Combination Therapy For Tumors Research Articles

Research Progress in the Use of Small Molecule Smac Mimetics in Combination Therapy of Cancer.

Inhibitors of Apoptosis Proteins (IAP) are inhibitors that can block programmed cell death, are expressed at high levels in various cancers, and are recognized as a therapeutic target for cancer therapy. In the past few years, several small molecule IAP protein inhibitors have been designed to mimic the endogenous IAP antagonist, but no IAP inhibitors have been approved for marketing worldwide. Previously, xevinapant has been awarded a breakthrough therapy designation by the FDA. In addition, a combination of Smac-mimetics and chemotherapeutic compounds has been reported to improve anticancer efficacy. According to the phase II clinical data, xevinapant has the potential to significantly enhance the standard therapy for patients with head and neck cancer, which is expected to be approved as an innovative therapy for cancer patients. Therefore, this paper briefly describes the mechanism of IAPs (AT-406, APG-1387, GDC- 0152, TL32711, and LCL161) as single or in combination for cancer treatment, their application status as well as the synthetic pathway, and explores the research prospects and challenges of IAPs antagonists in the tumor combination therapy, with the hope of providing strong insights into the further development of Smac mimics in tumor therapy.

Acid-Triggered Degradation of Three-In-One Ag2S Quantum Dots for In Situ Ratiometric NIR-II Fluorescence Imaging-Guided Ion/Gas Combination Therapy.

Smart theranostic nanoprobes with the integration of multiple therapeutic modalities are preferred for precise diagnosis and efficient therapy of tumors. However, it remains a big challenge to arrange the imaging and two or more kinds of therapeutic agents without weakening the intended performances. In addition, most existing fluorescence (FL) imaging agents suffer from low spatiotemporal resolution due to the short emission wavelength (<900 nm). Here, novel three-in-one Ag2S quantum dot (QD)-based smart theranostic nanoprobes were proposed for in situ ratiometric NIR-II FL imaging-guided ion/gas combination therapy of tumors. Under the acidic tumor microenvironment, three-in-one Ag2S QDs underwent destructive degradation, generating toxic Ag+ and H2S. Meanwhile, their FL emission at 1270 nm was weakened. Upon introduction of a downconversion nanoparticle (DCNP) as the delivery carrier and NIR-II FL reference signal unit, the formed Ag2S QD-based theranostic nanoprobes could achieve precise diagnosis of tumors through ratiometric NIR-II FL signals. Also, the generated Ag+ and H2S enabled specific ion/gas combination therapy toward tumors. By combining the imaging and therapeutic functions, three-in-one Ag2S QDs may open a simple yet reliable avenue to design theranostic nanoprobes.

Dual regulation of the orderly aggregation of covalent organic frameworks at the molecular level and nanoscale to achieve efficient phototherapy and gene therapy

Numerous studies have established the promise of combining phototherapy and gene therapy. However, there are persistent obstacles hindering the full optimization of this combined therapeutic approach, such as the maximum development of photosensitizers and the construction of high-performance gene carriers. The LEGO stacking characteristics of COFs have brought infinite imagination to the construction of delivery systems, allowing for the design of responsive nano castles based on different application scenarios. Here, we have constructed a novel cationic multifunctional nano COF nucleic acid delivery system based on photosensitizer and cationic monomers. The long-range ordered structure of COF effectively regulates the spatial distribution of photosensitizer, thereby preserving their phototherapy efficacy. Simultaneously, the inherent cationic porous nanostructure equips COF with exceptional capabilities for delivering nucleic acids. This integrated multifunctional nano delivery system significantly enhances the combined efficacy of phototherapy and gene therapy. The phototherapy capacity of COF enables precise tumor elimination in a spatiotemporal manner, inducing robust ICD and activating immune cells at the tumor site. Furthermore, loaded siPD-L1 significantly enhances immune cell recognition and killing of tumor cells, effectively shielding mice from re-invasion and tumor metastasis. The development of multifunctional nanomedicine based on COF provides new ideas for efficient tumor combination therapy.

