Molecular Pharmaceutics最新文献

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of anticancer agents with limited effective preventive or therapeutic interventions. Although fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, has demonstrated neuroprotective and analgesic properties, its clinical utility is hindered by low receptor affinity, poor subtype selectivity, and suboptimal bioavailability. A190, a highly selective and potent nonfibrate PPARα agonist, offers a promising alternative but is limited by poor aqueous solubility, resulting in reduced oral bioavailability and therapeutic efficacy. To address these limitations, an optimized oil-in-water (o/w) microemulsion formulation was developed using Box-Behnken design to enhance the solubility and intestinal permeability of A190. The A190 microemulsion exhibited physical stability with a droplet size of approximately 100 nm and a drug loading efficiency of greater than 95%. The effective and apparent permeability of A190 from the microemulsion was significantly higher compared to that of free A190 dispersion, respectively. Additionally, no significant impact on the cell viability was observed, indicating less toxicity and a good biocompatibility of the formulation components. The oral bioavailability of A190 microemulsion was approximately 5-fold higher compared to A190 dispersion, demonstrating the microemulsion's potential to greatly enhance the oral bioavailability of hydrophobic drugs. Furthermore, our findings reveal that orally administered A190 microemulsion effectively reduced CIPN-induced mechanical hypersensitivity, likely mediated through PPARα activation. A190 microemulsion was found to be equally effective at reducing the chronic inflammatory complete Freund's adjuvant-induced pain. These results underscore A190s potential as a nonopioid therapeutic candidate, utilizing a novel microemulsion formulation for the management of chemotherapy-induced neuropathic pain and chronic inflammatory pain.

Lipid-mediated delivery of active pharmaceutical ingredients (API) opened new possibilities in advanced therapies. By encapsulating an API into a lipid nanocarrier (LNC), one can safely deliver APIs not soluble in water, those with otherwise strong adverse effects, or very fragile ones such as nucleic acids. However, for the rational design of LNCs, a detailed understanding of the composition-structure-function relationships is missing. This review presents currently available computational methods for LNC investigation, screening, and design. The state-of-the-art physics-based approaches are described, with the focus on molecular dynamics simulations in all-atom and coarse-grained resolution. Their strengths and weaknesses are discussed, highlighting the aspects necessary for obtaining reliable results in the simulations. Furthermore, a machine learning, i.e., data-based learning, approach to the design of lipid-mediated API delivery is introduced. The data produced by the experimental and theoretical approaches provide valuable insights. Processing these data can help optimize the design of LNCs for better performance. In the final section of this Review, state-of-the-art of computer simulations of LNCs are reviewed, specifically addressing the compatibility of experimental and computational insights.

Lipid nanoparticles (LNPs) are an effective delivery system for gene therapeutics. By optimizing their formulation, the physiochemical properties of LNPs can be tailored to improve tissue penetration, cellular uptake, and precise targeting. The application of these targeted delivery strategies within the LNP framework ensures efficient delivery of therapeutic agents to specific organs or cell types, thereby maximizing therapeutic efficacy. In the realm of genome editing, LNPs have emerged as a potent vehicle for delivering CRISPR/Cas components, offering significant advantages such as high in vivo efficacy. The incorporation of machine learning into the optimization of LNP platforms for gene therapeutics represents a significant advancement, harnessing its predictive capabilities to substantially accelerate the research and development process. This review highlights the dynamic evolution of LNP technology, which is expected to drive transformative progress in the field of gene therapy.

Natural killer (NK) cell immunotherapy is a significant category in tumor therapy due to its potent tumor-killing and immunomodulatory effects. This research delves into exploring the mechanisms underlying the ability of amoxicillin to boost NK cell cytotoxicity in NK cell immunotherapy. Amoxicillin significantly enhances the cytotoxic activity of NK-92MI cells against MCF-7 cells by triggering the initiation of a cytolytic program in target cell-deficient NK-92MI cells and augmenting the degranulation level of NK-92MI cells in the presence of target cells. The ability of NK cells to recognize target cells was increased upon exposure to amoxicillin at low concentration (10 ng/mL). Additionally, the utilization of amoxicillin loaded in liposome (AMO@Liposome) for NK cell immunotherapy in a mouse breast cancer model resulted in an increased antitumor effect in comparison to without the treatment of AMO@Liposome. RNA transcriptome analysis showed that amoxicillin upregulated differential genes related to the synaptic vesicle cycle pathway and calcium signaling pathway, and FOSB, TNFRSF18, and H4C1 were identified as critical players. These studies suggest that the strategy of using amoxicillin in NK cell immunotherapy has potential applications in the field of tumor therapy.

