Rapamycin circumvents anti PD-1 therapy resistance in colorectal cancer by reducing PD-L1 expression and optimizing the tumor microenvironment.

The unresectable or postoperative recurrence of advanced metastatic colorectal cancer (CRC) is the difficulty of its clinical management, and pharmacological therapy is the main source of benefit. Immune checkpoint inhibitors are therapeutic options but are effective in approximately 5 % of patients with deficient mismatch repair (MMR)/microsatellite instability CRC and are ineffective in patients with MMR-proficient (pMMR)/microsatellite stable (MSS) CRCs, which may be associated with the tumor microenvironment (TME). Here, we propose a new combination strategy and evaluate the efficacy of rapamycin (Rapa) combined with anti-PD-1 (αPD-1) in CT26 tumor-bearing mice, azoxymethane (AOM)/dextran sodium sulfate (DSS) inflammation-associated CRC mice, CT26-Luc tumor-bearing mice with postoperative recurrence, and CT26 liver metastasis mice. The results revealed that Rapa improved the therapeutic effect of αPD-1 and effectively inhibited colorectal carcinogenesis, postoperative recurrence, and liver metastasis. Mechanistically, Rapa improved the anticancer effect of αPD-1, associated with Rapa reprograming of the immunosuppressive TME. Rapa effectively depleted α-SMA+ cancer-associated fibroblasts and degraded collagen in the tumor tissue, increasing T lymphocyte infiltration into the tumor tissue. Rapa induced the downregulation of programed cell death 1 ligand 1 (PD-L1) protein and transcript levels in CT26 cells, which may be associated with the inhibition of the mTOR/P70S6K signaling axis. Furthermore, co-culture of tumor cells and CD8+ T lymphocytes demonstrated that Rapa-induced PD-L1 downregulation in tumor cells increased spleen-derived CD8+ T lymphocyte activation. Therefore, Rapa improves the anti-tumor effect of αPD-1 in CRCs, providing new ideas for its use to improve combinatorial strategies for anti-PD-1 immunotherapy.

Nanoliposomes Encapsulated Rapamycin/Resveratrol to Induce Apoptosis and Ferroptosis for Enhanced Colorectal Cancer Therapy.

OBJECTIVES: Monotherapy is often ineffective for treating colorectal cancer. In this study, we developed PEG-modified liposomes loaded with rapamycin (Rapa) and resveratrol (Res) (Rapa/Res liposomes, or RRL) to investigate their therapeutic potential in colorectal cancer. METHODS: RRL were constructed using the reversed-phase evaporation method. We assessed the cytotoxicity, apoptosis, and ferroptotic effects of RRL on colorectal cancer HCT116 cells. The anti-tumor efficacy of RRL was evaluated in HCT116 xenograft mice. RESULTS: RRL had a particle size of 86.67 ± 1.10 nm and a zeta potential of -33.13 ± 0.49 mV. The coloaded formulation demonstrated satisfactory performance both in vitro and in vivo, resulting in increased cytotoxicity to HCT116 cells and significant suppression of HCT116 xenografts tumor growth. Mechanically, RRL significantly increased the apoptosis rate of HCT116 cells, induced ROS accumulation in tumor cells, and effectively downregulated the expression of the ferroptosis-associated proteins GPX4 and SLC7A11, demonstrating its superior efficacy compared to that of Rapa liposomes (Rapa/Lps) or Res liposomes (Res/Lps) alone. CONCLUSION: Coloading Rapa and Res into liposomes to promote apoptosis and ferroptosis in tumor cells represents a promising strategy for the treatment of colorectal cancer.

Stromal and tumor immune microenvironment reprogramming through multifunctional cisplatin-based liposomes boosts the efficacy of anti-PD-1 immunotherapy in pancreatic cancer.

