The majority of clinically approved nanoparticle-mediated therapeutics are lipid nanoparticles (LNPs), and most of these LNPs are liposomes containing cholesterol. LNP formulations significantly alter the drug pharmacokinetics (PK) due to the propensity of nanoparticles for uptake by macrophages. In addition to readily engulfing LNPs, the high expression of cholesterol hydroxylases and reactive oxygen species (ROS) in macrophages suggests that they will readily produce oxysterols from LNP-associated cholesterol. Oxysterols are a heterogeneous group of cholesterol oxidation products that have potent immune modulatory effects. Oxysterols are implicated in the pathogenesis of atherosclerosis and certain malignancies; they have also been found in commercial liposome preparations. Yet, the in vivo metabolic fate of LNP-associated cholesterol remains unclear. We review herein the mechanisms of cellular uptake, trafficking, metabolism, and immune modulation of endogenous nanometer-sized cholesterol particles (i.e., lipoproteins) that are also relevant for cholesterol-containing nanoparticles. We believe that it would be imperative to better understand the in vivo metabolic fate of LNP-associated cholesterol and the immune implications for LNP-therapeutics. We highlight critical knowledge gaps that we believe need to be addressed in order to develop safer and more efficacious lipid nanoparticle delivery systems.

While tumor-associated macrophages (TAM) have pro-tumoral activity, the ablation of macrophages in cancer may be undesirable since they also have anti-tumoral functions, including T cell priming and activation against tumor antigens. Alendronate is a potent amino-bisphosphonate that modulates the function of macrophages in vitro, with potential as an immunotherapy if its low systemic bioavailability can be addressed. We repurposed alendronate in a non-leaky and long-circulating liposomal carrier similar to that of the clinically approved pegylated liposomal doxorubicin to facilitate rapid clinical translation. Here, we tested liposomal alendronate (PLA) as an immunotherapeutic agent for cancer in comparison with a standard of care immunotherapy, a PD-1 immune checkpoint inhibitor. We showed that the PLA induced bone marrow-derived murine non-activated macrophages and M2-macrophages to polarize towards an M1-functionality, as evidenced by gene expression, cytokine secretion, and lipidomic profiles. Free alendronate had negligible effects, indicating that liposome encapsulation is necessary for the modulation of macrophage activity. In vivo, the PLA showed significant accumulation in tumor and tumor-draining lymph nodes, sites of tumor immunosuppression that are targets of immunotherapy. The PLA remodeled the tumor microenvironment towards a less immunosuppressive milieu, as indicated by a decrease in TAM and helper T cells, and inhibited the growth of established tumors in the B16-OVA melanoma model. The improved bioavailability and the beneficial effects of PLA on macrophages suggest its potential application as immunotherapy that could synergize with T-cell-targeted therapies and chemotherapies to induce immunogenic cell death. PLA warrants further clinical development, and these clinical trials should incorporate tumor and blood biomarkers or immunophenotyping studies to verify the anti-immunosuppressive effect of PLA in humans.

Keywords can be considered as condensed versions of documents, which can play important role in some text processing tasks such as text indexing, summarization and categorization. However, there are many digital documents especially on the Internet that do not have a list of assigned keywords. Assigning keywords to these documents manually is a difficult task and requires appropriate knowledge of the topic. Automatic keyword extraction process can solve this problem. In this paper, we introduce a new improved method for keyword extraction using random walk model by considering position of terms within the document and information gain of terms corresponds to the whole set of documents. We also incorporate mutual information (MI) of terms with random walk model to extract keywords from documents. The experiments on standard test collections show that our method outperforms the previously proposed methods.

The immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma by significantly increasing survival rates, with the promise of durable disease remission in some pati... Plain language summary Immune checkpoint inhibitors are a class of medication called immunotherapy that use the patient’s immune system as a tool to combat cancer. When used in advanced melanoma, t...

Cholesterol is a component of most clinically approved lipid nanoparticles (LNPs) to enhance the stability, fluidity, and organization of the lipid structure. Endogenous cholesterol undergoes oxidation, producing cholesterol oxidation products (oxysterols), which are potent regulators of cellular processes implicated in immune dysfunction and the pathogenesis of cancers. LNP-associated cholesterol (LNP-cholesterol) is internalized by macrophages, and these cells also play critical roles in cholesterol metabolism and regulation of immune responses against cancer. Yet, the metabolic fate of LNP-cholesterol remains unclear. In this work, we elucidated the in vivo metabolic fate of LNP-cholesterol and demonstrated that LNP-oxysterols affect tumor cell proliferation and modulate macrophage functionality, impacting tumor growth in a murine model of cancer. Importantly, we showed that LNP-associated 7α-hydroxycholesterol, 7β-hydroxycholesterol, 24-hydroxycholesterol, and 27-hydroxycholesterol have antitumoral effects, while LNP-associated 7-ketocholesterol and 5,6-epoxycholesterol have protumoral effects, suggesting that cholesterol metabolism and cholesterol analogs can be leveraged to enhance LNP drug efficacy in cancer. Our findings indicate that LNP carriers have an unintended impact on tumor growth, which has the potential to diminish or enhance the anticancer efficacy of LNP-associated therapeutic cargo. Our results highlight the potential to engineer LNP carriers with immune-modulatory activity that combines the advantages of both nanoparticle-mediated drug delivery and immunotherapy.

Aims: Our study was carried out to appraise acetylcholinestrase (AChE) and butyrylcholinestrase (BChE) inhibitory activities of Grewia asiatica and Grewia tiliaefolia leaves extracts. Study Design: For the purpose of these experiments the extracts were subjected to an ex-vivo study. Place and Duration of Study: The study was carried out between June 2018 to December 2018 in the Department of Pharmacy, Southeast University, Dhaka, Bangladesh. Methodology: In this study, cholinesterase inhibitory activities of different fractions of crude ethanol extract of both plants were examined using swiss albino mice at 300 mg/kg b.w. dose. We determined anti-acetylcholinestrase (AChE) and anti-butyrylcholinestrase (BChE) activities using slightly modified Elman coupled enzyme assay. Results: The highest inhibition of bovine brain acetylcholinesterase and human blood butyrylcholinesterase were exhibited by PEF and CLF of G. asiatica with the IC₅₀ values were found to be 55.88 μg/ml and 26.14 μg/ml respectively whereas the highest inhibition of bovine brain acetylcholinesterase and human blood butyrylcholinesterase were exhibited by CLF of G. tiliaefolia. Conclusion: The result of the present study on various fractions of these plants has a considerable anti-acetylcholinesterase and anti-butyrylcholinesterase activities which suggest its effectiveness against various neurodegenerative disorders.