Aptamer-Functionalized Nanoscale Metal–Organic Frameworks for Targeted Photothermal-Chemo Combined Tumor Therapy

Aptamer-Functionalized Nanoscale Metal–Organic Frameworks for Targeted Photothermal-Chemo Combined Tumor Therapy

Synthesis and application of multifunctional magnetic mesoporous nanomaterials with redox reaction and NIR response in tumor treatment

In recent years, the novel minimally invasive combination therapy for tumors has garnered widespread attention due to its controllable therapeutic target, effective combination therapy outcome, and minimal toxic side effects. This study integrated inorganic nanospheres of ferric oxide (Fe3O4) with mesoporous silica nanoparticles (MSN), along with polymeric organic polymers—polyaniline (PANI) and hyaluronic acid (HA)—to create a multifunctional tumor treatment platform (Fe3O4@MSN@PANI@HA), aiming to enhance the efficacy of therapies that have monotherapy limitations. The Fe2+ within the Fe3O4@MSN@PANI@HA nanoparticles can react with the unique hydrogen peroxide present in the tumor microenvironment to generate hydroxyl radicals (·OH), which possess cytotoxic properties that can selectively eradicate tumor cells, thereby facilitating chemodynamic therapy (CDT). Moreover, Fe3O4@MSN@PANI@HA nanoparticles, when loaded with the chemotherapy drug doxorubicin hydrochloride (DOX), yield Fe3O4@MSN@PANI@HA-DOX nanoparticles. It has been demonstrated that these nanoparticles exhibit commendable drug-loading efficiency and controlled drug-release capabilities, contributing to the chemotherapy of tumors. The inclusion of PANI in the Fe3O4@MSN@PANI@HA nanoparticles endows them with an exceptional photothermal conversion capability. Upon exposure to an 808-nm near-infrared laser (NIR), the photothermal conversion efficiency of the composite nanomaterials reaches 42.76 %, thereby enabling photothermal therapy (PTT) through the thermal ablation of tumor cells. The HA component of the composite nanoparticles provides excellent biocompatibility and a sustained drug-release effect. Simultaneously, it could target tumor cells by recognizing specific receptors that are overexpressed on the cell surfaces, directing the transport of the composite nanoparticles to the tumor site, and selectively destroying tumor cells. This paper confirms the potent therapeutic impact of composite nanoparticles on tumors and offers a novel perspective for designing multifunctional composite nanomaterials.

Glutathione-Responsive Polymersome with Continuous Glutathione Depletion for Enhanced Photodynamic Therapy and Hypoxia-Activated Chemotherapy.

The high glutathione (GSH) level of the tumor microenvironment severely affects the efficacy of photodynamic therapy (PDT). The current GSH depletion strategies have difficulty meeting the dual needs of security and efficiency. In this study, we report a photosensitizer Chlorin e6 (Ce6) and hypoxia-activated prodrug tirapazamine (TPZ) coloaded cross-linked multifunctional polymersome (TPZ/Ce6@SSPS) with GSH-triggered continuous GSH depletion for enhanced photodynamic therapy and hypoxia-activated chemotherapy. At tumor sites, the disulfide bonds of TPZ/Ce6@SSPS react with GSH to realize decross-linking for on-demand drug release. Meanwhile, the generated highly reactive quinone methide (QM) can further deplete GSH. This continuous GSH depletion will amplify tumor oxidative stress, enhancing the PDT effect of Ce6. Aggravated tumor hypoxia induced by PDT activates the prodrug TPZ, resulting in an enhanced combination of PDT and hypoxia-activated chemotherapy. Both in vitro and in vivo results demonstrate the efficient GSH depletion and potent antitumor activities by TPZ/Ce6@SSPS. This work provides a strategy for the design of a continuous GSH depletion platform, which holds great promise for enhanced combination tumor therapy.

