Advanced Therapeutics最新文献

The associations of the Notch pathway with the major oncogenic pathways (especially the receptor tyrosine kinases, RTKs) are primarily responsible for inducing EMT (epithelial to mesenchymal transition), angiogenesis, and chemoresistance. In this study, Axitinib is used in combination with LY411575 (γ-secretase inhibitor) and it is observed that the co-treatment synergistically induced apoptosis (by 37.36% in MDAMB231 and 27.9% in MDAMB468), arrests cells at the G2/M phase, decreases the stemness properties of the triple-negative breast cancer (TNBC) cells. It also diminishes the spheroid forming ability, enhances the expression of epithelial markers, such as E-cadherin (by 2.2 fold in MDAMB231 and 2.51 fold in MDAMB468), and downregulated the expression of mesenchymal markers. Additionally, the protein expression profile of the pro-oncogenic and pro-survival genes also reduces significantly after the administration of co-therapy, which is highlighted by a reduction in the levels of pEGFR, pFAK, pMAPK, NF-κB, etc. Moreover, the expression of pericyte markers (such as PDGFRs, α-SMA, c-kit, and NG2) reduces significantly in both TNBC cells upon co-treatment, thereby hinting toward the inhibition of epithelial-to-pericyte transition (EPT). The current work endows with the effectiveness of the co-therapy on the EMT and EPT dynamics of TNBC upon inhibition of the major crosstalk between the Vascular endothelial growth factor (VEGF)t and Notch pathway.

Dendritic cell (DC) vaccines play an important role in anti-tumor immunotherapy. Tumor-associated cells or cytokines in the tumor microenvironment (TME) can inhibit the antigen-presenting function of DC. Immunogenic cell death (ICD) can enhance the uptake and presentation of tumor antigens by DC. This study investigates the maturation mechanism of DC induced by low-temperature plasma (LTP), as well as the therapeutic and protective effects of LTP-induced DC vaccine in a tumor model. DC2.4 that is co-cultured with LTP-treated B16F10 (LTP-B16) or with these supernatants exhibited decreased phagocytic activity, increased production of cytokines (IL-12, IL-6, TNF-α, and IL-1β), and increased expression of cell surface activation markers (CD80, CD86, and MHC II). The expression of CD80⁺/CD86⁺ is decreased after pre-treatment with TLR4 and NF-κB (p65) inhibitors, respectively. In vivo, trials indicated that the LTP-induced DC vaccine-induced anti-tumor immunity and, when combined with cisplatin, synergistically reduced tumor growth.

Excessive scar formation is a major complication of wound healing. Premature release of anti-scarring drugs can negatively impact healing. This study aims to develop a targeted delivery system for the controlled release of anti-scarring drugs during the scar formation stage. Solid lipid nanoparticles (SLNs) coated with Clathrin, a cage-like protein, to prevent premature drug release is developed. Insulin-like growth factor (IGF) is conjugated to the SLNs for targeted delivery via its affinity for connective tissue growth factor (CTGF), a protein overexpressed during scar formation. The IGF-Clathrin-SLNs exhibited a size of 300 ± 20 nm and a zeta potential of 9.23 ± 0.4 mV. In vitro studies demonstrated sustained release of the encapsulated drug- kynurenic acid; less than 10% of kynurenic acid is released within three days, while over 50% is released within 10 h upon Clathrin removal using a surfactant at pH 8. Cellular uptake studies confirmed targeting efficacy. Fibroblasts with low CTGF expression displayed low uptake (<10%), whereas MCF7 cells with high CTGF expression showed significantly higher uptake (80%). This work demonstrates a promising targeted delivery platform for the controlled release of anti-scarring drugs during scar formation.

Wounds caused by radiation exposure are often hard to heal. The functional hydrogel can be used as a wound treatment material of multiple dimensions according to patients' needs. Hyaluronic acid hydrogel can be used to create a moist environment conducive to wound healing. In this study, new complex hydrogels based on physically crosslinked hyaluronic acid are investigated, which adopt the freeze-thaw technique, loaded with small molecule drugs deferoxamine and retinoic acid, and effectively promote the healing of radiation-induced skin ulcers. The combined application of deferoxamine and retinoic acid can improve skin injury after radiation, promoting angiogenesis, reducing inflammation, and protecting skin appendages. In vitro and in vivo results show enhanced cell viability and biological function, significantly accelerate healing of the irradiated wounds, and improve collagen deposition in the skin of the irradiated rats. Also, the skin appendages, such as hair follicles, are protected to a certain extent, implying functionally repairing the skin. Considering the ease of use of the hydrogel system in clinical applications, complex hydrogels can be considered a suitable candidate for treating radiation-induced skin injury.

