Medicine in Drug Discovery最新文献

In recent years, drug delivery has emerged as a more and more popular drug administration means for the improvement of pharmacokinetics, minimization of side effects, and enhancement of clinical outcomes. However, rapid clearance from the blood flow by immune systems limits the performance of drugs injected into the blood circulation. Thus, a new avenue for drug delivery systems by using the blood cells has drawn increasing attention. Blood cells can protect the drugs from macrophage uptake, prolong their circulation time, and improve their biocompatibility and stability. Here, we review recent advances in the developments and applications of numerous blood cell-based drug delivery systems and those inspired by blood cells. We highlight examples of vascular drug delivery using carriers red blood cells, white blood cells as well as platelets. We expect that this review will provide a jumping-off point or an inspiration for further investigation in this area.

Current antitubercular drug therapy requires more than six months and is unable to kill latent or dormant forms of tuberculosis. Thus, it is a need of new drug therapy to fight against dormant tuberculosis. However, the major obstacle in the development of novel drugs for dormant tuberculosis is the lack of relevant screening systems and using reliable probes to measure growth inhibition. Until now, several probes used in active state assays are significantly determining the inhibitory effect against the active state of mycobacteria. The dormant condition assays are based on hypoxia-derived dormancy which include resazurin reduction assay, nitrite reductase assay, XTT reduction menadione assay and low oxygen recovery assay. Major probes used in those assays are colorimetric/fluorescent dyes, enzymatic activity, and reporter genes include luciferase and fluorescent proteins. Although these dormant assays are based on hypoxia-induced features and difficult to maintain for a longer duration. Also, they further complicated by growth detection and pursuit of high throughput screening criteria. Here we reviewed complications of probes and assay techniques used for anti-dormant drug screening programs of tuberculosis. This will provide the knowledge to design better alternative drug screening method for the anti-dormant form of tuberculosis.

Brain metastases are intracranial recurrence of extracranial malignant tumors with a high incidence and poor prognosis. Owing to the particularity of intracranial localization, clinical diagnosis (neuroimaging and biopsy) of brain metastases is associated with shortcomings such as delayed diagnosis and biopsy invasiveness. Clinical treatment modalities consist of local therapies (resection and radiotherapy) and systemic therapies (chemotherapy, targeted therapy and immunotherapy). However, the efficiency of clinical therapies is severely hindered by 1) neurological impairment, 2) relapse, 3) blood–brain barrier, and 4) therapy resistance. Nanomedicine possesses great potentials in combating these clinical issues. This article reviewed backgrounds and recent advances of applying nanomedicine to address these above issues in clinical diagnosis and treatment of brain metastases.

Cancer immunotherapy is becoming an important option for treating patients with cancer in clinic. Given the heterogeneity of tumors between individuals, personalized cancer immunotherapy is the most promising one. Tremendous progresses have been achieved to initialize personalized immunity in patients through delivering tumor-derived neoantigens or adoptive transfer of engineered immune cells such as T cells and nature killer cells. However, the objective response rate and therapeutic efficiency of most personalized immunotherapies are hampered by the biophysical barriers against drug delivery and the limited infiltration of engineered cells into solid tumors. To overcome these limitations, versatile drug delivery systems have been developed to deliver personalized tumor antigens to target and promote intratumoral infiltration of lymphocytes, thus generating a local immunogenic niche to induce potent and durable antitumor immune responses. In this review, we will summarize the major barriers for efficient personalized immunization, highlight our lab and several other groups’ efforts in versatile drug delivery systems for delivering tumor-specific antigens, autologous tumor cell-derived antigens and combining with adoptive transfer of engineered immune cells. At the end of this review, we also look forward to the future development of drug delivery system-based personalized immunotherapy and its challenges for clinical translation.

