Combination Therapy For Tumors Research Articles

Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) gene in cancer cells may be associated with immunosuppressive tumor microenvironment (TME) and poor response to immune checkpoint blockade (ICB) therapy. Therefore, efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy. Here, we screened an adeno-associated virus (AAV) capsid for efficient PTEN gene delivery into B16F10 tumor cells. We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death (ICD) and increasing immune cell infiltration. Moreover, we developed an anti-PD-1 loaded phospholipid-based phase separation gel (PPSG), which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo. In order to effectively inhibit the recurrence of melanoma, we further applied a triple therapy based on AAV6-PTEN, PPSG@anti-PD-1 and CpG, and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory, which completely rejected tumor recurrence. We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

Employing single valency polyphenol to prepare metal-phenolic network antitumor reagents through FeOOH assistance.

Metal-phenolic networks (MPNs) have been conventionally formed by the coordination of metal ions and polyphenols, which can responsively release metal ions and polyphenols under the trigger of tumor microenvironment (TME), showing high potential in the field of antitumor. However, MPNs are mainly limited to multi-valency polyphenols, and the unavailability of single valency polyphenols greatly hinders their applications even though they have excellent antitumor activity. Herein, we demonstrate a FeOOH assisted preparation method for MPNs antitumor reagent by introducing the complexes of Fe3+, H2O and polyphenol (Fe(H2O)x-polyphenoly) in the preparation process, which overcomes the shortage of single valency polyphenols. Taking apigenin (Ap) as an example, Fe(H2O)x-Apy complexes are foremost formed, in which the Fe(H2O)x is capable of hydrolyzing to generate FeOOH, thus producing Fe3+-Ap networks-coated FeOOH nanoparticles (FeOOH@Fe-Ap NPs). Under the stimulation of the TME, FeOOH@Fe-Ap NPs could release Fe2+ and Ap, realizing ferroptosis and apoptosis for tumor combination therapy. In addition, FeOOH can shorten transverse relaxation time, acting as a T2-weighted magnetic resonance imaging contrast agent. The current efforts provide an alternative strategy for constructing MPNs by exploiting single valency polyphenols, which strengthens the potential of MPNs in antitumor applications.

An Intelligent Vascular Disrupting Dendritic Nanodevice Incorporating Copper Sulfide Nanoparticles for Immune Modulation-Mediated Combination Tumor Therapy.

Development of intelligent nanoplatforms that can simultaneously target multiple factors associated with tumor growth and metastasis remains an extreme challenge. Here, an intelligent dendritic nanodevice incorporating both copper sulfide nanoparticles (CuS NPs) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a vascular disrupting agent) within the dendrimer internal cavities and surface modified with a targeting agent LyP-1 peptide is reported. The resulting generation 5 (G5) dendrimer-based nanodevice, known as G5-PEG-LyP-1-CuS-DMXAA NPs (GLCD NPs), possess good colloidal stability, pH-sensitive drug release kinetics, and high photothermal conversion efficiency (59.3%). These functional GLCD NPs exert a LyP-1-targeted killing effect on breast tumors by combining CuS-mediated photothermal therapy (PTT) and DMXAA-induced vascular disruption, while also triggering antitumor immune responses through PTT-induced immunogenic cell death and DMXAA-mediated immune regulation via M1 polarization of tumor-associated macrophages and dendritic cell maturation. In addition, with the LyP-1-mediated proapoptotic activity, the GLCD NPs can specifically kill tumor lymphatic endothelial cells. The simultaneous disruption of tumor blood vessels and lymphatic vessels cuts off the two main pathways of tumor metastasis, which plays a two-pronged role in inhibiting lung metastasis of the breast cancer model. Thus, the developed GLCD NPs represent an advanced intelligent nanoformulation for immune modulation-mediated combination tumor therapy with potential for clinical translations.

Frontispiece: A Remotely Controlled Nanosystem for Spatiotemporally Specific Gene Regulation and Combinational Tumor Therapy

Nanobiotechnology. A remotely controlled nanosystem for spatiotemporally specific gene regulation and combinational tumor therapy is reported by Jian Zhao, Lele Li et al. in their Research Article (e202217702).

Frontispiz: A Remotely Controlled Nanosystem for Spatiotemporally Specific Gene Regulation and Combinational Tumor Therapy

Nanobiotechnology. A remotely controlled nanosystem for spatiotemporally specific gene regulation and combinational tumor therapy is reported by Jian Zhao, Lele Li et al. in their Research Article (e202217702).

