Advanced Therapeutics最新文献

Breast cancer in canines is one of the leading causes of death globally due to client misinterpretation and improper diagnosis and treatment. In past centuries, the diagnosis and treatment of breast carcinoma in dogs followed conventional techniques adopted from human oncology. However, with increasing demand and scientific advancements in the upcoming future, there is an emerging necessity to modernize the diagnostic and treatments in canine breast cancer (CBC) patients. This review explores recent advances in diagnostic techniques and novel therapeutic approaches such as adjuvant-based targeted therapy, nanomaterial therapy, immune-based therapy, adoptive cell therapy, tumor vaccine, oncolytic virotherapy, and the use of noncoding RNAs in CBCs. In addition, the review discusses the healthcare policies aimed at improving diagnostic and therapeutic efficacy and future directions for translation from human oncology into veterinary oncology. By adopting these modern strategies, the quality of care can be significantly enhanced by translating them into practical applications with better outcomes and improved survival rates for canine patients.

Boosting the response rate of immune checkpoint blockade (ICB) therapy to improve treatment efficacy is a primary goal in cancer immunotherapy. One of the promising approaches involves focal tumor ablation to reduce tumor burden and trigger the in situ vaccination. Even though this combination strategy has demonstrated enhanced therapeutic outcomes in both preclinical research and clinical trials, limited research has comparatively investigated diverse ablation techniques. The optimal choice among focal therapy techniques remains largely unknown. In a murine colorectal cancer model (MC-38), the therapeutic efficacy of anti-PD-1 in combination with thermal ablation, cryoablation, and irreversible electroporation (IRE) is evaluated, utilizing well-characterized miniature probes. In this model, ICB monotherapy has limited effect in controlling tumor growth. IRE exhibits the most favorable synergistic effect with anti-PD-1 immunotherapy than thermal ablation or cryoablation, leading to the greatest primary tumor growth delay, longest tumor-free survival, and highest protection against secondary tumor challenge. Furthermore, the co-administration of IRE and anti-PD-1 significantly fosters the infiltration of CD8+ T cells into the tumor coupled with a remarkable stem-like progenitor phenotype. The findings demonstrate that IRE stands as a promising modality that can potentiate the antitumor efficacy when the tumor is poorly responding to ICB monotherapy.

Glucose-derived carbon nanospheres (CSP), uniquely derived by hydrothermal condensation process, inherently cross blood–brain-barrier (BBB) but distribute all over the brain. Albeit its potential to treat glioma as an effective drug delivery system, it is challenging to restrict drug-associated CSP within the glioma region and reduce non-specific side effects. Incidentally, gliomas moderately express sigma receptors (SR). Earlier, a cationic lipid-conjugated neuropsychotic drug, haloperidol (H8) is developed with SR-targetability and anticancer effect but with zero BBB-crossing ability. In this study, the CSP surface is modified with H8 (CH8 nano-conjugate) and dual targeting is achieved within glioma-tumor microenvironment: 1) glioma cells and 2) pro-proliferative M2 tumor-associated macrophages (TAM), as both express SR. CH8-treatment increases the survivability of orthotopic glioma-tumor bearing mice and significantly reduces tumor burden in the glioma-subcutaneous model. Further CH8-surface is modified by combining the brain tumor drug, carmustine (CH8-CRM). CH8-CRM nano-conjugate selectively enhances the survivability of orthotopic glioma-carrying mice and reduces tumor aggressiveness significantly in comparison to other treatment groups. Lysates from CH8-CRM-treated tumor show upregulation of cleaved-caspase 3, p53, but downregulation of pAkt. The combination treatment pronouncedly enhances the anti-glioma effect of H8. Conclusively, CH8-mediated dual-targeting via SR within orthotopic glioma-associated mice exemplifies the repurposing of neuropsychotic drugs for treating glioma.

Bacterial-derived molecules are at the basis of bacteria–bacteria and bacteria–host communication. In the context of cystic fibrosis (CF), they are considered possible therapeutic molecules for their natural binding capability on the immunomodulatory cytoplasmic aryl hydrocarbon receptor (AhR). An exponentially growing number of bacteria-derived molecules are identified as AhR activators, highlighting the need for systems to screen possible lead candidates. This challenge is addressed by applying an in vitro tool mimicking the two main barriers that potential AhR-targeting drugs must overcome: the cytoplasmic membrane and the CF pathological mucus. A small dataset of AhR ligands with potential therapeutic applications is selected. The apparent permeability of bacterial-derived molecules across a cellular membrane model is quantified and molecules capable of reaching the cytoplasmic target (AhR) are identified. In a second step, a CF in vitro mucus model is integrated with the phospholipid membrane and the impact of mucus on permeability is assessed. Overall, this study proposes an integrated mucosal platform as a suitable tool in the emerging field of postbiotics as a therapeutic strategy for CF. The mucosal platform can enable the rapid identification of molecules compatible with cytoplasmic targeting of AhR among candidate-drug representatives.