Assembly of Glycopeptides in Living Cells Resembling Viral Infection for Cargo Delivery

Self‐assembly in living cells represents one versatile strategy for drug delivery; however, it suffers from the limited precision and efficiency. Inspired by viral traits, we here report a cascade targeting‐hydrolysis‐transformation (THT) assembly of glycosylated peptides in living cells holistically resembling viral infection for efficient cargo delivery and combined tumor therapy. We design a glycosylated peptide via incorporating a β‐galactose‐serine residue into bola‐amphiphilic sequences. Co‐assembling of the glycosylated peptide with two counterparts containing irinotecan (IRI) or ligand TSFAEYWNLLSP (PMI) results in formation of the glycosylated co‐assemblies SgVEIP, which target cancer cells via β‐galactose‐galectin‐1 association and undergo galactosidase‐induced morphological transformation. While GSH‐reduction causes release of IRI from the co‐assemblies, the PMI moieties release p53 and facilitate cell death via binding with protein MDM2. Cellular experiments show membrane targeting, endo‐/lysosome‐mediated internalization and in situ formation of nanofibers in cytoplasm by SgVEIP. This cascade THT process enables efficient delivery of IRI and PMI into cancer cells secreting Gal‐1 and overexpressing β‐galactosidase. In vivo studies illustrate enhanced tumor accumulation and retention of the glycosylated co‐assemblies, thereby suppressing tumor growth. Our findings demonstrate an in situ assembly strategy mimicking viral infection, thus providing a new route for drug delivery and cancer therapy in the future.

Assembly of Glycopeptides in Living Cells Resembling Viral Infection for Cargo Delivery.

Self-assembly in living cells represents one versatile strategy for drug delivery; however, it suffers from the limited precision and efficiency. Inspired by viral traits, we here report a cascade targeting-hydrolysis-transformation (THT) assembly of glycosylated peptides in living cells holistically resembling viral infection for efficient cargo delivery and combined tumor therapy. We design a glycosylated peptide via incorporating a β-galactose-serine residue into bola-amphiphilic sequences. Co-assembling of the glycosylated peptide with two counterparts containing irinotecan (IRI) or ligand TSFAEYWNLLSP (PMI) results in formation of the glycosylated co-assemblies SgVEIP, which target cancer cells via β-galactose-galectin-1 association and undergo galactosidase-induced morphological transformation. While GSH-reduction causes release of IRI from the co-assemblies, the PMI moieties release p53 and facilitate cell death via binding with protein MDM2. Cellular experiments show membrane targeting, endo-/lysosome-mediated internalization and in situ formation of nanofibers in cytoplasm by SgVEIP. This cascade THT process enables efficient delivery of IRI and PMI into cancer cells secreting Gal-1 and overexpressing β-galactosidase. In vivo studies illustrate enhanced tumor accumulation and retention of the glycosylated co-assemblies, thereby suppressing tumor growth. Our findings demonstrate an in situ assembly strategy mimicking viral infection, thus providing a new route for drug delivery and cancer therapy in the future.

Zinc peroxide-based nanotheranostic platform with endogenous hydrogen peroxide/oxygen generation for enhanced photodynamic-chemo therapy of tumors

