Genetic effect of metformin use on risk of cancers: evidence from Mendelian randomization analysis.

BACKGROUND: Increasing number of studies reported the positive effect of metformin on the prevention and treatment of cancers. However, the genetic causal effect of metformin utilization on the risk of common cancers was not completely demonstrated. METHODS: Two-sample Mendelian Randomization (two-sample MR) analysis was conducted to uncover the genetically predicted causal association between metformin use and 26 kinds of cancers. Besides, two-step Mendelian Randomization (two-step MR) assessment was applied to clarify the mediators which mediated the causal effect of metformin on certain cancer. We utilized five robust analytical methods, in which the inverse variance weighting (IVW) method served as the major one. Sensitivity, pleiotropy, and heterogeneity were assessed. The genetic statistics of exposure, outcomes, and mediators were downloaded from publicly available datasets, including the Open Genome-Wide Association Study (GWAS), FinnGen consortium (FinnGen), and UK Biobank (UKB). RESULTS: Among 26 kinds of common cancers, HER-positive breast cancer was presented with a significant causal relationship with metformin use [Beta: - 4.0982; OR: 0.0166 (95% CI: 0.0008, 0.3376); P value: 0.0077], which indicated metformin could prevent people from HER-positive breast cancer. Other cancers only showed modest associations with metformin use. Potential mediators were included in two-step MR, among which total testosterone levels (mediating effect: 24.52%) displayed significant mediating roles. Leave-one-out, MR-Egger, and MR-PRESSO analyses produced consistent outcomes. CONCLUSION: Metformin use exhibited a genetically protective effect on HER-positive breast cancer, which was partially mediated by total testosterone levels.

Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis.

The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases. Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment. However, only a limited number of nanotherapies have enter clinical trials or are clinically approved. Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system (MPS), resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors. Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy. Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages. Polymer conjugation revived the parent camptothecin agent (e.g., 7-ethyl-10-hydroxy-camptothecin), enabling lipid nanoparticle encapsulation. Furthermore, macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin, increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy. When tested in a preclinical murine model of breast cancer, macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles. Furthermore, intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity. Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity. This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers.

Anti-PD-1 combined with targeted therapy: Theory and practice in gastric and colorectal cancer.

Gastric cancer (GC) and colorectal cancer (CRC) are frequent and aggressive malignancies worldwide. Despite the emergence of various therapeutic regimens, the prognosis of gastric and colorectal cancer is relatively poor. Immunotherapy targeting PD-1 is one of the most prevalent approaches, but it has a low response rate in most patients, particularly those with microsatellite stability (MSS). Recently, some targeted drugs have been found to remarkably enhance the anti-tumor immunity of cancer models, mainly through increasing the level of CD8+ T cells, M1-type macrophages, expression of PD-L1, and decreasing the level of regulatory T cells and M2 macrophages. The above finding implies that the combination of anti-PD-1 and targeted therapies may be a potential treatment for gastric and colorectal cancer patients. Although many encouraging preclinical results have been shown, the clinical outcomes were not approving enough. To further enhance the therapeutic efficacy and improve the prognosis in GC and CRC patients, deeper and larger-scale studies should be done to determine the complicated interactions between the two therapies and the concrete use of combination regimens.

Orally Administrable Therapeutic Nanoparticles for the Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common and lethal human malignancies worldwide; however, the therapeutic outcomes in the clinic still are unsatisfactory due to the lack of effective and safe therapeutic regimens. Orally administrable and CRC-targetable drug delivery is an attractive approach for CRC therapy as it improves the efficacy by local drug delivery and reduces systemic toxicity. Currently, chemotherapy remains the mainstay modality for CRC therapy; however, most of chemo drugs have low water solubility and are unstable in the gastrointestinal tract (GIT), poor intestinal permeability, and are susceptible to P-glycoprotein (P-gp) efflux, resulting in limited therapeutic outcomes. Orally administrable nanoformulations hold the great potential for improving the bioavailability of poorly permeable and poorly soluble therapeutics, but there are still limitations associated with these regimes. This review focuses on the barriers for oral drug delivery and various oral therapeutic nanoparticles for the management of CRC.

Therapeutic effects of dihydroartemisinin in multiple stages of colitis-associated colorectal cancer.

Colitis-associated colorectal cancer (CAC) develops from chronic intestinal inflammation. Dihydroartemisinin (DHA) is an antimalarial drug exhibiting anti-inflammatory and anti-tumor effects. Nonetheless, the therapeutic effects of DHA on CAC remain unestablished. Methods: Mice were challenged with azoxymethane (AOM) and dextran sulfate sodium (DSS) to establish CAC models. DHA was administered via oral gavage in different stages of CAC models. Colon and tumor tissues were obtained from the AOM/DSS models to investigate inflammatory responses and tumor development. Inflammatory cytokines in the murine models were detected through qRT-PCR and ELISA. Toll-like receptor 4 (TLR4) signaling-related proteins were detected by western blot. Macrophage infiltration was measured using immunostaining analysis, and apoptosis in the colon cancer cells was detected by flow cytometry and western blot. Results: DHA inhibited inflammatory responses in the early stage of the AOM/DSS model and subsequent tumor formation. In the early stage, DHA reversed macrophage infiltration in colon mucosa and decreased the expression of pro-inflammatory cytokines. DHA inhibited the activation of macrophage by suppressing the TLR4 signal pathway. In the late stage of CAC, DHA inhibited tumor growth by enhancing cell cycle arrest and apoptosis in tumor cells. Administration of DHA during the whole period of the AOM/DSS model generated an addictive effect based on the inhibition of inflammation and tumor growth, thereby improving the therapeutic effect of DHA on CAC. Conclusion: Our study indicated that DHA could be a potent agent in managing the initiation and development of CAC without obvious side effects, warranting further clinical translation of DHA for CAC treatment.

Tuning the efficacy of esterase-activatable prodrug nanoparticles for the treatment of colorectal malignancies.

Colorectal cancer (CRC) is one of the most common and lethal human cancers, and the clinical outcomes remain unsatisfactory because of the lack of effective and safe therapeutic regimens. Here, we describe a practical and potent delivery approach for the human topoisomerase I inhibitor 7-ethyl-10-hydroxycamptothecin (SN38) against CRC. Injectable SN38-loaded nanoparticles are obtained through covalent ligation of the SN38 agent with oligo-ε-caprolactone (oligoCL) to form oligoCL-SN38 conjugates via an esterase-activatable linkage followed by encapsulation of these prodrugs in exogenous polymer matrices. Prodrug nanoparticles with adaptive features are sufficiently stable during blood circulation, while active drugs can be released in response to intracellular esterase. The administration of nanoparticle drugs results in durable tumor recession, and the efficacy is superior to that of the current standard-of-care therapy, CPT-11, in multiple mouse models of CRC, one of which is a chemically induced orthotopic CRC. Elucidation of the mechanism underlying these differing efficacies shows that nanoparticle delivery produces a substantial increase in the intratumoral concentration of the therapeutic agent relative to CPT-11, which contributes to improved antitumor efficacy. Finally, these nanoparticle drugs are potentially less toxic in animals than CPT-11, as evidenced by the low incidence of bloody diarrhea and attenuated colonic damage. Overall, these results demonstrate that precisely engineered therapeutic nanoparticles are capable of enhancing efficacy, addressing the risk of tumor recurrence, and increasing drug tolerance, thus deserving further investigation.