This study aimed to develop and evaluate a novel fibroblast activation protein (FAP)-specific tracer, fluorine-18-labeled fibroblast activation protein inhibitor-FUSCC-07 ([¹⁸F]F-FAPI-FUSCC-07), for use in both preclinical and clinical settings. Preclinical evaluations were conducted to assess the stability and partition coefficient of [¹⁸F]F-FAPI-FUSCC-07. Experiments involving human glioma U87MG cells demonstrated its cellular uptake and inhibitory properties. Further investigations included biodistribution analysis and micropositron emission tomography/computed tomography (PET/CT) imaging in U87MG tumor-bearing mice, which revealed strong tumor uptake and prolonged retention. In the clinical setting, [¹⁸F]F-FAPI-FUSCC-07 was compared directly with [¹⁸F]F-FAPI-42 and [¹⁸F]F-FAPI-74 to evaluate its performance in imaging various cancers. By expanding the patient cohort, the study provided a more comprehensive assessment of tracer uptake in lesions. The findings demonstrated that [¹⁸F]F-FAPI-FUSCC-07 exhibited high stability in phosphate-buffered saline and fetal bovine serum, as well as hydrophilic properties. Clinical imaging results indicated significantly higher tumor uptake and improved target-to-blood pool ratios compared to the other tracers. Moreover, PET imaging of patients with diverse cancers showed that [¹⁸F]F-FAPI-FUSCC-07 consistently provided superior image contrast in most cases. These results represent the first clinical evidence supporting the feasibility of [¹⁸F]F-FAPI-FUSCC-07 for imaging across multiple tumor types. The study highlights its potential as a promising tracer for FAPI PET imaging, offering enhanced diagnostic precision and broader applicability in oncology.

The development of malignant tumors is a complex process that involves the tumor microenvironment (TME). An immunosuppressive TME presents significant challenges to current cancer therapies, serving as a key mechanism through which tumor cells evade immune detection and play a crucial role in tumor progression and metastasis. This impedes the optimal effectiveness of immunotherapeutic approaches, including cytokines, immune checkpoint inhibitors, and cancer vaccines. Tumor-associated macrophages (TAMs), a major component of tumor-infiltrating immune cells, exhibit dual functionalities: M1-like TAMs suppress tumorigenesis, while M2-like TAMs promote tumor growth and metastasis. Consequently, the development of various nanocarriers aimed at polarizing M2-like TAMs to M1-like phenotypes through distinct mechanisms has emerged as a promising therapeutic strategy to inhibit tumor immune escape and enhance antitumor responses. This Review covers the origin and types of TAMs, common pathways regulating macrophage polarization, the role of TAMs in tumor progression, and therapeutic strategies targeting TAMs, aiming to provide a comprehensive understanding and guidance for future research and clinical applications.

Resistant pathogens are increasingly posing a heightened risk to healthcare systems, leading to a growing concern due to the lack of effective antimicrobial treatments. This has prompted the adoption of antimicrobial photodynamic therapy (aPDT), which eradicates microorganisms by generating reactive oxygen species (ROS) through the utilization of a photosensitizer, photons, and molecular oxygen. However, a challenge arises from the inherent characteristics of photosensitizers, including photobleaching, aggregation, and self-quenching. Consequently, a strategy has been devised to adsorb or bind photosensitizers to diverse carriers to facilitate their delivery. Notably, metal–organic frameworks (MOFs) have emerged as a promising means of transporting photosensitizers, even though achieving uniform particle sizes through room-temperature synthesis remains a complex task. In this work, we have tackled the issue of heterogeneous particle size distribution in MOFs, achieving a particle size of 150 ± 50 nm. Subsequently, we harnessed Zeolite Imidazolate Framework 8 (ZIF-8), an excellent subclass of biocompatible MOF, to effectively load two distinct categories of photosensitizers, namely, Rose Bengal (RB) and porphyrin, using a simple, straightforward, and single-step process. Our findings indicate that the prepared RB@ZIF-8 complex generates a more substantial amount of reactive singlet oxygen species when subjected to photoirradiation (using green light-emitting diode (LED)) at low concentrations, in comparison with porphyrin@ZIF-8, as demonstrated in in vitro experiments. Additionally, we investigated the pH-responsive behavior of the complex to ascertain its implications under biological conditions. Correspondingly, the RB@ZIF-8 complex exhibited a more favorable IC₅₀ value against Escherichia coli compared to bare photosensitizers, ZIF-8 alone, and other photosensitizer-loaded ZIF-8 complexes. This underscores the potential of BioMOF as a promising strategy for combatting multidrug-resistant bacteria across a spectrum of infection scenarios, complemented by its responsiveness to stimuli.

