计算机辅助药物设计在新药研究中的应用

计算机辅助药物设计（CADD）是在计算机技术、分子药理学和分子生物学等多学科交叉发展的基础上形成的药物研发新技术,它的快速发展,极大地减少了新药创制的盲目性和偶然性。该文在介绍了CADD原理、方法及策略的基础上,对CADD在新药研发中的应用进展进行了回顾,并对其存在问题和应用前景进行了展望。     

DDGrid:一种大规模药物虚拟筛选网格

化合物活性筛选是创新药物研究的起点和具有决定意义的步骤,利用网格计算技术进行药物虚拟筛选能够极大提高药物筛选的有效性,同时可以大量减少新药研制的成本和时间。新药研发网格DDGrid是中国国家网格CNGrid的重要支持项目,通过实施主从模式架构并在网格资源监控中使用适配器模式,DDGrid可以对超过10万规模的化合物分子数据库进行虚拟筛选。     

Latch Applicator for Efficient Delivery of Dissolving Microneedles Based on Rapid Release of Elastic Strain Energy by Thumb Force (Adv. Funct. Mater. 11/2023)

Dissolving microneedle (DMN) is an attractive alternative to parenteral and enteral drug administration owing to its painless self-administration and safety due to non-generation of medical waste. For reproducible and efficient DMN administration, various DMN application methods, such as weights, springs, and electromagnetic devices, have been studied. However, these applicators have complex structures that are complicated to use and high production costs. In this study, a latch applicator that consists of only simple plastic parts and operates via thumb force without any external complex device is developed. Protrusion-shaped latches and impact distances are designed to accumulate thumb force energy through elastic deformation and to control impact velocity. The optimized latch applicator with a pressing force of 25 N and an impact velocity of 5.9 m s⁻¹ fully inserts the drug-loaded tip of the two-layered DMN into the skin. In an ovalbumin immunization test, DMN with the latch applicator shows a significantly higher IgG antibody production rate than that of intramuscular injection. The latch applicator, which provides effective DMN insertion and a competitive price compared with conventional syringes, has great potential to improve delivery of drugs, including vaccines.     

A NIR-II AIEgen-Based Supramolecular Nanodot for Peroxynitrite-Potentiated Mild-Temperature Photothermal Therapy of Hepatocellular Carcinoma

Compared to conventional photothermal therapy (PTT) which requires hyperthermia higher than 50 °C, mild-temperature PTT is a more promising antitumor strategy with much lower phototoxicity to neighboring normal tissues. However, the therapeutic efficacy of mild-temperature PTT is always restricted by the thermoresistance of cancer cells. To address this issue, a supramolecular drug nanocarrier is fabricated to co-deliver nitric oxide (NO) and photothermal agent DCTBT with NIR-II aggregation-induced emission (AIE) characteristic for mild-temperature PTT. NO can be effectively released from the nanocarriers in intracellular reductive environment and DCTBT is capable of simultaneously producing reactive oxygen species (ROS) and hyperthermia upon 808 nm laser irradiation. The generated ROS can further react with NO to produce peroxynitrite (ONOOˉ) bearing strong oxidization and nitration capability. ONOOˉ can inhibit the expression of heat shock proteins (HSP) to reduce the thermoresistance of cancer cells, which is necessary to achieve excellent therapeutic efficacy of DCTBT-based PTT at mild temperature (<50 °C). The antitumor performance of ONOOˉ-potentiated mild-temperature PTT is validated on subcutaneous and orthotopic hepatocellular carcinoma (HCC) models. This research puts forward an innovative strategy to overcome thermoresistance for mild-temperature PTT, which provides new inspirations to explore ONOOˉ-sensitized tumor therapy strategies.     

Freely Tailorable Yolk-Shell Encapsulation: Versatile Applications in Ultralow-k Dielectric,Drug Delivery Systems,and Catalysts

Herein, a facile, controllable, and versatile method is reported to prepare monodisperse yolk-shell and yolk-multishell silica nanoparticles (NPs) with mesoporous shells by a novel selective etching strategy. The mechanism of selective etching based on fluoride-silica chemistry is investigated in detail and thus provides a fundamentally novel principle for the fabrication of yolk-shell NPs. Specifically, this unprecedented and versatile synthesis strategy can be used to encapsulate essentially any silica-based, carbon-based, metal, metal oxide, or other possible NPs. Noteworthy is that most of the yolk-shell mesoporous silica (mSiO₂) NPs are prepared for the first time. To demonstrate the major structural and compositional advantages of the designed yolk-shell NPs, their applications in the fields of ultralow-dielectric constant (k) materials, drug delivery systems, and catalysts were explored. In detail, the lowest k value of the prepared yolk-shellordered mesoporous silica@mSiO₂/fluorinated polybenzoxazole composite films is 2.02; The obtained yolk-shell mSiO₂/C@mSiO₂/C NPs possess high hydrophilicity and pH-responsive sensitivity; The conversion of the catalytic reaction of the designed magnetic yolk-shell hollow Fe₃O₄@SiO₂/Au@mSiO₂ NPs at 20 min is 97% with a high conversion rate (92%) and recyclability even after 10 reuses. This innovative work lays a solid foundation for freely tailorable yolk-shell encapsulation and will greatly stimulate more efforts devoted to relevant research and development.     

