HA-PPS@DOX NMs shown by the concurrent chemoradiation tumor therapy resulted in an ideal tumor inhibition rate of 70.4%, thus providing a promising ROS-sensitive nanomedicine for cancer treatment.

SUBMITTER: Yu Y

PROVIDER: S-EPMC8340104 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Thymoquinone (TQ) is the main biologically active constituent of Nigella sativa. Many studies have confirmed its anticancer actions. Herein, we investigated the different anticancer activities of, and considered resistance mechanisms to, TQ. MTT and clonogenic data showed TQ's ability to suppress breast MDA-MB-468 and T-47D proliferation at lower concentrations compared to other cancer and non-transformed cell lines tested (GI50 values ≤ 1.5 µM). Flow-cytometric analyses revealed that TQ consistently induced MDA-MB-468 and T-47D cell-cycle perturbation, specifically inducing pre-G1 populations. In comparison, less sensitive breast MCF-7 and colon HCT-116 cells exhibited only transient increases in pre-G1 events. Annexin V/PI staining confirmed apoptosis induction in MDA-MB-468 and HCT-116 cells, which was continuous in the former and transient in the latter. Experiments revealed the role of reactive oxygen species (ROS) generation and aneuploidy induction in MDA-MB-468 cells within the first 24 h of treatment. The ROS-scavenger NAD(P)H dehydrogenase (quinone 1) (NQO1; DT-diaphorase) and glutathione (GSH) were implicated in resistance to TQ. Indeed, western blot analyses showed that NQO1 is expressed in all cell lines in this study, except those most sensitive to TQ-MDA-MB-468 and T-47D. Moreover, TQ treatment increased NQO1 expression in HCT-116 in a concentration-dependent fashion. Measurement of GSH activity in MDA-MB-468 and HCT-116 cells found that GSH is similarly active in both cell lines. Furthermore, GSH depletion rendered these cells more sensitive to TQ's antiproliferative actions. Therefore, to bypass putative inactivation of the TQ semiquinone metabolite, the benzylamine analogue was designed and synthesised following modification of TQ's carbon-3 atom. However, the structural modification negatively impacted potency against MDA-MB-468 cells. In conclusion, we disclose the following: (i) The anticancer activity of TQ may be a consequence of ROS generation and aneuploidy; (ii) Early GSH depletion could substantially enhance TQ's anticancer activity; (iii) Benzylamine substitution at TQ's carbon-3 failed to enhance anticancer activity.

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γ-Ray-Triggered Drug Release of Reactive Oxygen Species-Sensitive Nanomedicine for Enhanced Concurrent Chemoradiation Therapy.

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