Thermo-sensitive injectable hydrogel loading with elemene-loaded liposomes for enhanced anti-tumor effect.

Due to the heterogeneity and the complexity of the tumor microenvironment, combination therapy, especially the combination of chemotherapy and photothermal therapy (PTT), had received increasing attention. However, the co-delivery of small molecule drugs for chemotherapy and photothermal agents was a key issue. Herein, we prepared a novel thermo-sensitive hydrogel loading with elemene (ELE)-loaded and nano graphene oxide (NGO)-based liposomes for enhanced combined therapy. ELE was applied as the model drug for chemotherapy because it was a natural sesquiterpene drug with broad-spectrum and efficient antitumor activity. NGO was applied as drug carrier and photothermal agent simultaneously due to its two-dimensional structure and high photo-thermal conversion efficacy. NGO was further modified with glycyrrhetinic acid (GA) to improve its water dispersion, biocompatibility and tumor-targeting ability. ELE was loaded by GA-modified NGO (GA/NGO) to prepare the liposomes designated as ELE-GA/NGO-Lip, which was further mixed with chitosan (CS) solution and β-glycerin sodium phosphate (β-GP) solution to prepare the thermo-sensitive hydrogel designated as ELE-GA/NGO-Lip-gel. The obtained ELE-GA/NGO-Lip-gel had the gelling temperature of 37°C, temperature and pH-response gel dissolution and high photo-thermal conversion effect. More importantly, ELE-GA/NGO-Lip-gel upon 808nm laser irradiation had relative high anti-tumor efficiency against SMMC-7721 cells in vitro. This research might provide a potent platform for the application of thermos-sensitive injectable hydrogel in combined tumor therapy.

Trojan nanobacteria hybridized with prodrug nanocapsules for efficient combined tumor therapy

Trojan nanobacteria hybridized with prodrug nanocapsules for efficient combined tumor therapy

A Remotely Controlled Nanosystem for Spatiotemporally Specific Gene Regulation and Combinational Tumor Therapy

AbstractThe dearth of technologies that allow gene modulation and therapy with high spatiotemporal precision remains a bottleneck in biomedical research and applications. Here we present a near‐infrared (NIR) light‐controlled nanosystem that allows spatiotemporally controlled regulation of gene expression and thus combinational tumor therapy. The nanosystem is built by engineering of an enzyme‐activatable antisense oligonucleotide and further combination with an upconversion nanoparticle‐based photodynamic system and a mitochondria localization signal. The system relies on photodynamic effect‐induced translocation of a DNA repair enzyme from nucleus into mitochondria, which enables spatially selective gene regulation via enzymatic reactions. We demonstrate that the NIR light‐induced mitochondrial photodamage and gene regulation enable enhanced antitumor effect. Our approach may enable the specific gene regulation and tumor treatment with high precision both spatially and temporally.

A Remotely Controlled Nanosystem for Spatiotemporally Specific Gene Regulation and Combinational Tumor Therapy.

The dearth of technologies that allow gene modulation and therapy with high spatiotemporal precision remains a bottleneck in biomedical research and applications. Here we present a near-infrared (NIR) light-controlled nanosystem that allows spatiotemporally controlled regulation of gene expression and thus combinational tumor therapy. The nanosystem is built by engineering of an enzyme-activatable antisense oligonucleotide and further combination with an upconversion nanoparticle-based photodynamic system and a mitochondria localization signal. The system relies on photodynamic effect-induced translocation of a DNA repair enzyme from nucleus into mitochondria, which enables spatially selective gene regulation via enzymatic reactions. We demonstrate that the NIR light-induced mitochondrial photodamage and gene regulation enable enhanced antitumor effect. Our approach may enable the specific gene regulation and tumor treatment with high precision both spatially and temporally.

Modulating tumor-stromal crosstalk via a redox-responsive nanomedicine for combination tumor therapy.

