Artificial Assembled Macrophage Co-Deliver Black Phosphorus Quantum Dot and CDK4/6 Inhibitor for Colorectal Cancer Triple-Therapy.

In recent years, therapeutic strategies based on macrophages have been inspiringly developed, but due to the high intricacy and immunosuppression of the tumor microenvironment, the widespread use of these strategies still faces significant challenges. Herein, an artificial assembled macrophage concept (AB@LM) was presented to imitate the main antitumor abilities of macrophages of tumor targeting, promoting the antitumor immunity, and direct tumor-killing effects. The artificial assembled macrophage (AB@LM) was prepared through an extrusion method, which is to fuse the macrophage membrane with abemaciclib and black phosphorus quantum dot (BPQD)-loaded liposomes. AB@LM showed good stability and tumor targeting ability with the help of macrophage membrane. Furthermore, AB@LM reversed the immunosuppressive tumor microenvironment by inhibiting regulatory T cells (Tregs) and stimulating the maturation of antigen-presenting cells to activate the antitumor immune response through triggering an immunogenic cell death effect. More importantly, in the colorectal tumor model in vivo, a strong cooperative therapeutic effect of photo/chemo/immunotherapy was observed with high tumor inhibition rate (95.3 ± 2.05%). In conclusion, AB@LM exhibits excellent antitumor efficacy by intelligently mimicking the abilities of macrophages. A promising therapeutic strategy for tumor treatment based on imitating macrophages was provided in this study.

Multipoint Costriking Nanodevice Eliminates Primary Tumor Cells and Associated-Circulating Tumor Cells for Enhancing Metastasis Inhibition and Therapeutic Effect on HCC.

Eliminating primary tumor ("roots") and inhibiting associated-circulating tumor cells (associated-CTCs, "seeds") are vital issues that need to be urgently addressed in cancer therapy. Associated-CTCs, which include single CTCs, CTC clusters, and CTC-neutrophil clusters, are essential executors in metastasis and the cause of metastasis-related death in cancer patients. Herein, a "roots and seeds" multipoint costriking nanodevice (GV-Lipo/sorafenib (SF)/digitoxin (DT)) is developed to eliminate primary tumors and inhibit the spread of associated-CTCs for enhancing metastasis inhibition and the therapeutic effect on hepatocellular carcinoma (HCC). GV-Lipo/SF/DT eliminates primary tumor cells by the action of SF, thus reducing CTC production at the roots and improving the therapeutic effect on HCC. GV-Lipo/SF/DT inhibits associated-CTCs effectively via the enhanced identification and capture effects of glypican-3 and/or vascular cell adhesion molecule 1 (VCAM1) targeting, dissociating CTC clusters using DT, blocking the formation of CTC-neutrophil clusters using anti-VCAM1 monoclonal antibody, and killing CTCs with SF. It is successfully verified that GV-Lipo/SF/DT increases the CTC elimination efficiency in vivo, thus effectively preventing metastasis, and shows enhanced antitumor efficacy in both an H22-bearing tumor model and orthotopic HCC models. Overall, the "roots and seeds" multipoint costriking strategy may open a new cancer treatment model for the clinic.

Depleting Tumor Infiltrating B Cells to Boost Antitumor Immunity with Tumor Immune-Microenvironment Reshaped Hybrid Nanocage.