The Wnt signaling pathway regulates cell proliferation, differentiation, migration, genetic stability, and apoptosis in almost all tissues and organs. It plays a crucial role in the normal development of embryos and the dynamic balance of adult tissues. When mutated or maladjusted, the Wnt signaling pathway activates its downstream signals and causes many diseases, especially cancer. Wnt/β-catenin is a classic Wnt signaling pathway whose high activation is closely related to tumor metastasis, migration, invasion, and chemotherapy resistance. Among them, the occurrence and development of lung cancer are closely related to the Wnt/β-catenin signaling pathway, and its key molecules, such as Wnt1, β-catenin, cyclinD1, and SOX-2, are expressed to varying degrees in the lung cancer tissue. This paper reviews the research status of the Wnt/β-catenin signaling pathway in lung cancer and the related drug research progress.

Microneedle (MN) patches have become an appealing approach for transdermal drug delivery due to their unique properties, such as enabling self-administration, causing no pain, increasing patient compliance, eliminating biohazardous sharps disposal and avoiding risk of needle-stick injury. Although dissolvable MN patches have achieved great success in bolus drug delivery in the skin, rapidly separable MN patches have recently attracted strong interest, especially in the treatment of chronic diseases, because of the short application time, long-acting efficacy and less frequent administration. In this review, we summarized three types of rapidly separable long-acting MN patches with different working mechanisms, followed by discussion of biomedical applications of those MN patches, including antigen delivery for vaccination, contraceptives delivery for long-term contraception, insulin delivery for diabetes treatment, ocular drug delivery for long-term therapy of ocular diseases, anti-tumor drug delivery for cancer therapy, pain relief drug delivery for analgesia, drug delivery for bacterial killing, and anti-obesity drug delivery for weight loss. Finally, we provided our perspectives on the future development of rapidly separable long-acting MN patches.

Due to the expanding and ageing world population, the importance and use of medicines is expected to increase. However, this will lead to a greater impact on the ecosystem and our health in the long term.

The concept of sustainability is rather slowly gaining traction and is currently still fragmented in the pharmaceutical field. A consortium of researchers from five European universities therefore advocates a global, systematic approach and places the emphasis on sustainability already in early stages of drug development, i.e. drug discovery. According to the researchers, the competent authorities, universities, research institutions and industrial organizations all need to take sustainability more into account. They summarized the most important opportunities on the basis of ten sustainability principles.

The paper of Gregory Gregoriadis brings into sharp relief the contrast in time taken for ‘individual technologies to emerge from research, find market opportunities and make a tangible impact’ [1]. This short commentary highlights some early events that were to underpin the success of a new anti-COVID vaccine.

Quercetin and isoquercitrin were reported to have anti-inflammatory effects on typical asthma. Therefore, we investigated quercetin-3-O-glycosides to clarify the potential for treating atypical asthma. The inhibitions of quercetin-3-O-glycosides on PDE1–5 activities and on high-affinity rolipram binding sites were measured. The sensitized guinea-pig trachealis was challenged by ovalbumin (OVA) to induce contractions. Ten female BABL/c mice in each group were sensitized by OVA on days 0 and 14. On day 21, these mice were injected a mixture of 1% OVA and Freund’s complete adjuvant (1:1). Mice were challenged using 1% OVA in saline for 30 min on days 28, 29, and 30 by ultrasonic nebulization. Twenty-four hours after the last nebulization, the blood and bronchoalveolar lavage fluid (BALF) of these mice were collected. Total immunoglobulin (Ig)E or IgG_2a level in the serum and cytokines in the both were determined. The number of inflammatory cells was counted using a hemocytometer. Rutin (30 and100 μmol/kg, p.o.) and quercitrin (100 μmol/kg, p.o.) significantly suppressed the increases in the inflammatory cells and cytokines in the BALF of mice. In contrast to rutin, quercitrin significantly increased the IFN-γ level. Both significantly increased the IgG_2a level in the serum and suppressed total and OVA-specific IgE levels in the serum and BALF of mice. Rutin, quercitrin, and isoquercitrin did not affect xylazine/ketamine-induced anesthesia. In conclusion, the above results suggest that quercetin-3-O-glycosides have few adverse effects and that rutin and quercitrin, but not isoquercitrin, may have the potential for treating atypical asthma.