Nanotheranostic platforms, which can respond to tumor microenvironments (TME, such as low pH and hypoxia), are immensely appealing for photodynamic therapy (PDT). However, hypoxia in solid tumors harms the treatment outcome of PDT which depends on oxygen molecules to generate cytotoxic singlet oxygen (1O2). Herein, we report the design of TME-responsive smart nanotheranostic platform (DOX/ZnO2@Zr-Ce6/Pt/PEG) which can generate endogenously hydrogen peroxide (H2O2) and oxygen (O2) to alleviate hypoxia for improving photodynamic-chemo combination therapy of tumors. DOX/ZnO2@Zr-Ce6/Pt/PEG nanocomposite was prepared by the synthesis of ZnO2 nanoparticles, in-situ assembly of Zr-Ce6 as typical metal–organic framework (MOF) on ZnO2 surface, in-situ reduction of Pt nanozymes, amphiphilic lipids surface coating and then doxorubicin (DOX) loading. DOX/ZnO2@Zr-Ce6/Pt/PEG nanocomposite exhibits average sizes of ∼78 nm and possesses a good loading capacity (48.8 %) for DOX. When DOX/ZnO2@Zr-Ce6/Pt/PEG dispersions are intratumorally injected into mice, the weak acidic TEM induces the decomposition of ZnO2 core to generate endogenously H2O2, then Pt nanozymes catalyze H2O2 to produce O2 for alleviating tumor hypoxia. Upon laser (630 nm) irradiation, the Zr-Ce6 component in DOX/ZnO2@Zr-Ce6/Pt/PEG can produce cytotoxic 1O2, and 1O2 generation rate can be enhanced by 2.94 times due to the cascaded generation of endogenous H2O2/O2. Furthermore, the generated O2 can suppress the expression of hypoxia-inducible factor α, and further enable tumor cells to become more sensitive to chemotherapy, thereby leading to an increased effectiveness of chemotherapy treatment. The photodynamic-chemo combination therapy from DOX/ZnO2@Zr-Ce6/Pt/PEG nanoplatform exhibits remarkable tumor growth inhibition compared to chemotherapy or PDT. Thus, the present study is a good demonstration of a TME-responsive nanoplatform in a multimodal approach for cancer therapy.

Composite Microparticles from Microfluidics for Chemo-/Photothermal Therapy of Hepatocellular Carcinoma.

Hydrogel microcarrier-based drug delivery systems are of great value in the combination therapy of tumors. Current research directions concentrate on the development of more economic, convenient, and effective combined therapeutic platforms. Herein, we developed novel adhesive composite microparticles (MPPMD) with combined chemo- and photothermal therapy ability via microfluidic electrospray technology for local hepatocellular carcinoma treatment. These composite microparticles consisted of doxorubicin (DOX)-loaded and polydopamine-wrapped mesoporous silicon and alginate. Benefiting from such a strategy of hierarchical structure drug loading, DOX could be gradually released from the system, effectively avoiding the direct toxicity of chemotherapeutics to the body. Additionally, the designed microparticles could not only effectively treat tumors by releasing the chemotherapy drug DOX but also show excellent photothermal properties under the irradiation of near-infrared light, achieving combined chemo- and photothermal treatment effects. Based on these advantages, the MPPMD could remarkably eliminate tumor cells in vitro and enormously restrict tumor development in vivo. These results illustrate that such composite microparticles are ideal combination treatment platforms, possessing promising expectations for cancer therapy.

Abstract CT163: FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors

Abstract Background: Farnesyl transferase inhibitors (FTIs) block post-translational modification of RAS and other farnesylated proteins. HRAS-driven tumors are highly sensitive to FTI treatment. Recent clinical trials (NCT03719690, NCT02383927) of the FTI, tipifarnib, in patients with HRAS-mutant (HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ≥20%), showed objective response rates of up to 50% and favorable long-term outcomes. KO-2806 is a next-generation FTI that has increased potency and improved pharmacokinetic properties. In preclinical studies, KO-2806 has been shown to: (1) enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell renal cell carcinoma (ccRCC) cell line- and patient-derived xenograft models; and (2) enhance activity of KRAS inhibitors, including adagrasib, in KRAS mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC) mouse models. These preclinical data support clinical investigation of KO-2806 alone and in combination therapy. Study Design: FIT-001 is a first-in-human, multicenter, open-label clinical trial that will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics (Pd), and preliminary antitumor activity of KO-2806 as monotherapy or in combination therapy in advanced solid tumors (KO-2806-001; NCT06026410). Up to 270 patients will be enrolled in phase 1a and phase 1b combined across 50 sites. Phase 1a will have separate monotherapy and combination dose-escalation arms. As monotherapy, the study will enroll patients with N/K/HRAS alterations in specific solid tumor types, such as NSCLC, CRC, and PDAC, who are refractory to standard-of-care therapies. KO-2806 and cabozantinib will be combined in patients with advanced or metastatic ccRCC who progressed on ≥1 prior line of immunotherapy-based systemic therapy; KO-2806 and adagrasib will be combined in patients with KRAS-G12C mutant locally advanced or metastatic NSCLC who received ≥1 prior systemic therapy. On the basis of emerging data from phase 1a, two Pd cohorts (n≤12) with mandatory pre- and on-treatment tumor biopsies may be enrolled. In each Phase 1b dose expansion, patients will receive the recommended phase 2 dose [RP2D] of KO-2806 with cabozantinib (in ccRCC) or adagrasib (in NSCLC), or will be randomized by dose if 2 potential KO-2806 RP2Ds are identified for a combination. Other combination arms may also be considered. The study began accrual in October 2023. Citation Format: Glenn J. Hanna, Douglas R. Adkins, Jacob S. Thomas, Justine Y. Bruce, Manish R. Patel, Guru Sonpavde, Jason Henry, Nawal Bendris, Zijing Zhang, Amitava Mitra, Amaya Gascó, Andrew Saunders, Stephen Dale. FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT163.