The dense stromal barrier in pancreatic cancer tissues blocks intratumoral delivery and distribution of chemotherapeutics and therapeutic antibodies, causing poor chemoimmunotherapy responses. We designed a multi-targeted pH-sensitive liposome which encapsulates cisplatin (Pt) in its water core (denoted as ATF@Pt Lps) and shows high affinity for uPAR receptors in pancreatic cancer cells, tumor-associated macrophages, and cancer-associated fibroblasts. Systemic administration of ATF@Pt Lps enabled overcoming the central stromal cellular barrier and effective drug delivery into tumor cells, resulting in a strong therapeutic response in a Panc02 cell derived transplanted tumor mouse model. More importantly, ATF@Pt Lps degradation of collagen contributes to the infiltration of CD8+ T cells into tumors as well as an enhanced accumulation of anti PD-1 monoclonal antibodies. Furthermore, the killing of tumor cells by Pt also leads to the release of tumor antigens, which promote the proliferation of immune cells, especially CD83+ cells, Th1 CD4+ cells, and CD8+ cytotoxic T cells, that converted an immunoscore "cold" pancreatic cancer into a pro-immune "hot" tumor. A further combination with an immune checkpoint agent, anti PD-1 antibodies that inhibit PD-1, can enhance tumor specific cytotoxic T cell response. Accordingly, ATF@Pt Lps displays multi-targeting, controlled drug release, stromal disruption, enhanced penetration, killing of cancer cells, modification of the immunosuppressive microenvironment, and enhancement of immunity. This study provides important mechanistic information for the further development of a combination of ATF@Pt Lps and anti PD-1 antibodies for the effective treatment of pancreatic cancer.

Multi-targeting liposomal codelivery of cisplatin and rapamycin inhibits pancreatic cancer growth and metastasis through stromal modulation.

Pancreatic cancer treatment faces challenges due to drug resistance as well as liver metastasis. As a new strategy for treating pancreatic cancer, combination therapy is now available, but the dense mesenchymal barrier in the tumor tissue blocks drug delivery and impairs its therapeutic efficacy. To address this issue, we prepared an ATF peptide-decorated liposomal co-loaded with cisplatin and rapamycin (ATF@Pt/Rapa Lps), which targets both tumor cells and cancer-associated fibroblasts that express uPAR receptors. In tumor sphere penetration experiments, ATF peptide modified liposomes significantly enhanced deep penetration. More importantly, the ATF@Pt/Rapa Lps disrupted the stroma, as demonstrated by the downregulation of ɑ-SMA, I collagen, and fibronectin protein in vivo and in vitro. In this way, highly effective drug delivery to tumor cells can be achieved. As expected, there was a stronger inhibition of cell proliferation and migration by ATF@Pt/Rapa Lps in vitro compared to free Pt/Rapa and Pt/Rapa Lps. Furthermore, ATF@Pt/Rapa Lps showed greater therapeutic effects in PANC02 transplanted tumor mice and liver metastasis mice models. Ultimately, multi-targeting nanomedicines co-loaded with Rapa and cisplatin may provide a new approach to treating metastatic pancreatic cancer.

Synergistic anti-tumour activity of ginsenoside Rg3 and doxorubicin on proliferation, metastasis and angiogenesis in osteosarcoma by modulating mTOR/HIF-1α/VEGF and EMT signalling pathways.

OBJECTIVES: The most common cause of osteosarcoma (OS) death is lung metastasis. Currently, doxorubicin is the primary chemotherapy drug used to treat OS, however, it is not effective in inhibiting metastasis, and it has obvious cardiotoxicity. The anticancer activity of ginsenoside Rg3 has been demonstrated in a variety of malignant tumours. The aim of this study was to determine the potential role of ginsenoside Rg3 and doxorubicin in OS and the possible mechanism. METHODS: The potential synergistic effects of ginsenoside Rg3 and doxorubicin on human osteosarcoma cells 143B and U2OS, human umbilical vein endothelial cells, and mice receiving 143B xenografts and lung metastases were investigated. KEY FINDINGS: Our study demonstrated that the combination of ginsenoside Rg3 and doxorubicin significantly inhibited cell proliferation, metastasis and angiogenesis in vitro. Mechanically, the anti-tumour activity of ginsenoside Rg3 and doxorubicin by modulating mTOR/HIF-1α/VEGF and EMT signalling pathways. Furthermore, ginsenoside Rg3 combined with doxorubicin inhibits tumour growth and lung metastasis in 143B-derived murine osteosarcoma models. More importantly, ginsenoside Rg3 can effectively ameliorate doxorubicin-induced weight loss and cardiotoxicity in mice. CONCLUSIONS: Consequently, we concluded that the combination of ginsenoside Rg3 and doxorubicin displayed an evidently synergistic effect, which has the potential to be used as an effective and safe therapeutic approach for OS treatment.

(2×1) Reconstruction Mechanism of Rutile TiO2(011) Surface.

