Tong Gao

Bio: Tong Gao is an academic researcher from Shandong University. The author has contributed to research in topics: Immune checkpoint & Tumor microenvironment. The author has an hindex of 2, co-authored 5 publications receiving 10 citations.

Nanoparticle-Loaded Polarized-Macrophages for Enhanced Tumor Targeting and Cell-Chemotherapy

Abstract: Cell therapy is a promising strategy for cancer therapy. However, its therapeutic efficiency remains limited due to the complex and immunosuppressive nature of tumor microenvironments. In this study, the “cell-chemotherapy” strategy was presented to enhance antitumor efficacy. M1-type macrophages, which are therapeutic immune cells with both of immunotherapeutic ability and targeting ability, carried sorafenib (SF)-loaded lipid nanoparticles (M1/SLNPs) were developed. M1-type macrophages were used both as therapeutic tool to provide immunotherapy and as delivery vessel to target deliver SF to tumor tissues for chemotherapy simultaneously. M1-type macrophages were obtained by polarizing macrophages using lipopolysaccharide, and M1/SLNPs were obtained by incubating M1-type macrophages with SLNP. Tumor accumulation of M1/SLNP was increased compared with SLNP (p < 0.01), which proved M1/SLNP could enhance tumor targeting of SF. An increased ratio of M1-type macrophages to M2-type macrophages, and the CD3+CD4+ T cells and CD3+CD8+ T cell quantities in tumor tissues after treatment with M1/SLNP indicated M1/SLNP could relieve the immunosuppressive tumor microenvironments. The tumor volumes in the M1/SLNP group were significantly smaller than those in the SLNP group (p < 0.01), indicating M1/SLNP exhibited enhanced antitumor efficacy. Consequently, M1/SLNP showed great potential as a novel cell-chemotherapeutic strategy combining both cell therapy and targeting chemotherapy. Highlights: 1 A polarized-macrophages-based drug delivery system (M1/SLNP) was presented for the cell-chemotherapy of cancer.2 Polarized-macrophages were used both as therapeutic tool to provide immunotherapy and as delivery vessel to target deliver chemotherapeutic drugs to tumor tissues for chemotherapy simultaneously.3 M1/SLNP was a multifunctional delivery system with simple structure, excellent safety, and without complex synthesis process.

Charge and Size Dual Switchable Nanocage for Novel Triple-Interlocked Combination Therapy Pattern

Abstract: Combination therapy is a current hot topic in cancer treatment. Multiple synergistic effects elicited by combined drugs are essential in improving antitumor activity. Herein, a pH-triggered charge and size dual switchable nanocage co-loaded with abemaciclib and IMD-0354 (PA/PI-ND) is reported, exhibiting a novel triple-interlocked combination of chemotherapy, immunotherapy, and chemoimmunotherapy. The charge reversal polymer NGR-poly(ethylene glycol)-poly(l-lysine)-dimethylmaleic anhydride (NGR-PEG-PLL-DMA, ND) in PA/PI-ND promotes the pH-triggered charge reversal from negative to positive and size reduction from about 180 to 10 nm in an acidic tumor microenvironment, which greatly enhances cellular uptake and tumor tissue deep penetration. With the PA/PI-ND triple-interlocked combination therapy, the chemotherapeutic effect is enhanced by the action of abemaciclib to induce cell cycle arrest in the G1 phase, together with the reduction in cyclin D levels caused by IMD-0354. The dual anti-tumor promoting immunotherapy is achieved by abemaciclib selectively inhibiting the proliferation of regulatory T cells (Tregs) and by IMD-0354 promoting tumor-associated macrophage (TAM) repolarization from an M2 to M1 phenotype. Furthermore, PA/PI-ND has improved anti-tumor efficiency resulting from the third synergistic effect provided by chemoimmunotherapy. Taken together, PA/PI-ND is a promising strategy to guide the design of future drug delivery carriers and cancer combination therapy.

High-Specific Isolation and Instant Observation of Circulating Tumour Cell from HCC Patients via Glypican-3 Immunomagnetic Fluorescent Nanodevice.

