Engineered platelet-based immune engager for tumor post-surgery treatment.

Tumor metastasis and recurrence are principal reasons for the high mortality and poor prognosis of cancers. Inefficient engagement between T cell and tumor cell, as well as the universal existence of immune checkpoints, are important factors to the limited immunological surveillance of the immune systems to tumor cells. Herein, an immune engager based on engineered platelets with CD3 antibody modification (P-aCD3) was constructed to facilitate the contact between T cell and tumor cell via providing the anchoring sites of above two cells. Combined with the immune checkpoint blockade strategy, P-aCD3 effectively enhanced T cell mediated cytotoxicity and inhibited tumor recurrence and metastasis in mice melanoma postoperative model and breast cancer model, resulting in significantly prolonged survival of mice.

Potentiating cancer vaccination by adjuvant-loaded cryo-shocked tumor cells.

Cancer vaccine holds vast promise in potentiating tumor immunotherapy. Here, we developed a simple cancer vaccine based on the liquid nitrogen-treated cells (LNT cells) that engineered by one-shot shocking of the live tumor cells in liquid nitrogen. In this vaccine, the obtained LNT cells served as both tumor antigens and delivery vehicles to load the adjuvant imiquimod (R837). This design could achieve efficient co-uptake of antigen/adjuvant by antigen presenting cells (APCs) and prolong in vivo retention of tumor antigens and adjuvants. This adjuvant-loaded LNT cells augmented in vivo antitumor responses and enhanced survival in melanoma-bearing mouse model compared with conventional whole-cell vaccine of the mixture of tumor lysis and adjuvant.

A competing risk nomogram to predict cancer-specific mortality of patients with late-onset colorectal cancer.

OBJECTIVE: This study aimed to compare the clinical characteristics and survival differences between early-onset colorectal cancer (EOCRC) patients and late-onset colorectal cancer (LOCRC) patients, identify the risk factors for cancer-specific mortality (CSM) in LOCRC patients and construct a mortality risk assessment nomogram. METHODS: CRC patients diagnosed pathologically between 2010 and 2019 in the SEER database were included and divided into the early-onset group and the late-onset group, and the late-onset group was divided into the training and validation sets. The Fine-Gray competing risk model was applied to analyze the prognostic factors of LOCRC patients and establish a competing risk nomogram for CSM. RESULTS: There are differences in the distribution of multiple clinical features between the early-onset group and the late-onset group. Age, tumor size, histological type, pathological grading, T stage, N stage, M stage, SEER stage, primary tumor surgery, metastatic lesion surgery, radiotherapy, chemotherapy, neural invasion, and carcinoembryonic antigen (CEA) were independent influencing factors of the CSM rate in LOCRC patients. The C-index of the prognosis model outweighed 0.8, and the calibration curves fitted the reference line well. CONCLUSION: The CSM competing risk nomogram for LOCRC patients in this study had acceptable predictive performance that could be applied to the clinic.

Redox modulation with a perfluorocarbon nanoparticle to reverse Treg-mediated immunosuppression and enhance anti-tumor immunity.

Tumor hypoxia and high glutathione (GSH) expression promote regulatory T cell (Treg) infiltration and maintain its immunosuppressive function, which significantly reduces the response rate of cancer immunotherapy. Here, we developed an immunomodulatory nano-formulation (FEM@PFC) to reverse Treg-mediated immunosuppression by redox regulation in the tumor microenvironment (TME). Oxygen carried in perfluorocarbon (PFC) was delivered to the TME, thus relieving the hypoxic condition and inhibiting Treg infiltration. More importantly, GSH depletion by the prodrug efficiently restricted the Foxp3 expression and immunosuppressive function of Tregs, thus breaking the shackles of tumor immunosuppression. Additionally, the supplement of oxygen cooperated with the consumption of GSH to enhance the irradiation-induced immunogenic cell death and subsequent dendritic cell (DC) maturation, thereby efficiently promoting the activation of effector T cells and restricting the immunosuppression of Tregs. Collectively, the FEM@PFC nano-formulation reverses Treg-mediated immunosuppression and regulates the redox balance in the TME to boost anti-tumor immunity and prolong the survival of tumor-bearing mice, which provides a new immunoregulatory strategy from the perspective of redox modulation.

Site-Specific Polyplex on CCR7 Down-Regulation and T Cell Elevation for Lymphatic Metastasis Blocking on Breast Cancer.

Tumor metastasis contributes to high cancer mortality. Tumor cells in lymph nodes (LNs) are difficult to eliminate but underlie uncontrollable systemic metastasis. The CC chemokine receptor 7 (CCR7) is overexpressed in tumor cells and interacts with CC chemokine ligand 21 (CCL21) secreted from LNs, potentiating their lymphatic migration. Here, a site-specific polyplex is developed to block the CCR7-CCL21 signal and kill tumor cells toward LNs, greatly limiting their lymphatic infiltration. A CCR7-targeting small interfering RNA (siCCR7) is condensed by mPEG-poly-(lysine) with chlorin e6 (Ce6) modification (PPLC) to form PPLC/siCCR7. The knockdown of CCR7 by siCCR7 in tumor cells significantly reduced their response on CCL21 and LN tropism. Additionally, photodynamic therapy-mediated immune activation precisely targets and kills tumor cells released from the primary foci before they reaches the LNs, reducing the number of tumor cells entering the LNs. Consequently, the PPLC/siCCR7 polyplexes inhibited up to 92% of lung metastasis in 4T1 tumor bearing mice and reduced tumor cell migration to LNs by up to 80%. This site-specific strategy optimized anti-metastasis efficacy and promotes the clinical translational development of anti-metastatic therapy.