Drug‐Loaded Mesoporous Tantalum Oxide Nanoparticles for Enhanced Synergetic Chemoradiotherapy with Reduced Systemic Toxicity

Combining chemotherapy and radiotherapy (chemoradiotherapy) has been widely applied in many clinical practices, showing promises in enhancing therapeutic outcomes. Nontoxic nanocarriers that not only are able to deliver chemotherapeutics into tumors, but could also act as radiosensitizers to enhance radiotherapy would thus be of great interest in the development of chemoradiotherapies. To achieve this aim, herein mesoporous tantalum oxide (mTa₂O₅) nanoparticles with polyethylene glycol (PEG) modification are fabricated. Those mTa₂O₅‐PEG nanoparticles could serve as a drug delivery vehicle to allow efficient loading of chemotherapeutics such as doxorubicin (DOX), whose release appears to be pH responsive. Meanwhile, owing to the interaction of Ta with X‐ray, mTa₂O₅‐PEG nanoparticles could offer an intrinsic radiosensitization effect to increase X‐ray‐induced DNA damages during radiotherapy. As a result, DOX‐loaded mTa₂O₅‐PEG (mTa₂O₅‐PEG/DOX) nanoparticles can offer a strong synergistic therapeutic effect during the combined chemoradiotherapy. Furthermore, in chemoradiotherapy, such mTa₂O₅‐PEG/DOX shows remarkably reduced side effects compared to free DOX, which at the same dose appears to be lethal to animals. This work thus presents a new type of mesoporous nanocarrier particularly useful for the delivery of safe and effective chemoradiotherapy.     

Emergence of Gold‐Mesoporous Silica Hybrid Nanotheranostics: Dox‐Encoded,Folate Targeted Chemotherapy with Modulation of SERS Fingerprinting for Apoptosis Toward Tumor Eradication

Strategically fabricated theranostic nanocarrier delivery system is an unmet need in personalized medicine. Herein, this study reports a versatile folate receptor (FR) targeted nanoenvelope delivery system (TNEDS) fabricated with gold core silica shell followed by chitosan–folic acid conjugate surface functionalization by for precise loading of doxorubicin (Dox), resembled as Au@SiO₂‐Dox‐CS‐FA. TNEDS possesses up to 90% Dox loading efficiency and internalized through endocytosis pathway leading to pH and redox‐sensitive release kinetics. The superior FR‐targeted cytotoxicity is evaluated by the nanocarrier in comparison with US Food and Drug Administration (FDA)‐approved liposomal Dox conjugate, Lipodox. Moreover, TNEDS exhibits theranostic features through caspase‐mediated apoptosis and envisages high surface plasmon resonance enabling the nanoconstruct as a promising surface enhanced Raman scattering (SERS) nanotag. Minuscule changes in the biochemical components inside cells exerted by the TNEDS along with the Dox release are evaluated explicitly in a time‐dependent fashion using bimodal SERS/fluorescence nanoprobe. Finally, TNEDS displays superior antitumor response in FR‐positive ascites as well as solid tumor syngraft mouse models. Therefore, this futuristic TNEDS is expected to be a potential alternative as a clinically relevant theranostic nanomedicine to effectively combat neoplasia.     

Redox and pH Dual Responsive Polymer Based Nanoparticles for In Vivo Drug Delivery

Responsive nanomaterials have emerged as promising candidates as drug delivery vehicles in order to address biomedical diseases such as cancer. In this work, polymer‐based responsive nanoparticles prepared by a supramolecular approach are loaded with doxorubicin (DOX) for the cancer therapy. The nanoparticles contain disulfide bonds within the polymer network, allowing the release of the DOX payload in a reducing environment within the endoplasm of cancer cells. In addition, the loaded drug can also be released under acidic environment. In vitro anticancer studies using redox and pH dual responsive nanoparticles show excellent performance in inducing cell death and apoptosis. Zebrafish larvae treated with DOX‐loaded nanoparticles exhibit an improved viability as compared with the cases treated with free DOX by the end of a 3 d treatment. Confocal imaging is utilized to provide the daily assessment of tumor size on zebrafish larva models treated with DOX‐loaded nanoparticles, presenting sustainable reduction of tumor. This work demonstrates the development of functional nanoparticles with dual responsive properties for both in vitro and in vivo drug delivery in the cancer therapy.     

Dual‐Action Cancer Therapy with Targeted Porous Silicon Nanovectors

There is a pressing need to develop more effective therapeutics to fight cancer. An idyllic chemotherapeutic is expected to overcome drug resistance of tumors and minimize harmful side effects to healthy tissues. Antibody‐functionalized porous silicon nanoparticles loaded with a combination of chemotherapy drug and gold nanoclusters (AuNCs) are developed. These nanocarriers are observed to selectively deliver both payloads, the chemotherapy drug and AuNCs, to human B cells. The accumulation of AuNCs to target cells and subsequent exposure to an external electromagnetic field in the microwave region render them more susceptible to the codelivered drug. This approach represents a targeted two‐stage delivery nanocarrier that benefits from a dual therapeutic action that results in enhanced cytotoxicity.