Figure 5. (a) Schematic illustration of the formation of PEGylated Pd SAzyme and (b) the mechanism of ferroptosis promoted by MPTT. (c) TEM image of Pd@ZIF-8; the inset (scale bar 5 nm) is the enlarged image of Pd@ZIF-8, showing visible Pd NPs. (d) TEM image of Pd SAzyme. (e) HAADF-STEM images of Pd SAzyme showing the atomically dispersed Pd atoms highlighted by yellow circles. (f) The EDS elemental mapping of Pd SAzyme. Western blots of (g) HSP70 and (h) GPX4 after different treatments. Reproduced from Ref. [169] with permission. Copyright 2022 Wiley-VCH.
3.3.2. Other coordination complex
Yang et al. developed a unique nanodrug called Qu-FeIIP, where quercetin serves not only as a HSP70 inhibitor but also as the framework for Qu-FeIIP. This innovative nanodrug allows for MPTT, effectively eradicating tumors without subjecting normal tissues to heat stress. Qu-FeIIP possesses the ability to scavenge ROS due to the presence of quercetin. Consequently, Qu-FeIIP effectively reduced intracellular ROS levels and lowered in vivo inflammatory factors such as TNF-α, IL-6, and IFN-γ. Simultaneously, the coordination between quercetin and Fe weakens during ROS scavenging, leading to the disassembly of Qu-FeIIP and efficient clearance of NPs from major organs within 168 hours post intravenous injection. Moreover, Qu-FeIIP exhibits dual-imaging capabilities, offering PAI and MRI for precise tumor diagnosis and real-time monitoring of nanodrug disassembly in vivo.[173] Qu-FeIIP combines precise diagnosis, effective MPTT, ROS elimination, anti-inflammatory action, dynamic disassembly, and renal clearance into a single nanodrug, holding significant promise for future clinical cancer treatment. Yu et al. introduced a self-assembling nanoagent termed ZCNA, which is formed by the integration of hydrophobic Cu2-xS nanoparticles and zinc protoporphyrin (ZnPP) using a simple volatilization-driven approach, without the need for additional stabilizing or carrier materials. This nanoagent offers several notable features, including a straightforward preparation process, high loading efficiency and capacity for ZnPP, and excellent biocompatibility. ZCNA serves as both a contrast agent for PAI and a photothermal agent for MPTT.[174] Importantly, ZnPP released from ZCNA during PTT effectively inhibits the expression of heme oxygenase-1 (HO-1, a critical type of HSPs), thereby depleting the antioxidant defense systems of tumor cells. This mechanism contributes to the significantly enhanced antitumor effect of ZCNA during MPTT. The ingeniously designed ZCNA represented an effective theranostic platform with PAI capabilities and synergistic antitumor effects, promoting the clinical translation of MPTT. Yu et al. developed a novel multifunctional nanotherapeutic agent, referred to as FeEP-NP, through a one-pot self-assembly method. This approach relies on the coordination between Fe II ions and (-)-epigallocatechin gallate (EGCG), with poly(vinylpyrrolidone) acting as a stabilizer. The FeEP-NPs have been designed to effectively generate toxic •OH via the Fenton reaction via CDT. Interestingly, the specific binding between EGCG and Fe II ions imparts the NPs with strong absorption and photothermal conversion capabilities in NIR region, allowing them to achieve mild hyperthermia-enhanced CDT when exposed to NIR laser irradiation. Furthermore, the partially released EGCG accelerates the conversion of Fe III to Fe II, boosting •OH generation and simultaneously reducing the intracellular expression of HSP 90 to enhance MPTT.[175] The combination of low-temperature PTT and CDT leads to more efficient tumor suppression. Overall, these works introduce novel multifunctional nanoplatform with a streamlined design, offering promising prospects for future clinical applications.
4.Biomedical applications of MPTT
4.1. Cancer
Cancer is a very serious disease, especially due to the characteristics of diffusion and metastasis of cancerous cells, so the disease can often develop to the middle and late stages in a short time, resulting in high mortality.[11, 176, 177] Therefore, once patients are diagnosed, they should be actively treated. Cancer patients are mainly treated by surgery, radical surgery or palliative surgery can be selected according to the condition. At the same time, chemotherapeutics can be used for chemotherapy, and radiation therapy can also be received. However, these traditional treatment methods cannot significantly improve the quality of life of patients due to limitations such as many contraindications and severe adverse reactions.[178, 179] Therefore, there is an urgent need for treatment methods with a wide range of applications and few adverse reactions.