Different effects of silica added internal or external on in vitro dissolution of indomethacin hot-melt extrudates.

The purpose of this work was to investigate the effect on the dissolution behavior when silica was added in different ways. The solid dispersion was prepared by hot-melt extrusion (HME) using indomethacin (IND) as a model drug and Kollidon VA64 as a carrier. In order to change the dissolution behavior, the silica was added during or after the HME respectively, to obtain the corresponding silica internal-added solid dispersion (InSD) and silica external-added solid dispersion (ExSD). According to the results, the internal-added silicon dioxide could reduce the dissolution rate from 66.91%/h to 24.12%/h and the water infiltration rate from 0.37mm/h to 0.16mm/h in the phosphate buffer solution (PBS) of pH 6.8, so the formulation of InSD had a significant sustained release effect. But the infiltration rate of the ExSD was increased to 13.22mm/h when silica was added external, and the density of VA64 in the powder was decreased from 541.87mg/cm3 to 141.87mg/cm3, leading to a weak resistance to the external force, and the powder was easy to be dispersed after wetted by water so that the formulation of ExSD had a relatively higher dissolution rate. This phenomenon was more visible when the phosphate buffer solution was changed to pH 5.6 in which the API was more difficult to be dissolved. Accordingly, different addition ways of aerosil would change release behavior of the HME preparation.

Effects of surface charge of low molecular weight heparin-modified cationic liposomes on drug efficacy and toxicity.

Cationic liposome is a potential nanocarrier to deliver drugs to solid tumor with proven efficiency in targeting tumor tissues. However, the major limitation is their charge-related instability and blood toxicity via intravenous injection. In order to overcome these problems and to maintain tumor targeting potency, we modified the cationic liposomes with low molecular weight heparin (LMWH) to obtain series of liposomes with different surface charges. Both in vitro and in vivo studies including serum stability, blood hemolysis, cellular uptake, cytotoxicity and in vivo biodistribution were evaluated. The results indicated the cationic liposome with surface charge of 5 mV (denoted as LLip-C) had the similar stability in serum and mild hemocytolysis compared with that of anionic liposome (LLip-D), but better cellular uptake owing to electrostatic interaction between cationic liposomes and cell membranes. Furthermore, we prepared curcumin-loaded liposomes to investigate the therapy efficiency. The intracellular distribution of curcumin-loaded LLip-C (Curcumin-LLip-C) was inclined to locate in cytoplasm and nuclei than curcumin-loaded LLip-D (Curcumin-LLip-D). In vitro cytotoxicity of Curcumin-LLip-C also exhibited higher inhibition of tumor cells than that of Curcumin-LLip-D. These results certified that a slightly positive surface charge of nanocarriers could achieve the balance between well antitumor efficiency and mild adverse effects.

Near-infrared light triggered drug delivery system for higher efficacy of combined chemo-photothermal treatment.

The combination of chemotherapy and photothermal therapy is a promising strategy for cancer treatment. In the present study, indocyanine green (ICG), a widely used near-infrared (NIR) dye in photothermal therapy, and chemotherapeutic drug-doxorubicin (DOX) were loaded within the nanoparticles of novel designed arylboronic ester and cholesterol modified hyaluronic acid (PPE-Chol1-HA), denoted as PCH-DI. We take advantage of reactive oxygen species (ROS) production capability of ICG and ROS-sensitivity of arylboronic ester to realize controllable drug release. It was confirmed that PCH-DI exhibited remarkable photothermal effect and light-triggered faster release of DOX with NIR laser irradiation. DOX in PCH-DI/Laser group exhibited the most efficient nucleus binding toward HCT-116 colon cells in vitro. Furthermore, enhanced cytotoxicity and promoted tumor growth suppression effect of PCH-DI on HCT-116 tumor xenograft nude mice and AOM-induced murine orthotopic colorectal cancer model was achieved under NIR laser irradiation. Thus, the co-delivery system based on PCH appears to be a promising platform for the combined chemo-photothermal therapy in tumor treatment. STATEMENT OF SIGNIFICANCE: In case of chemo-photothermal combination therapy, the synchronism of treatments plays an important role in achieving expected antitumor efficiency. In this study, a light triggered ROS mediated drug delivery system was developed with the help of ROS-sensitive moieties of arylboronic ester and ROS producer of ICG. We innovatively make use of the ROS production capability of ICG under NIR laser irradiation to promote a faster release of DOX resulting from swelling of PCH-DI due to the presence of arylboronic ester. Intracellular ROS detection demonstrated that ROS level of PCH-I increased under irradiation. Moreover, the faster release behavior of DOX from PCH-DI with NIR laser irradiation was confirmed by the in vitro drug release and cellular uptake study. Meanwhile, local hyperthermia was verified by photothermal effect tests. Therefore, the synchronism of the combination therapy was achieved via light triggered faster release of DOX (chemo-therapy) and local hyperthermia (thermal-therapy) using PCH-DI under irradiation. It was reasonable to attribute the efficient anti-tumor efficiency of PCH-DI both in vitro and in vivo to the enhanced synergistic effect of chemo-photothermal combination therapy with realization of synchronism. To this end, this novel co-delivery system has provided a promising solution for achieving the synchronism of treatment to strengthen the efficiency of combination therapy.