Nanoparticles integrated withmild photothermal therapy and oxaliplatin for tumor chemotherapy and immunotherapy.

Aims: Preparation and evaluation of nanoparticles for tumor chemotherapy and immunotherapy mild photothermal therapy and oxaliplatin. Methods: The double emulsion method was used for nanoparticle preparations. Polydopamine was deposited on the surface, which was further modified with folic acid. Cytotoxicity assays were carried out by cell counting kit-8. In vivo antitumor assays were carried out on 4T1 tumor-bearing mice. Results: The nanoparticles exhibited a 190nm-diameter pomegranate-like sphere, which could increase temperature to 43-46°C. In vivo distribution showed enhanced accumulation. The nanoparticles generated stronger immunogenic cell death effects. By stimulating the maturation of dendritic cells, mild photothermal therapy combined with oxaliplatin significantly increased the antitumor effect by a direct killing effect and activation of immunotherapy. Conclusion: This study provided a promising strategy of combination therapy for tumors.

Cardiovascular Eligibility Criteria and Adverse Event Reporting in Combined Immune Checkpoint and VEGF Inhibitor Trials

BackgroundCombination therapy with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor inhibitors (VEGFIs) has improved cancer outcomes and is increasingly used. These drug classes are associated with cardiovascular toxicities when used alone, but heterogeneity in trial design and reporting may limit knowledge of toxicities in patients receiving these in combination. ObjectivesThe aim of this study was to assess consistency and clarity in definitions and reporting of cardiovascular eligibility criteria, baseline characteristics, and cardiovascular adverse events in ICI and VEGFI combination trials. MethodsA scoping review was conducted of phase 2 to 4 randomized controlled trials of ICI and VEGFI combination therapy for solid tumors. Trial cardiovascular eligibility criteria and baseline cardiovascular characteristic reporting in trial publications was assessed, and cardiovascular adverse event definitions and reporting criteria were also examined. ResultsSeventeen trials (N = 10,313; published 2018-2022) were included. There were multiple cardiovascular exclusion criteria in 15 trials. No primary trial publication reported baseline cardiovascular characteristics. Thirteen trials excluded patients with prior heart failure, myocardial infarction, hypertension, or stroke. There was heterogeneity in defining cardiovascular conditions. “Grade 1 to 4” cardiovascular adverse events were reported when incidence was ≥5% to 25% in 15 trials. Incident hypertension was recorded in all trials, but other cardiovascular events were not consistently reported. No trial specifically noted the absence of cardiovascular events. ConclusionsIn ICI and VEGFI combination trials, there is heterogeneity in cardiovascular exclusion criteria, reporting of baseline characteristics, and reporting of cardiovascular adverse events. This limits an optimal understanding of the incidence and severity of events relating to these combinations. Better standardization of these elements should be pursued. (Exclusions and Representation of Patients With Kidney Disease and Cardiovascular Disease in Drug Trials of the Novel Systemic Anti-Cancer Therapies VEGF-Signalling Pathway Inhibitors Alone or in Combination With Immune Checkpoint Inhibitors; CRD42022337942)