Abstract: Purpose Specific targeting receptors for efficiently capturing and applicable nanodevice for separating and instant observing of circulating tumour cells (CTC) are critical for early diagnosis of cancer. However, the existing CTC detection system based on epithelial cell adhesion molecule (EpCAM) was seriously limited by low expression and poor specificity of targeting receptors, and not instant observation in clinical application. Methods Herein, an alternative glypican-3 (GPC3)-based immunomagnetic fluorescent system (C6/MMSN-GPC3) for high-specific isolation and instant observation of CTC from hepatocellular carcinoma (HCC) patients' peripheral blood was developed. The high-specific HCC targeting receptor, GPC3, was employed for improving the sensitivity and accuracy in CTC detection. GPC3 monoclonal antibody (mAb) was linked to immunomagnetic mesoporous silica for specific targeting capture and separate CTC, and fluorescent molecule coumarin-6 (C6) was loaded for instant detection of CTC. Results The cell recovery (%) of C6/MMSN-GPC3 increased in 106 HL-60 cells (from 49.7% to 83.0%) and in whole blood (from 42% to 80.3%) compared with MACS® Beads. In clinical samples, the C6/MMSN-GPC3 could capture more CTC in the 13 cases of HCC patients and the capture efficiency was improved by 83.3%-350%. Meanwhile, the capture process of C6/MMSN-GPC3 was harmless, facilitating for the subsequent culture. Significantly, the C6/MMSN-GPC3 achieved the high-specific isolation and instant observation of CTC from HCC patients' blood samples, and successfully separated CTC from one patient with early stage of HCC (Stage I) and one post-surgery patient, further indicating the potential ability of C6/MMSN-GPC3 for HCC early diagnosis and prognosis evaluation. Conclusion Our study provides a feasible glypican-3 (GPC3)-based immunomagnetic fluorescent system (C6/MMSN-GPC3) for high-specific isolation and instant observation of HCC CTC.

Tumor-associated macrophages in cancer: recent advancements in cancer nanoimmunotherapies

Abstract: Cancer immunotherapy has emerged as a novel cancer treatment, although recent immunotherapy trials have produced suboptimal outcomes, with durable responses seen only in a small number of patients. The tumor microenvironment (TME) has been shown to be responsible for tumor immune escape and therapy failure. The vital component of the TME is tumor-associated macrophages (TAMs), which are usually associated with poor prognosis and drug resistance, including immunotherapies, and have emerged as promising targets for cancer immunotherapy. Recently, nanoparticles, because of their unique physicochemical characteristics, have emerged as crucial translational moieties in tackling tumor-promoting TAMs that amplify immune responses and sensitize tumors to immunotherapies in a safe and effective manner. In this review, we mainly described the current potential nanomaterial-based therapeutic strategies that target TAMs, including restricting TAMs survival, inhibiting TAMs recruitment to tumors and functionally repolarizing tumor-supportive TAMs to antitumor type. The current understanding of the origin and polarization of TAMs, their crucial role in cancer progression and prognostic significance was also discussed in this review. We also highlighted the recent evolution of chimeric antigen receptor (CAR)-macrophage cell therapy.

Tumor-associated macrophages in cancer: recent advancements in cancer nanoimmunotherapies

Abstract: Cancer immunotherapy has emerged as a novel cancer treatment, although recent immunotherapy trials have produced suboptimal outcomes, with durable responses seen only in a small number of patients. The tumor microenvironment (TME) has been shown to be responsible for tumor immune escape and therapy failure. The vital component of the TME is tumor-associated macrophages (TAMs), which are usually associated with poor prognosis and drug resistance, including immunotherapies, and have emerged as promising targets for cancer immunotherapy. Recently, nanoparticles, because of their unique physicochemical characteristics, have emerged as crucial translational moieties in tackling tumor-promoting TAMs that amplify immune responses and sensitize tumors to immunotherapies in a safe and effective manner. In this review, we mainly described the current potential nanomaterial-based therapeutic strategies that target TAMs, including restricting TAMs survival, inhibiting TAMs recruitment to tumors and functionally repolarizing tumor-supportive TAMs to antitumor type. The current understanding of the origin and polarization of TAMs, their crucial role in cancer progression and prognostic significance was also discussed in this review. We also highlighted the recent evolution of chimeric antigen receptor (CAR)-macrophage cell therapy.