Temperature-responsive biodegradable injectable polymer (IP) hydrogel attains sustained-release of antigens and adjuvants persistently stimulating antigen-presenting cells. The degradability of IP hydrogels is adjustable by using tri-PCG whose termini are chemically modified. The release behavior of antigens and adjuvants is controlled by changing the composition of the injectable polymer system. Cellular and humoral responses induced by IP hydrogel vaccine formulations are investigated and discussed herein. More details can be found in article 2300296 by Yuta Yoshizaki, Yuichi Ohya, and co-workers.

Here, hybrid polymer-lipid nanoparticles are designed as colloidal carriers for Rapamycin, to improve the aqueous drug stability and to support the drug repositioning for cancer treatment, that is, against rhabdomyosarcoma (RMS). With this aim, Rapamycin – loaded hybrid nanoparticles are produced by using as nanoparticle core a graft copolymer obtained from the functionalization of the α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) with Rhodamine B (RhB), Polylactic acid (PLA), the PHEA-g-RhB-g-PLA, and different phospholipids, that is, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) coated, pegylated and Mannose/PEG, for the surface coating. The drug loading of these samples allows for controlled release, and improves drug stability at pH 5.5 and 7.4 compared to the free drug. Chemical-physical characterization confirms the nanostructure size below 200 nm, ideal for systemic administration, and easy re-dispersibility in aqueous media. Moreover, biological characterization to test the potential use as antitumor agent shows induction of cytotoxicity in human rhabdomyosarcoma (RD) and macrophage (RAW) cell lines in a time- and concentration – dependent manner, and stimulated autophagy, comparable to the free drug. The uptake study following the fluorescence of the copolymer reveals that the hybrid nanoparticles are internalized by both tested cell lines, with a significantly higher amounts of internalized particles in the case of surface mannosylated and/or pegylated systems.

In future, mRNA drugs likely play crucial roles in vaccines and protein replacement therapy etc. Lipid nanoparticles (LNPs) are the only formulation approved for mRNA delivery. However, in cancer vaccine, the mRNA encapsulated in LNP can only encode limited (20–40) tumor antigens. Due to highly heterogeneous of tumor cells and tumor antigens, including more diverse antigens could improve the efficacy of cancer vaccines. Including both strong immunogenic antigens and more diverse antigens could maximize the efficacy of cancer vaccines. Herein, poly (lactic-co-glycolic acid) (PLGA) nanoparticles and activated dendritic cell membrane were designed as mRNA delivery platforms, which possess merits such as prolonged protein expression, lyophilized formulation, and greater efficacy etc. Dendritic cells were activated with particles loading whole tumor antigens which can activate broad range antigen-specific T cells. The sustained release of mRNA in PLGA nanoparticles can significantly prolong protein expression in APCs, and lyophilization improved the stability of mRNA formulation. Compared with LNPs, these nanovaccines significantly improved the therapeutic efficacy of mRNA. In addition, tumor antigen-specific T cells in mice treated with nanovaccines was significantly greater than that treated with LNPs. Overall, a new platform for delivering mRNA was demonstrated, that can prolong protein expression and have better efficacy.

Doxorubicin is a widely used chemotherapeutic agent that can be hampered in its efficacy by the occurrence of multidrug resistance (MDR), due to the overexpression of the drug efflux transporter P-glycoprotein. As overcoming MDR still remains an unmet clinical need, this work aims at investigating an innovative strategy. Sonodynamic therapy (SDT) selectively kills cancer cells by combining low-intensity ultrasound (US) with a responsive chemical agent (sonosensitiser) that can be activated to produce reactive oxygen species (ROS). Therefore, the efficacy of SDT, using doxorubicin as sonosensitiser, is studied on human MDR ovarian (A2780/MDR) and colon (HT-29/MDR) cancer cells. The ultrasound exposure of MDR cells pre-incubated with non-cytotoxic concentrations of doxorubicin for 1 h has induced a statistically significant decrease of cell proliferation after 72 h. Interestingly, US has selectively triggered the ROS-mediated cytotoxicity of the doxorubicin entrapped into the cancer cell membrane leading to necrotic cancer cell death by lipid peroxidation. Moving from 2D to 3D HT-29/MDR cell cultures, the ability of SDT to reduce the growth of MDR spheroids by inducing significant necrotic cancer cell death is also confirmed. In conclusion, SDT can have a role in treating MDR tumors by eliciting the ROS-mediated cytotoxicity of doxorubicin.