Interaction between carcinoma-associated fibroblasts (CAFs) and tumor cells leads to the invasion and metastasis of breast cancer. Herein, we prepared a redox-responsive chondroitin sulfate (CS)-based nanomedicine, in which hydrophobic cabazitaxel (CTX) was conjugated to the backbone of CS via glutathione (GSH)-sensitive dithiomaleimide (DTM) to form an amphipathic CS-DTM-CTX (CDC) conjugate, and dasatinib (DAS) co-assembled with the CDC conjugate to obtain DAS@CDC. After CD44 receptor-mediated internalization by CAFs, the nanomedicine could reverse CAFs to normal fibroblasts, blocking their crosstalk with tumor cells and reducing synthesis of major tumor extracellular matrix proteins, including collagen and fibronectin. Meanwhile, the nanomedicine internalized by tumor cells could effectively inhibit tumor proliferation and metastasis, leading to shrinkage of the tumor volume and inhibition of lung metastasis in a subcutaneous 4 T1 tumor model with low side effects. Collectively, the nanomedicine showed a remarkably synergistic therapy effect against breast cancer by modulating tumor-stromal crosstalk.

A co-delivery system based on chlorin e6-loaded ROS-sensitive polymeric prodrug with self-amplified drug release to enhance the efficacy of combination therapy for breast tumor cells.

Background: Recently, various combination therapies for tumors have garnered popularity because of their synergistic effects in improving therapeutic efficacy and reducing side effects. However, incomplete intracellular drug release and a single method of combining drugs are inadequate to achieve the desired therapeutic effect. Methods: A reactive oxygen species (ROS)-sensitive co-delivery micelle (Ce6@PTP/DP). It was a photosensitizer and a ROS-sensitive paclitaxel (PTX) prodrug for synergistic chemo-photodynamic therapy. Micelles size and surface potential were measured. In vitro drug release, cytotoxicity and apoptosis were investigated. Results: Ce6@PTP/DP prodrug micelles exhibited good colloidal stability and biocompatibility, high PTX and Ce6 loading contents of 21.7% and 7.38%, respectively. Upon light irradiation, Ce6@PTP/DP micelles endocytosed by tumor cells can generate sufficient ROS, not only leading to photodynamic therapy and the inhibition of tumor cell proliferation, but also triggering locoregional PTX release by cleaving the thioketal (TK) bridged bond between PTX and methoxyl poly (ethylene glycol). Furthermore, compared with single drug-loaded micelles, the light-triggered Ce6@PTP/DP micelles exhibited self-amplified drug release and significantly greater inhibition of HeLa cell growth. Conclusion: The results support that PTX and Ce6 in Ce6@PTP/DP micelles exhibited synergistic effects on cell-growth inhibition. Thus, Ce6@PTP/DP micelles represent an alternative for realizing synergistic chemo-photodynamic therapy.

Defect‐Engineering Bismuth‐Based Homologous Schottky Heterojunction for Metabolic Regulation‐Augmented Sonodynamic Tumor Therapy

AbstractSonodynamic therapy demonstrates tremendous potential in biomedicine due to its non‐invasiveness, deep tissue penetration, and spatiotemporal controllability. However, the lack of favorable nanosonosensitizers with prominent reactive oxygen species generation capability and green chemical constituents remains a significant challenge for its broad biomedical applications. Herein, a homologous bismuth‐based nanosonosensitizer (Bi‐HJ) is designed and fabricated by direct defect engineering for combinational tumor therapy. Specifically, self‐derived Schottky heterojunction and oxygen vacancies are concurrently constructed in Bi‐HJ, which prominently promotes the separation of ultrasound‐triggered electron–hole pairs and improves the charge utilization efficiency. With the porous structure, Bi‐HJ is loaded with a metabolic regulation drug atovaquone to block the mitochondrial respiration for oxygen‐economized sonodynamic tumor suppression. The strong near‐infrared absorption of Bi‐HJ imparted by oxygen vacancies allows the implementation of photothermal therapy. Accordingly, Bi‐HJ rationally combines two therapeutic modalities and metabolic regulation function, as well as computed tomography imaging ability, thus achieving effective tumor theranostics in vitro and in vivo. Therefore, this study provides new insight into the fabrication of homologous nanosonosensitizers without the introduction of other constituents for synergistically enhanced tumor therapy.

Ferroptosis and tumor immunotherapy: A promising combination therapy for tumors.

Low response rate and treatment resistance are frequent problems in the immunotherapy of tumors, resulting in the unsatisfactory therapeutic effects. Ferroptosis is a form of cell death characterized by the accumulation of lipid peroxides. In recent years, it has been found that ferroptosis may be related to the treatment of cancer. Various immune cells (including macrophages and CD8+ T cells) can induce ferroptosis of tumor cells, and synergistically enhance the anti-tumor immune effects. However, the mechanisms are different for each cell types. DAMP released in vitro by cancer cells undergoing ferroptosis lead to the maturation of dendritic cells, cross-induction of CD8+ T cells, IFN-γ production and M1 macrophage production. Thus, it activates the adaptability of the tumor microenvironment and forms positive feedback of the immune response. It suggests that induction of ferroptosis may contribute to reducing resistance of cancer immunotherapy and has great potential in cancer therapy. Further research into the link between ferroptosis and tumor immunotherapy may offer hope for those cancers that are difficult to treat. In this review, we focus on the role of ferroptosis in tumor immunotherapy, explore the role of ferroptosis in various immune cells, and discuss potential applications of ferroptosis in tumor immunotherapy.