Dual-functional nano-carrier system based on NIR-laser-triggered dynamic Au[sbnd]Se interaction for chemo-photothermal synergistic tumor therapy

Photothermal therapy (PTT) combined with chemotherapy has been highly desirable to improve the tumor treatment efficacy. Here, we report a novel controlled release nano-carrier system named Se-PEG-Au NPs-DOX (SePAD) for achieving chemo-photothermal synergistic tumor therapy. In this system, the diselenide-containing co-polymers (mPEG-Se–Se-PEGm) were anchored onto the surface of Au NPs via AuSe interactions and the soluble chemotherapeutic doxorubicin (Dox) was loaded into the monolayers. This structure is proved to be stable in a high biological thiols environment. Strikingly, the SePAD presents an ideal efficient photothermal capability and a controllable Dox release behavior by dynamic AuSe interaction in GSH-rich tumor cells when irradiated under 808 nm NIR laser. Following, the results of in vitro and in vivo experiments all demonstrat the superior antitumor properties of SePAD in murine breast cancer. Thus, this system provides a promising strategy to realize chemo-photothermal synergistic combination therapy for breast tumors.

Progress of PD-1/PD-L1 inhibitor combination therapy in immune treatment for HER2-positive tumors.

Patients with HER2-positive cancers often face a poor prognosis, and treatment regimens containing anti-HER2 have become the first-line treatment options for breast and gastric cancers. However, these approaches are faced with significant challenges in terms of drug resistance. Hence, it is crucial to explore precise treatment strategies aimed at improving survival outcomes. Over the past few years, there has been rapid advancement in the realm of tumor therapy, particularly with the swift progress of immune checkpoint inhibitors, including PD-1/PD-L1 inhibitors. They exert anti-tumor effects by disrupting immune-suppressive factors within the tumor microenvironment. However, monotherapy with PD-1/PD-L1 inhibitors has several limitations. Consequently, numerous studies have explored combinatorial immunotherapeutic strategies and demonstrated highly promising avenues of development. This article aims to review the clinical trials investigating PD-1/PD-L1 inhibitor combination therapy for HER2-positive tumors. Additionally, it provides a summary of ongoing trials evaluating the efficacy and safety of these combined treatments, with the intention of furnishing valuable insights for the clinical management of HER2-positive cancer. Combinatorial immunotherapeutic strategies involving PD-1/PD-L1 inhibitors hold considerable promise in the treatment of HER2-positive tumors. Continued research efforts and clinical trials are warranted to elucidate optimal treatment regimens that maximize therapeutic benefits while minimizing adverse effects.

Cascade Co8FeS8@Co1-xS nano-enzymes trigger efficiently apoptosis-ferroptosis combination tumor therapy

This study involved the preparation of Metal Organic Frameworks (MOF)-derived Co8FeS8@Co1-xS nanoenzymes with strong interfacial interactions. The nanoenzymes presented the peroxidase (POD)-like activity and the oxidation activity of reduced glutathione (GSH). Accordingly, the dual activities of Co8FeS8@Co1-xS provided a self-cascading platform for producing significant amounts of hydroxyl radical (•OH) and depleting reduced glutathione, thereby inducing tumor cell apoptosis and ferroptosis. More importantly, the Co8FeS8@Co1-xS inhibited the anti-apoptosis protein B-cell lymphoma-2 (Bcl-2) and activated caspase family proteins, which caused tumor cell apoptosis. Simultaneously, Co8FeS8@Co1-xS affected the iron metabolism-related genes such as Heme oxygenase-1 (Hmox-1), amplifying the Fenton response and promoting apoptosis and ferroptosis. Therefore, the nanoenzyme synergistically killed anti-apoptotic tumor cells carrying Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Furthermore, Co8FeS8@Co1-xS demonstrated good biocompatibility, which paved the way for constructing a synergistic catalytic nanoplatform for an efficient tumor treatment.