Understanding the reconstruction kinetics of solid surfaces involving an ensemble of atomic movements is practically important but challenging due to the complexity of high-dimensional potential energy surfaces. Herein, we develop a step-deciding technique incorporated with the nudged elastic band method, which enables multidirection pathway sampling and ensures the capture of a minimum energy path (MEP). Using this approach, the (2×1) reconstruction mechanism of a rutile-TiO2(011) surface, a classic and long-standing open problem in the fields of surface science and heterogeneous catalysis, is quantified, and the MEP is explicitly identified and explained. Following the least-bond-breaking rule, it gives a stepwise Ti-O bond cleavage mechanism with a collection of decoupled local structural relaxation modes at an overall barrier of 1.25 eV critically affected by initial Ti-O bond opening, which is much lower than the common synergy mechanism. Moreover, the adsorption-induced reconstruction is rationalized considering practical reaction conditions, where H atom adsorbate is shown to effectively stabilize the labile one-fold O1c intermediate and promote the reconstruction kinetics. This work reveals the reconstruction mechanism regarding multiatom movements and provides a general method for the structural exploration of other complicated systems.

Rapamycin Liposomes Combined with 5-Fluorouracil Inhibits Angiogenesis and Tumor Growth of APC (Min/+) Mice and AOM/DSS-Induced Colorectal Cancer Mice.

Background: Transgenic C57BL/6-APC(Min/+) spontaneous cancer mouse model and the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS) chemically induced orthotopic colorectal cancer mouse model represented distinct pathogenesis of colorectal cancers. Our previous study revealed that the combination of Rapamycin liposomes (Rapa/Lps) and 5-Fluorouracil (5-FU) has anti-colorectal cancer effects. However, the therapeutic efficacy of Rapa/Lps and 5-FU in other colorectal cancer mice models is yet to be thoroughly explored. The purpose of this study was to investigate the anti-tumor effect of Rapa/Lps combined with 5-FU in vivo and in vitro. Methods: In this study, we evaluated the effect of Rapa/Lps and 5-FU on APC (Min/+) mice and AOM/DSS-induced colorectal cancer mice. The small intestine, colorectum, serum, and plasma of mice in each group were collected following sacrifice to record the number of tumors. HE staining was utilized for observing pathological damage to intestine tissues. Tube formation assay, Transwell assay, wound healing assay, Western Blot were used to explore the anti-angiogenesis effect of drugs in HUVECs. Results: As expected, Rapa/Lps and 5-FU significantly suppressed tumor formation, decreased the number of tumors, and tumor load both in two mouse models, and had no influence on mouse weight. Mechanically, the anti-tumor effect of the drug also was associated in inhibiting angiogenesis and proliferation. Furthermore, we found that Rapa/Lps obviously inhibited HUVECs tube formation and migration. Conclusion: Altogether, we revealed the Rapa/Lps synergism with 5-FU decreased colon and small intestinal tumorigenesis in AOM/DSS-treated and APC (Min/+) mice, respectively, and correlated with anti-angiogenesis.

SSIA: A sensitivity-supervised interlock algorithm for high-performance microkinetic solving.

Microkinetic modeling has drawn increasing attention for quantitatively analyzing catalytic networks in recent decades, in which the speed and stability of the solver play a crucial role. However, for the multi-step complex systems with a wide variation of rate constants, the often encountered stiff problem leads to the low success rate and high computational cost in the numerical solution. Here, we report a new efficient sensitivity-supervised interlock algorithm (SSIA), which enables us to solve the steady state of heterogeneous catalytic systems in the microkinetic modeling with a 100% success rate. In SSIA, we introduce the coverage sensitivity of surface intermediates to monitor the low-precision time-integration of ordinary differential equations, through which a quasi-steady-state is located. Further optimized by the high-precision damped Newton's method, this quasi-steady-state can converge with a low computational cost. Besides, to simulate the large differences (usually by orders of magnitude) among the practical coverages of different intermediates, we propose the initial coverages in SSIA to be generated in exponential space, which allows a larger and more realistic search scope. On examining three representative catalytic models, we demonstrate that SSIA is superior in both speed and robustness compared with its traditional counterparts. This efficient algorithm can be promisingly applied in existing microkinetic solvers to achieve large-scale modeling of stiff catalytic networks.

CATKINAS: A large-scale catalytic microkinetic analysis software for mechanism auto-analysis and catalyst screening.

As an effective method to analyze complex catalytic reaction networks, microkinetic modeling is gaining increasing popularity in the catalytic activity evaluation and rational design of heterogeneous catalysts. An automated simulator with stable and reliable performance is especially useful and in great request. Here we introduce the CATKINAS package developed for large-scale microkinetic modeling and analysis. Featuring with a multilevel solver and a multifunctional analyzer, CATKINAS can provide both accurate solutions and various quantitative and automatic analysis for a wide range of catalytic systems. The structure and the basic workflow are overviewed with the multilevel solver particularly illustrated. Also, we take the CO methanation reaction as an example to illustrate the application and efficiency of the CATKINAS package.