Reduction-responsive dextran-based Pt(IV) nano-prodrug showed a synergistic effect with doxorubicin for effective melanoma treatment

Melanoma, the deadliest skin cancer with high metastasis potential, has posed a great threat to human health. Accordingly, early efficient blocking of melanoma progression is vital in antitumor treatment. Herein, a reduction-responsive dextran-based Pt(IV) nano-prodrug (PDPN) was synthesized and used for doxorubicin (DOX) delivery to combat melanoma synergistically. First, PDPN was prepared by one-pot chemical coupling of carboxylated methoxy poly(ethylene glycol) (mPEG), dextran (Dex), and the crosslinking agent cisPt (IV)-COOH. PDPN had a spherical structure (Rh = 34 ± 11.3 nm). Then, DOX was encapsulated into the PDPN core to form DOX-loaded PDPN (PDPN-DOX). The obtained PDPN-DOX displayed reduction-responsive release of DOX and Pt, thus showing a synergistic anticancer effect in B16F10 cells (combination index, 0.46). Furthermore, in vivo experiments demonstrated that PDPN-DOX was effective for the synergistic treatment of subcutaneous melanoma. Collectively, the as-prepared PDPN could serve as a promising and versatile nano-prodrug carrier for the co-delivery of chemotherapeutics in tumor combination therapy.

DUCNP@Mn-MOF/FOE as a Highly Selective and Bioavailable Drug Delivery System for Synergistic Combination Cancer Therapy.

Heterostructures comprising lanthanide-doped upconversion nanoparticles (DUCNPs) and metal-organic frameworks (MOFs) are emerging as promising nanosystems for integrating medical diagnosis and treatment. Here, the DUCNP@Mn-MOF nanocarrier was developed, which showed good efficiency for loading and delivering a cytotoxic antitumor agent (3-F-10-OH-evodiamine, FOE). The combined advantages of the pH-responsive and peroxidase-like properties of Mn-MOF and the unique optical features of DUCNPs granted the DUCNP@Mn-MOF/FOE system synergistic chemodynamic and chemotherapeutic effects. The DUCNP@Mn-MOF nanocarrier effectively overcame the intrinsic limitations of FOE, such as its unfavorable physicochemical properties and limited in vivo potency. This complexed nanosystem was responsive to the tumor microenvironment and showed excellent tumor targeting capability. Thus, DUCNP@Mn-MOF/FOE exhibited highly selective and bioavailable drug delivery properties and is promising for cancer therapy. In a mouse breast cancer model, DUCNP@Mn-MOF/FOE inhibited tumor growth without significant toxicity. Therefore, the proposed nanosystem represents a promising theragnostic platform for multimodal combination diagnosis and therapy of tumors.

Recent advances in drug delivery systems for targeting brain tumors

Brain tumor accounts for about 1.6% of incidence and 2.5% of mortality of all tumors, and the median survival for brain tumor patients is only about 20 months. The treatment for brain tumor still faces many challenges, such as the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), the overexpressed efflux pumps, the infiltration, invasion, high heterogeneity of tumor cells, drug resistance and immune escape caused by tumor microenvironment (TME) and cancer stem cells (CSC). This review attempts to clarify the challenges for multi-functional nano drug delivery systems (NDDS) to cross the BBB and target the cancer cells or organelles, and also provides a brief description of the different types of targeted multi-functional NDDS that have shown potential for success in delivering drugs to the brain. Further, this review also summarizes the research progress of multi-functional NDDS in the combination therapy of brain tumors from the following sections, the combination of chemotherapy drugs, chemotherapy-chemodynamic combination therapy, chemotherapy-immunization combination therapy, and chemotherapy-gene combination therapy. We also provide an insight into the recent advances in designing multi-functional NDDS for combination therapy.

Advanced strategies for nucleic acids and small-molecular drugs in combined anticancer therapy.

