Cancer cells are more vulnerable to reactive oxygen species (ROS)-mediated oxidative stress than normal cells due to disturbed redox balance. It can be postulated that ROS-generating drug carriers exert anticancer actions, leading to combination anticancer therapy with drug payloads. Here, we report a ROS-generating polyprodrug of cinnamaldehyde (CA) that not only serves as a drug carrier but also synergizes with drug payloads. The polyprodrug of CA (pCA) incorporates ROS-generating CA in the backbone of an amphiphilic polymer through an acid-cleavable acetal linkage. pCA could self-assemble with tumor-targeting lipopeptide (DSPE-PEG-RGD) and encapsulate doxorubicin (DOX) to form T-pCAD micelles. At acidic pH, T-pCAD micelles release both CA and DOX to exert synergistic anticancer actions. Animal studies using mouse xenograft models revealed that T-pCAD micelles accumulate in tumors preferentially and suppress the tumor growth significantly. Based on the oxidative stress amplification and acid-responsiveness, ROS-generating pCAD micelles hold tremendous potential as drug carriers for combination anticancer therapy.
Prodrug-type polymer–drug conjugates based on highly biocompatible functional polyethers are developed through mechanochemical post-polymerization modification. Herein, we design functional epoxide monomers of ethoxyethyl glycidyl ether (EEGE) and azidohexyl glycidyl ether (AHGE) and synthesize diblock copolyethers of PEEGE-b-PAHGE via sequential anionic ring-opening polymerization. Subsequent conversion of the functional monomers to the corresponding hydroxyl and amine groups allows for the preparation of double hydrophilic block copolyethers. Most notably, mechanochemical modification allows for the conjugation of these polymers with a highly hydrophobic and potent anticancer agent, cinnamaldehyde, through an imine linkage. The self-assembly of the resulting polymer–drug conjugates into polymeric micelles is characterized by dynamic light scattering and atomic force microscopy. The pH-responsive cleavage of the imine linkages under acidic conditions leads to the release of cinnamaldehyde with a concomitant disassembly of the polymeric micelles. The superior biocompatibility coupled with the solvent-less mechanochemical conjugation approach provides a convenient means to introduce various therapeutics for smart drug delivery.
A main challenge in the development of anticancer drugs that eradicate cancer cells specifically with minimal toxicity to normal cells is to identify the cancer-specific properties. Cancer cells sustain a higher level of reactive oxygen species, owing to metabolic and signaling aberrations and unrestrained growth. Cancer cells are also furnished with a powerful reducing environment, owing to the overproduction of antioxidants such as glutathione (GSH). Therefore, the altered redox balance is probably the most prevailing property of cancer cells distinct from normal cells, which could serve as a plausible therapeutic target. In this work, we developed a GSH-depleting pro-oxidant, benzoyloxy dibenzyl carbonate, termed B2C, which is capable of rapidly declining GSH and elevating oxidative stress to a threshold level above which cancer cells cannot survive. B2C was designed to release quinone methide (QM) that rapidly depletes GSH through esterase-mediated hydrolysis. B2C was able to rapidly deplete GSH and induce an overwhelming level of oxidative stress in cancer cells, leading to mitochondrial disruption, activation of procaspase-3 and PARP-1, and cleavage of Bcl-2. In the study of tumor xenograft models, intravenously injected B2C caused apoptotic cell death in tumors and significantly suppressed tumor growth. These findings provide a new insight into the design of more effective anticancer drugs, which exploit altered redox balance in cancer cells.
Cowpea mosaic virus (CPMV) has been developed as a promising nanoplatform technology for cancer immunotherapy; when applied as in situ vaccine, CPMV exhibits potent, systemic, and durable efficacy. While CPMV is not infectious to mammals, it is infectious to legumes; therefore, agronomic safety needs to be addressed to broaden the translational application of CPMV. RNA-containing formulations are preferred over RNA-free virus-like particles because the RNA and protein, each, contribute to CPMV's potent antitumor efficacy. We have previously optimized inactivation methods to develop CPMV that contains RNA but is not infectious to plants. We established that inactivated CPMV has reduced efficacy compared to untreated, native CPMV. However, a systematic comparison between native CPMV and different inactivated forms of CPMV was not done. Therefore, in this study, we directly compared the therapeutic efficacies and mechanisms of immune activation of CPMV, ultraviolet- (UV-), and formalin (Form)-inactivated CPMV to explain the differential efficacies. In a B16F10 melanoma mouse tumor model, Form-CPMV suppressed the tumor growth with prolonged survival (there were no statistical differences comparing CPMV and Form-CPMV). In comparison, UV-CPMV inhibited tumor growth significantly but not as well as Form-CPMV or CPMV. The reduced therapeutic efficacy of UV-CPMV is explained by the degree of cross-linking and aggregated state of the RNA, which renders it inaccessible for sensing by Toll-like receptor (TLR) 7/8 to activate immune responses. The mechanistic studies showed that the highly aggregated state of UV-CPMV inhibited TLR7 signaling more so than for the Form-CPMV formulation, reducing the secretion of interleukin-6 (IL-6) and interferon-α (IFN-α), cytokines associated with TLR7 signaling. These findings support the translational development of Form-CPMV as a noninfectious immunotherapeutic agent.
To test the hypothesis that cryoablation combined with intratumoral immunomodulating nanoparticles from cowpea mosaic virus (CPMV) as an in situ vaccination approach induces systemic antitumoral immunity in a murine model of hepatocellular carcinoma (HCC).
Abstract The key challenge in cancer treatment is prevention of metastatic disease which is therapeutically resistant and carries poor prognoses necessitating efficacious prophylactic approaches that prevent metastasis and recurrence. It is previously demonstrated that cowpea mosaic virus (CPMV) induces durable antitumor responses when used in situ, i.e., intratumoral injection. As a new direction, it is showed that CPMV demonstrates widespread effectiveness as an immunoprophylactic agent – potent efficacy is demonstrated in four metastatic models of colon, ovarian, melanoma, and breast cancer. Systemic administration of CPMV stimulates the innate immune system, enabling attack of cancer cells; processing of the cancer cells and associated antigens leads to systemic, durable, and adaptive antitumor immunity. Overall, CPMV demonstrated broad efficacy as an immunoprophylactic agent in the rejection of metastatic cancer.
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