Bioengineered nanogels for cancer immunotherapy.

Abstract: Recent years have witnessed increasingly rapid advances in nanocarrier-based biomedicine aimed at improving treatment paradigms for cancer. Nanogels serve as multipurpose and constructed vectors formed via intramolecular cross-linking to generate drug delivery systems, which is attributed predominantly to their satisfactory biocompatibility, bio-responsiveness, high stability, and low toxicity. Recently, immunotherapy has experienced unprecedented growth and has become the preferred strategy for cancer treatment, and mainly involves the mobilisation of the immune system and an enhanced anti-tumour immunity of the tumour microenvironment. Despite the inspiring success, immunotherapeutic strategies are limited due to the low response rates and immune-related adverse events. Like other nanomedicines, nanogels are comparably limited by lower focal enrichment rates upon introduction into the organism via injection. Because nanogels are three-dimensional cross-linked aqueous materials that exhibit similar properties to natural tissues and are structurally stable, they can comfortably cope with shear forces and serum proteins in the bloodstream, and the longer circulation life increases the chance of nanogel accumulation in the tumour, conferring deep tumour penetration. The large specific surface area can reduce or eliminate off-target effects by introducing stimuli-responsive functional groups, allowing multiple physical and chemical modifications for specific purposes to improve targeting to specific immune cell subpopulations or immune organs, increasing the bioavailability of the drug, and conferring a low immune-related adverse events on nanogel therapies. The slow release upon reaching the tumour site facilitates long-term awakening of the host's immune system, ultimately achieving enhanced therapeutic effects. As an effective candidate for cancer immunotherapy, nanogel-based immunotherapy has been widely used. In this review, we mainly summarize the recent advances of nanogel-based immunotherapy to deliver immunomodulatory small molecule drugs, antibodies, genes and cytokines, to target antigen presenting cells, form cancer vaccines, and enable chimeric antigen receptor (CAR)-T cell therapy. Future challenges as well as expected and feasible prospects for clinical treatment are also highlighted.

Primary Macrophage-Based Microrobots: An Effective Tumor Therapy In Vivo by Dual-Targeting Function and Near-Infrared-Triggered Drug Release.

Abstract: Macrophages (MΦs) have the capability to sense chemotactic cues and to home tumors, therefore presenting a great approach to engineer these cells to deliver therapeutic agents to treat diseases. However, current cell-based drug delivery systems usually use commercial cell lines that may elicit an immune response when injected into a host animal. Furthermore, premature off-target drug release also remains an enormous challenge. Here, we isolated and differentiated MΦs from the spleens of BALB/c mice and developed dual-targeting MΦ-based microrobots, regulated by chemotaxis and an external magnetic field, and had a precise spatiotemporal controlled drug release at the tumor sites in response to the NIR laser irradiation. These microrobots were prepared by coloading citric acid (CA)-coated superparamagnetic nanoparticles (MNPs) and doxorubicin (DOX)-containing thermosensitive nanoliposomes (TSLPs) into the MΦs. CA-MNPs promoted a magnetic targeting function to the microrobots and also permitted photothermal heating in response to the NIR irradiation, triggering drug release from TSLPs. In vitro experiments showed that the microrobots effectively infiltrated tumors in 3D breast cancer tumor spheroids, particularly in the presence of the magnetic field, and effectively induced tumor cell death, further enhanced by the NIR laser irradiation. In vivo experiments confirmed that the application of the magnetic field and NIR laser could markedly inhibit the growth of tumors with a subtherapeutic dose of DOX and a single injection of the microrobots. In summary, the study proposes a strategy for the effective anticancer treatment using the developed microrobots.