Cancer has been considered as complex malignant consequence of genetic mutations that control the cellular proliferation, differentiation and homeostasis, thus making tumor treatment extremely challenging. To date, a variety of cargo molecules, including nucleic acids drugs (pDNA, miRNA and siRNA), therapeutic drugs (doxorubicin, paclitaxel, daunomycin and gefitinib) and imaging agents (radioisotopes, fluorescence dyes, and MRI contrast agents) have been regarded as the potential medicines in clinical application. However, non-single therapeutic drug could induce the satisfied clinical results because of tumor heterogeneity and multiple drug resistance and the nanotechnology-based combined therapy is becoming an advanced important mode for enhanced anticancer effects. The review gathers the current advanced development to co-deliver small-molecular drugs and nucleic acids for the anticancer therapy with nanomedicine-based combination. Furthermore, the superiority is definitely presented and the barriers are detail discussed to surmount the clinical challenges. In final, future perspectives in rational direction for combined tumor therapy of drugs and nucleic acids are exhibited.

Cancer-cell-membrane-camouflaged supramolecular self-assembly of antisense oligonucleotide and chemodrug for targeted combination therapy.

The anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins are critical regulators of cell death that are overexpressed in many cancer cells, especially in multi-drug resistant cancer cells. Combinatorial gene- and chemotherapies using antisense oligonucleotides (ASOs) to suppress the expression of Bcl-2-family mRNA and restore the sensitivity of the cell to chemodrugs provide a promising pathway for anticancer treatment. However, intrinsic differences between macromolecular ASOs and small molecular chemodrugs make their co-delivery challenging. Moreover, extraneous carriers may induce immunogenicity and inflammation problems. Herein, we develop a targeted nanodrug delivery system using the cationic amphiphilic chemodrug mitoxantrone (Mito), which interacts with Bcl-2 ASO through electrostatic interaction and self-assembles into nanoparticles (NP[Bcl-2/Mito]), whose size can be controlled by regulating the ratio of ASO and Mito. NP[Bcl-2/Mito] can protect the ASO from degradation during delivery and combine gene- and chemotherapies to improve the anticancer effect. Furthermore, cancer cell membranes (CCMs) derived from homologous tumors were used to camouflage NP[Bcl-2/Mito] (NP[Bcl-2/Mito]@CCM) to achieve immune escape and tumor targeting. Both in vitro and in vivo assessments demonstrate the excellent performance of NP[Bcl-2/Mito]@CCM for drug-resistant breast tumor therapy. This CCM-camouflaged ASO/chemodrug nanoplatform provides a promising pathway for the targeted delivery of ASOs and chemodrugs for tumor combination therapy.

A reactive oxygen species-responsive covalent organic framework for tumor combination therapy.

Herein, we report the first reactive oxygen species (ROS)-responsive dithioketal-linked covalent organic framework (COF) for synergetic chemotherapy and photodynamic therapy (PDT) of cancer. The singlet oxygen (1O2)-responsive COF dissociation and DC_AC50 drug release complement and reinforce each other to allow an efficient combination of PDT and chemotherapy.

Metal-rich cascade nanosystem for dual-pathway ferroptosis resistance regulation and photothermal effect for efficient tumor combination therapy.

Despite the therapeutic response of ferroptosis in various tumors, ferroptosis resistance has been found in numerous studies, significantly hindering the progress of ferroptosis anti-tumor therapy. Herein, we propose a metal-rich cascade nanosystem (Simvastatin-HMPB-Mn@GOx) combined with the dual-pathway regulation of ferroptosis resistance and photothermal therapy for efficient tumor combination therapy. The manganese-bonded hollow mesoporous Prussian blue (HMPB-Mn) serves as the photothermal agent and metal donor, and dissociates multivalent metal ions Mn2+, Fe3+ and Fe2+ to consume glutathione and amplify the Fenton reaction. Glucose oxidase (GOx) absorbed serves as the converter to provide hydrogen peroxide (H2O2) for the cascade Fenton reaction, causing a high burst of hydroxyl radicals (˙OH) and lipid peroxidation. Simvastatin innovatively acts as a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) inhibitor to decrease the expression of coenzyme Q10 (CoQ10) and glutathione peroxidase 4 (GPX4), eventually defeating ferroptosis resistance. The nanosystem acted in both classical and non-classical ferroptosis pathways and showed significant ferroptosis- and hyperthermia-induced anti-tumor efficacy both in vitro and in vivo. Thus, this study offers a promising way for ferroptosis and phototherapy to achieve complete tumor regression.