The exposure of mRNA to water is likely to contribute to the instability of RNA vaccines upon storage under nonfrozen conditions. Using atomistic molecular dynamics (MD) simulations, we investigated the pH-dependent structural transition and water penetration behavior of mRNA-lipid nanoparticles (LNPs) with the compositions of Moderna and Pfizer vaccines against COVID-19 in an aqueous solution. It was revealed that the ionizable lipid (IL) membranes of LNPs were extremely sensitive to pH, and the increased acidity could cause a rapid membrane collapse and hydration swelling of LNP, confirming the high releasing efficiency of both LNP vaccines. The free energy profiles of water penetration showed that the conical structure of IL played a key role in obstructing water from entering the inner core of LNPs: the molecular geometry with more tail chains, lower linearity, and looser packing structure resulted in higher water permeability, leading to lower stability in nonfrozen liquid environment. On the other hand, the geometry of IL also dominated the fusion behavior of LNP with endosomal membrane during the endosomal escape. Thus, for LNP-based vaccines with both high release efficiency and high stability, a suitable molecular structure of ILs should be selected to seek a balance between the packing tightness and fusion rate of membranes.

Tyrosine kinase inhibitors have been employed for the treatment of lung cancer, owing to their role in regulating irregulated pathways or mutated genes. Bosutinib, a nonreceptor tyrosine kinase, has been recently investigated for lung cancer treatment. Bosutinib can also be used with paclitaxel as a combinatorial approach to receive a synergistic effect for the effective management of lung cancer. Furthermore, the nanocrystals of each can also be prepared and in combination can produce a more pronounced impact than the drug combination. Herein, the prepared Soluplus/lipid-stabilized nanocrystals of paclitaxel and bosutinib were rod to cubic in shape of about 150–250 nm. The nanocrystals were stable, provided controlled drug release, and exhibited a higher aerosolization performance. The nanocrystal combination demonstrated higher anticancer activity than the drug combination synergy against A549 cancer cells. The nanocrystals increased the level of cellular internalization in cancer cells, thereby inducing higher ROS generation and apoptosis of cancer cells. Furthermore, the lipid/Soluplus-stabilized nanocrystals exhibited higher translocation potential compared with only Soluplus-stabilized nanocrystals. The nanocrystals administered intratracheally showed a lower drug distribution to other organs, with prolonged drug retention in the lungs, suggesting the higher efficacy of developed nanocrystals in targeting the lungs. In conclusion, lipid-modified nanocrystals can be a novel approach for the effective management of lung cancer.

It is well known that impaired wound healing associated with diabetes mellitus has led to a challenging problem as well as a global economic healthcare burden. Conventional wound care therapies like films, gauze, and bandages fail to cure diabetic wounds, thereby demanding a synergistic and promising wound care therapy. This investigation aimed to develop a novel, greener synthesis of a laser-responsive silver nanocolloid (LR-SNC) prepared using hyaluronic acid as a bioreductant. The prepared LR-SNC was embedded into a stimuli-responsive in situ gel (LR-SNC-in situ gel) for easy application to the wound region. The physicochemical characterization of LR-SNC revealed a nanometric hydrodynamic particle size of 25.59 ± 0.72 nm with an −31.8 ± 0.7 mV surface ζ-potential. The photothermal conversion efficiency of LR-SNC was observed up to 62.9 ± 0.1 °C. In vitro evaluation of LR-SNC with and without NIR laser irradiation exhibited >70% cell viability, confirming its cytocompatibility for human keratinocyte cells. The in vitro scratch assay showed significant wound closure of 75.50 ± 0.02%. Further, the addition of cytocompatible LR-SNC into an in situ gel followed by laser irradiation resulted in substantial in vivo wound closure (86.69 ± 2.48%) in a diabetic wound-bearing mouse. Histological evaluation demonstrated salient features of the healed wounds, such as increased neovascularization, collagen density, migration of keratinocytes, as well as growth of hair follicles. Additionally, the findings showed a decrease in the levels of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and enhanced angiogenesis gene expression (VEGF and CD31), thereby healing the diabetic wound efficiently. The present study confirmed the potential role of silver nanocolloids followed by laser irradiation in treating diabetic wound mouse models.