In recent years, precise treatment of tumor is becoming a trend in clinical treatment of tumor.[180-182] With the continuous efforts of researchers, MPTT, a tumor treatment based on nanomedicine, has gradually entered people’s vision. MPTT uses PTAs that are injected into the human body, so that they accumulate in tumor tissues, and under the irradiation of external light sources (generally NIR light) to generate heat energy to kill cancer cells. It has the characteristics of high selectivity, small systemic toxic side effects, short treatment time (about a few minutes), and obvious therapeutic effect. As a new type of tumor treatment, MPTT has the advantages of non-invasive, less adverse reactions and high targeting, which has great potential in the development of tumor treatment. Sun et al. have successfully obtained innocuous hollow mesoporous carbon spheres (HMCS) with a high PCE using a one-pot synthesis method. Through modification with DSPE-PEG, the resulting HMCS-PEG exhibited excellent stability in biological media, making it well-suited for various biological applications. Remarkably, when combined with the hydrophobic compound GA, which can downregulate HSP90, the HMCS-PEG-GA system demonstrated a significant enhancement of tumor therapeutic effects in vitro and in vivo under mild temperature conditions (around 43 °C). The combination index (CI) value of HMCS-PEG-GA was determined to be 0.72, indicating a strong synergistic effect. Additionally, this nano-system exhibited excellent photothermal imaging and PAI capabilities, which hold substantial potential for accurate tumor diagnosis and MPTT applications.[183] On the other hand, Gao et al. developed a ”smart” strategy using a peptide-hydroxychloroquine (HCQ) conjugate, Cypate-Phe-Phe-Lys(SAHCQ)-Tyr(H2PO3)-OH (Cyp-HCQ-Yp), which allowed for enzyme-triggered intracellular NPs formation and HCQ release. Through the sequential catalysis of alkaline phosphatase and carboxylesterase, Cyp-HCQ-Yp was converted to Cypate-Phe-Phe-Lys(SA)-Tyr-OH (Cyp-Y), which self-assembles into Cyp-NP while HCQ is released from Cyp-HCQ-Yp. This approach achieves remarkable therapeutic effects on tumors in vivo through dual-enzyme-controlled intracellular NPs formation and autophagy inhibition in tumors when compared to control agents.[184] These strategies offer promising avenues for enhancing the efficacy of MPTT and tumor treatment. Wen et al. introduced an innovative approach involving defect-rich glassy IrTe2(G-IrTe2) with weak Ir−Te bond strength for synergistic SDT, CDT, and MPTT. G-IrTe2, when used as a sonosensitizer under ultrasound (US) stimuli, demonstrates outstanding performance in the production of ROS. Additionally, G-IrTe2 exhibits catalase (CAT)-like activity, providing an ample supply of oxygen to enhance the SDT effect. Theoretical calculations validate that US stimuli can easily break the irregular Ir−Te bonds in amorphous IrTe2, releasing free electrons that combine with oxygen to generate1O2. Furthermore, G-IrTe2, with peroxidase (POD)-like activity, catalyzes endogenous H2O2 to produce more ROS for CDT, thereby facilitating improved tumor ablation. The ROS generated during sono-/chemodynamic processes can lead to mitochondrial dysfunction and subsequently downregulate the expression of HSPs, maximizing the efficacy of MPTT.[185] IrTe2 with rich defects played a significant role in synergistic cancer therapy, achieving outstanding antitumor efficacy. This study presented a novel research direction for expanding the application of inorganic glassy nanomaterials to enhance the therapeutic effects of tumors. Peng et al. have focused on the development of a nanoagent designed to induce heat-synergetic pro-survival autophagy to optimize the efficacy of MPTT. Their approach involved coating a carbon layer, polyethylenimine (PEI), and folic acid (FA) onto NaYF4:Er,Yb,Nd@NaNdF4 (DCNPs@C@PEI@FA, DCPF) NPs in succession. This modification allowed the nanoagent to induce pro-survival autophagy. The resulting imaging-guided photothermal nanoagent exhibited remarkable targeting ability and biocompatibility. When combined with the autophagy inhibitor chloroquine, a significant synergistic effect is observed in vitro and in vivo tumor models, enhancing the effectiveness of DCPF-mediated MPTT.[186] This study presented a promising strategy for improving the efficacy of imaging-guided PTT by modulating the autophagy induced by the nanoagent. Liu et al. have introduced an innovative strategy involving pyroptosis-boosted MPTT with a Mn-gallate nanoformulation. This nanoformulation was constructed through the coordination of GA and Mn2+. Notably, it exhibited acid-activated degradation, leading to the release of both Mn2+ and GA. This release resulted in the upregulation of ROS, mitochondrial dysfunction, and pyroptosis.[187] These cellular processes contributed to ATP deprivation, achieved through both the inhibition of ATP generation and increased ATP efflux. The reduction of ATP levels and the accumulation of ROS provided a potent approach for inhibiting the expression of HSPs, facilitating the MPTT. Hu et al. developed a supramolecular drug nanocarrier designed to co-deliver NO and NIR-II aggregation-induced emission (AIE) molecules for MPTT. Within the intracellular reductive environment, NO is effectively released from the nanocarriers, while DCTBT simultaneously generates ROS and hyperthermia upon exposure to an 808 nm laser. The generated ROS can further react with NO to produce peroxynitrite (ONOOˉ), which possessed strong oxidization and nitration capabilities. ONOOˉ played a crucial role in inhibiting the expression of HSPs, thereby reducing the thermoresistance of cancer cells. This reduction in thermoresistance is essential for achieving excellent therapeutic efficacy in DCTBT-based MPTT (Figure 6).[188] The study’s effectiveness is demonstrated through the antitumor performance of ONOOˉ-potentiated MPTT in subcutaneous and orthotopic hepatocellular carcinoma models. This research introduced an innovative strategy to overcome thermoresistance for MPTT, offering new insights into ONOOˉ-sensitized tumor therapy strategies.