Tumor infiltrating B cells (TIBs)-dependent immunotherapy has emerged as a promising method for tumor treatment. Depleting TIBs to boost antitumor immunity is a highly desirable yet challenging approach to TIBs-dependent immunotherapy. Herein, a tumor immune-microenvironment reshaped hybrid nanocage CPN-NLI/MLD coloaded with the Bruton's tyrosine kinase inhibitor ibrutinib, and cytotoxic drug docetaxel was developed for stepwise targeting TIBs and tumor cells, respectively. The tumor microenvironment responsive CPN-NLI/MLD promoted charge reversal and size reduction under acidic conditions (pH < 6.5). The accumulation of CPN-NLI/MLD in tumor tissues was achieved through CD13 targeting, and cellular uptake was increased due to the differ-targeting delivery. Targeting of docetaxel to tumor cells was achieved by the interaction of α-MSH modified on inner docetaxel-particle MLD and melanocortin-1 receptor on the surface of tumor cells. Targeting of ibrutinib to TIBs was achieved by the interaction of Neu5Ac modified on inner ibrutinib-particle NLI and CD22 on the surface of TIBs. The boosted antitumor immunity was achieved mainly by the inhibition of Bruton's tyrosine kinase activation mediated by ibrutinib, which reduced the proportion of TIBs, enhanced infiltration of CD8+ and CD4+ T cells, increased the secretion of immunogenic cytokines including IL-2 and IFN-γ, and inhibited the proliferation of regulatory T cells and secretion of immunosuppressive cytokines including IL-10, IL-4, and TGF-ß. Furthermore, CPN-NLI/MLD improved the antitumor efficiency of chemoimmunotherapy by reshaping tumor immune-microenvironment by TIBs depletion. Taken together, CPN-NLI/MLD represents a promising method for effective tumor treatment and combination therapy by TIBs-dependent immunotherapy.

Manipulation of TAMs functions to facilitate the immune therapy effects of immune checkpoint antibodies.

Immune checkpoint antibodies have emerged as novel therapeutics, while many patients are refractory. Researchers had identified tumor-associated macrophages (TAMs) is the pivotal factor involved in immune resistance and that manipulation of TAMs functions would improve the immunotherapies effectively. NF-κB pathway was one of the master regulators in TAMs manipulation. Inhibition of NF-κB pathway could achieve both re-polarization M2 TAMs and downregulation the expression of programmed cell death protein 1 (PD-1) ligand 1 (PD-L1) on TAMs to improve the effect of immunotherapies. Here, IMD-0354, inhibitor of NF-κB pathway was loaded in mannose modified lipid nanoparticles (M-IMD-LNP). Then, PD-1 antibody and M-IMD-LNP were co-loaded in matrix metalloproteinase 2 (MMP2) responsive and tumor target nanogels (P/ML-NNG). P/ML-NNG could co-deliver drugs to tumor site, disintegrated by MMP2 and release drugs to different targets. Evaluation of PD-1 expression, inhibition of NF-κB pathway, expression of PD-L1 on M2 TAMs and M2 TAMs re-polarization demonstrated that P/ML-NNG could block the PD-1/PD-L1 and NF-κB pathways simultaneously. Evaluation of CD4 + T cells, CD8 + T cells, Tregs, cytokines and antitumor immunity confirmed that IMD-0354 could improve the immunotherapies effectively. Those results provided forceful references for tumor immunetherapy.

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

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.

A Review on Nano-Based Drug Delivery System for Cancer Chemoimmunotherapy.

Although notable progress has been made on novel cancer treatments, the overall survival rate and therapeutic effects are still unsatisfactory for cancer patients. Chemoimmunotherapy, combining chemotherapeutics and immunotherapeutic drugs, has emerged as a promising approach for cancer treatment, with the advantages of cooperating two kinds of treatment mechanism, reducing the dosage of the drug and enhancing therapeutic effect. Moreover, nano-based drug delivery system (NDDS) was applied to encapsulate chemotherapeutic agents and exhibited outstanding properties such as targeted delivery, tumor microenvironment response and site-specific release. Several nanocarriers have been approved in clinical cancer chemotherapy and showed significant improvement in therapeutic efficiency compared with traditional formulations, such as liposomes (Doxil®, Lipusu®), nanoparticles (Abraxane®) and micelles (Genexol-PM®). The applications of NDDS to chemoimmunotherapy would be a powerful strategy for future cancer treatment, which could greatly enhance the therapeutic efficacy, reduce the side effects and optimize the clinical outcomes of cancer patients. Herein, the current approaches of cancer immunotherapy and chemoimmunotherapy were discussed, and recent advances of NDDS applied for chemoimmunotherapy were further reviewed.