Amplification of oxidative stress with lycorine and gold-based nanocomposites for synergistic cascade cancer therapy

Abstract

Background Despite advances of surgery and neoadjuvant chemotherapy during the past few decades, the therapeutic efficacy of current therapeutic protocol for osteosarcoma (OS) is still seriously compromised by multi-drug resistance and severe side effects. Amplification of intracellular oxidative stress is considered as an effective strategy to induce cancer cell death. The purpose of this study was to develop a novel strategy that can amplify the intracellular oxidative stress for synergistic cascade cancer therapy. Methods and results A novel nanocomposite, composed of folic acid (FA) modified mesoporous silica–coated gold nanostar (GNS@MSNs-FA) and traditional Chinese medicine lycorine (Ly), was rationally designed and developed. Under near-infrared (NIR) irradiation, the obtained GNS@MSNs-FA/Ly could promote a high level of ROS production via inducing mitochondrial dysfunction and potent endoplasmic reticulum (ER) stress. Moreover, glutathione (GSH) depletion during ER stress could reduce ROS scavenging and further enable efficient amplification of intracellular oxidative stress. Both in vitro and in vivo studies demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation exhibited excellent antitumor efficacy without noticeable toxicity in MNNG/HOS tumor-bearing mice. Conclusion All these results demonstrated that GNS@MSNs-FA/Ly coupled with NIR irradiation could dramatically amplify the intra-tumoral oxidative stress, exhibiting excellent antitumor ability without obvious systemic toxicity. Taken together, this promising strategy provides a new avenue for the effective cancer synergetic therapy and future clinical translation.

Recent Advances in Nanoplatforms for the Treatment of Osteosarcoma

“…It is worth mentioning that the in vivo experimental results showed that the RGD-Bi2S3 @MSN/DOX NPs synthesized by Liu et al combined with nearinfrared radiation can effectively ablate malignant OS and prevent its recurrence (66). Similarly, Hu et al developed a new type of mesoporous silica-coated gold nanostar (GNS@ MSNs-FA) modified by folic acid (FA) with the Chinese medicine lyricine (Ly) NPs (67). In summary, the researchers utilized gold nanostars (GNS) with multiple sharp branches as the core of the nanocomposite, employing MSNs to coat the core-shell GNS@MSNs with Ly, and then modified the GNS@ MSNs with amino groups, which played a role in targeting tumor cells.…”

“…Similarly, Hu et al. developed a new type of mesoporous silica-coated gold nanostar (GNS@MSNs-FA) modified by folic acid (FA) with the Chinese medicine lyricine (Ly) NPs ( 67 ). In summary, the researchers utilized gold nanostars (GNS) with multiple sharp branches as the core of the nanocomposite, employing MSNs to coat the core-shell GNS@MSNs with Ly, and then modified the GNS@MSNs with amino groups, which played a role in targeting tumor cells.…”

Nanodrugs Manipulating Endoplasmic Reticulum Stress for Highly Effective Antitumor Therapy

“…PRN@MSN strongly inhibited the formation of microvessels in murine hemangioma models via increased ER stress, where MSN induced ER stress and PRN inhibited autophagy that was resistant to ER stress. Moreover, Hu et al (2021) integrated gold nanostars (GNS) and the antineoplastic drug lycorine (Ly) into MSNs with modified tumor-targeted folate (FA). GNS@MSNs-FA/Ly exhibited highly specific tumor growth inhibition in osteosarcoma cell tumor–bearing mice without additional side effects, among which Ly promoted mitochondrial dysfunction to interfere with ER via endoplasmic reticulum–mitochondrial contact ( Giacomello et al, 2020 ).…”

Cavitation assisted endoplasmic reticulum targeted sonodynamic droplets to enhanced anti-PD-L1 immunotherapy in pancreatic cancer

“…To tackle these problems, a cavitation assisted endoplasmic reticulum (ER) targeted sonodynamic therapy can facilitate drug accumulation and penetration, thus elevating ER stress [ 23 , 24 ] in situ and boosting the efficacy of immunotherapy. Firstly, the tumor vascular targeted acoustic droplets evaporation (ADV) increases the aggregation and penetration of nanodroplets in the tumor microenvironment [ 25 ].…”