Nucleic acid vaccines play important roles in the prevention and treatment of diseases. However, limited immunogenicity remains a major obstacle for DNA vaccine applications in the clinic. To address the issue, the present study investigates a cocktail approach to DNA vaccination. In this proof-of-the-concept study, the cocktail consists of two DNAs encoding viral hemagglutinin (HA) and granulocyte-macrophage colony stimulatory factor (GM-CSF), respectively. Data from the study demonstrate that recruitment and activation of antigen-presenting cells (APCs) can be substantially improved by spatiotemporal regulation of GM-CSF and HA expressions at the site of vaccination. The types of recruited APCs and their phenotypes are also controllable by adjusting the cocktail compositions. Compared to the mono-ingredient vaccine, the optimized cocktail vaccine is able to enhance the anti-viral humoral and T cell immune responses. No significant systemic inflammation is detected after either prime or boost immunization using the cocktail vaccine. Data in the study suggest that the DNA cocktail is a safe, effective, and controllable platform for improving vaccine efficacy.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Currently, the efficacy of existing eye-preserving local treatments for primary UM is unsatisfactory, expressing a need to explore a new therapy for UM treatment. α-Hemolysin (Hla), a pathogenic toxin fom Staphylococcus aureus, can induce cell death by disrupting the cell membrane and has potential antitumor effects. However, the broad toxicity of Hla limits its application in tumor therapy. In this study, the Hla-based gene therapy strategy that uses plasmids to encode the Hla gene and applies tumor-targeting nanoparticles to load the plasmids to form a nanocomplex is proposed. This gene formulation can overcome the obstructions of ocular barriers with its favorable neutral surface charge and nano size, allowing for precise targeting of tumor cells after local administration. The nanocomplex can effectively transfect tumor cells, and the expression of Hla can significantly inhibit tumor growth and directly exert a killing effect. Moreover, the nanocomplex can enhance the antitumor effect by recruiting CD4⁺ and CD8⁺ T lymphocytes and reducing angiogenesis after local administration. The study provides a novel gene therapy strategy for primary UM treatment and demonstrates a potential application for future gene therapy in intraocular tumors.

Research into mechanisms and potential applications of nanomaterials in medicine has expanded steadily in recent decades, with increasing translational focus. Development costs, including for clinical trials, are often cited as factors limiting the translational viability of novel nanomedicines, especially compared to small new molecular entities (NMEs) and therapeutic biologics. Yet, to date, there has been no systematic investigation into the clinical programs or costs of translating and commercializing nanomedicines, nor a comparison to NMEs and therapeutic biologics, to support these claims. Here, nanomedicines approved by the United States Food and Drug Administration's Center for Drug Evaluation and Research (CDER) from 2011 to 2023 are systematically identified and categorized. Nanomedicines were identified as formulations where submicron particle size contributes to product function. Like biologics and NMEs, nanomedicines are most frequently approved for oncological indications. Notably, all anti-cancer nanomedicines are indicated to treat orphan diseases, which is representative of the potential for nanomedicines to occupy pharmaceutical niches in treating diseases affecting smaller patient cohorts. The median estimated cost of pivotal trials for nanomedicines is 47% that of biologics and NMEs approved in the same timeframe. The findings indicate higher manufacturing costs in nanomedicine development may be mitigated by savings elsewhere, increasing translational viability.

Injectable depots have received increasing notoriety as local drug delivery vehicles for tumor treatment. Here, an intratumoral formulation of doxorubicin (Dox) is proposed that relies on the electrostatic interaction between the carboxylic group of click-type crosslinked hyaluronic acid (Cx-HA) and cationic Dox to achieve effective tumor treatment. The Dox-loaded click-type crosslinked HA (Cx-HA-Dox) formulation exhibits adequate injectability for intratumoral injection and rapidly forms a depot at the tumor site, remaining inside the tumor for over 18 days. This enhances the bioavailability and therapeutic efficacy of Dox primarily within the tumor, minimizing off-target side effects. Intratumoral injection of Cx-HA-Dox in animal models significantly suppresses tumor growth, as evidenced by a decrease in tumor volume over time. Histological analysis reveals limited angiogenesis in the treated tumors and an increase in the number of large apoptotic cells. Overall, the findings suggest that the electrostatically crosslinked Cx-HA-Dox depot can synergistically enhance the anticancer activity of Dox.