PH-responsive degradable mesoporous organosilica nanoparticle for tumor targeting and phototherapy combined with chemotherapy

In the context of the tumor microenvironment, the design of a high concentration glutathione (GSH) driven degradation drug delivery system (ID@MON-HA) is according to a different quantity of GSH to normal tissues. This system involves loading doxorubicin (DOX) and new indocyanine green (IR820) onto mesoporous organosilica nanoparticles (MON). The disulfide linkages in MON are broken in response to high amounts of GSH in tumor cells, resulting in the degradation of the overall structure and preventing carrier accumulation. To connect the hyaluronic acid (HA) and the carrier with encapsulated drugs, a pH-sensitive Schiff based bond is utilized. Furthermore, MON specifically target to tumor sites due to the selective binding of HA to tumor cells that overexpress the CD44 receptor. Experiments have shown that increased GSH concentrations and pH levels below physiological can accelerate drug release. Additionally, in vitro cellular experiments have demonstrated that combining chemotherapy and phototherapy enhances the suppression of tumor cells (median inhibition concentration IC50 = 1.53 μg mL_1). These findings indicate that the study offers an acceptable approach for developing degradable nanoplatforms for tumor combination therapy.

Quercetin@UiO-66 NPs and chloroquine in combined tumor therapy by dual autophagy-ubiquitination system blockade.

In this study, we propose a novel therapy system composed of UiO-66 nanoparticles, which contain quercetin combined with chloroquine (UQCNP), to achieve dual autophagy-ubiquitination blockade. Through UiO-66 NP drug loading, the solubility of quercetin (a proteasome inhibitor) was improved under physiological conditions, thereby increasing its effective concentration at the tumor site. The cell experiment results showed that UQCNP significantly increased the apoptosis rate of 4T1 cells by 73.6%, which was significantly higher than other groups. Transmission electron microscopy results showed that the autophagosome of cells in the UQCNP treatment group was significantly lower than that in other treatment groups. Moreover, western blot results showed that, compared with other groups, LC3 expression and proteasome activity (p < 0.01), as well as the tumor volume of mice treated with UQCNP (p < 0.01) were significantly reduced. These results indicate that UQCNP achieves effective tumor therapy by blocking the autophagy and proteasome pathways synchronously.

A graphene oxide-based sequential nanocatalyst for efficient tumor combination therapy

We construct a simple, biocompatible, sequential catalytic nanocatalyst PMO@GO-GOD to realize enhanced chemodynamic therapy and photothermal therapy for combating breast cancers by taking advantage of the peroxidase-like activity of GO.

Smart iron-based metal–organic framework nanovehicles gated with CuII-tannic acid coordination polymers for combination therapy of chemotherapy and chemodynamic therapy

Smart iron-based metal–organic framework MIL-101(FeIII) nanovehicles gated with CuII-tannic acid (TA) coordination polymers were constructed via “on site” self-assembly. The controlled release of antitumor drugs encapsulated within MIL-101(FeIII) mesopores was realized in response to the tumor microenvironments [such as low pH, glutathione (GSH), H2O2, and adenosine-5’-triphosphate (ATP)] and near infrared light, due to the photothermal effect of the nanocarriers, by the disassembly of the CuII-TA gating films and/or the degradation of the MIL-101(FeIII) nanocarriers. The low pH gave rise to the disassembly of the CuII-TA gating films and the release of drugs. The competitive coordination of ATP with CuII/FeIII caused the disassembly of the CuII-TA gating films, the degradation of the nanocarriers, and the release of drugs. The overexpressed GSH could reduce CuII/FeIII to CuI/FeII and resulted in the disassembly of the CuII-TA gating films and the degradation of the nanocarriers, and the produced CuI/FeII could catalyze H2O2 of elevated level to generate more hydroxyl radicals via the Fenton/Fenton-like reactions for cell apoptosis. The cascade reactions of the depletion of GSH and the generation of hydroxyl radicals based on the gated nanovehicles achieved chemodynamic therapy (CDT) besides chemotherapy. The smart nanovehicles have promising applications in combination tumor therapy of chemotherapy and CDT.