Combinatorial drug-loaded quality by design adapted transliposome gel formulation for dermal delivery: In vitro and dermatokinetic study.

BACKGROUND: Ursolic acid is a powerful drug that possesses many therapeutic properties, such as hepatoprotection, immunomodulation, anti-inflammatory, antidiabetic, antibacterial, antiviral, antiulcer, and anticancer activity. Centella asiatica (L.) Urban (Umbelliferae) contains a triterpene called asiatic acid, which has been used effectively in traditional Chinese and Indian medicine system for centuries. Anticancer, anti-inflammatory, and neuroprotective properties are only some of the many pharmacological actions previously attributed to asiatic acid . AIM: The present work developed an optimized combinatorial drug-loaded nano-formulation by Quality by design approach. MATERIALS AND METHODS: The optimize transliposome for accentuated dermal delivery of dual drug. The optimization of drug-loaded transliposome was done using the "Box-Behnken design." The optimized formulation was characterized for vesicles size, entrapment efficiency (%), and in vitro drug release. Additionally, transmission electron microscopy (TEM), confocal laser scanning microscopy (CLSM), and dermatokinetic study were performed for further evaluation of drug-loaded optimized transliposome formulation. RESULTS: The optimized combinatorial drug-loaded transliposome formulation showed a particle size of 86.36 ± 2.54 nm, polydispersity index (PDI) 0.230 ± 0.008, and an entrapment efficiency of 87.43 ± 2.66% which depicted good entrapment efficiency. In vitro drug release of ursolic acid and asiatic acid transliposomes was found to be 85.12 ± 2.54% and 80.23 ± 3.23%, respectively, as compared to optimized ursolic acid and asiatic acid transliposome gel drug release that was 67.18 ± 2.85% and 60.28 ± 4.12%, respectively. The skin permeation study of ursolic and asiatic acid conventional formulation was only 32.48 ± 2.42%, compared with optimized combinatorial drug-loaded transliposome gel (79.83 ± 4.52%) at 12 h. After applying combinatorial drug-loaded transliposome gel, rhodamine was able to more easily cross rat skin, as observed by confocal laser scanning microscopy, in comparison with when the rhodamine control solution was used. DISCUSSION: The UA_AA-TL gel formulation absorbed more ursolic acid and asiatic acid than the UA_AA-CF gel formulation, as per dermatokinetic study. Even after being incorporated into transliposome vesicles, the antioxidant effects of ursolic and asiatic acid were still detectable. In most cases, transliposomes vesicular systems generate depots in the skin's deeper layers and gradually release the medicine over time, allowing for fewer applications. CONCLUSION: In overall our studies, it may be concluded that developed dual drug-loaded transliposomal formulation has great potential for effective topical drug delivery for skin cancer.

UPLC-MS/MS Method Development for Simultaneous Estimation of Diclofenac and Resveratrol-Loaded Liposomal Gel Formulation in Mice Skin Model: Application to Dermatokinetic Study.

The current research work describes the development of a simple, fast, sensitive and efficient bioanalytical UPLC/MS-MS method for the simultaneous estimation of diclofenac and resveratrol in mice skin samples. Quetiapine was used as an internal standard (IS). Analytical separation was performed on ACQUITY UPLC C18 Column (2.1 × 100 mm; 1.7 µm) using ammonium acetate (5 mM) in water and methanol (B) with isocratic elution at ratio of (50, 50 v/v) and flow rate of 0.4 mL/min. The duration of separation was maintained for 3 min. Electrospray ionization mass spectrometry in a positive and negative ionization mode was used for detection. Selective ion mode monitoring was used for the quantification of m/z 296.025> 249.93 for diclofenac, m/z 229.09 > 143.03 for resveratrol and MRM/ES+ve mode applied in m/z 384.25> 253.189 for IS transitions from parent to daughter ion. The lower detection and quantification limits were accomplished, and precision (repeatability and intermediate precision) with a coefficient of variation below 10% produced satisfactory results. The developed bioanalytical method was found to be useful for its suitability for the dermatokinetic evaluation of treatments through rat skin. Improvement in AUC (1.58-fold for diclofenac and 1.60-fold for resveratrol) and t1/2 in the dermis (2.13 for diclofenac and 2.21-fold for resveratrol) followed by epidermis was observed for diclofenac and resveratrol-loaded liposomal gel formulation over the conventional gel. Overall, the developed method for the dermatokinetic studies of the above-mentioned dual drugs-loaded liposome gel was found to be reproducible and effective for bioanalytical.

Nanomedicine-Based Drug-Targeting in Breast Cancer: Pharmacokinetics, Clinical Progress, and Challenges.

Breast cancer (BC) is a malignant neoplasm that begins in the breast tissue. After skin cancer, BC is the second most common type of cancer in women. At the end of 2040, the number of newly diagnosed BC cases is projected to increase by over 40%, reaching approximately 3 million worldwide annually. The hormonal and chemotherapeutic approaches based on conventional formulations have inappropriate therapeutic effects and suboptimal pharmacokinetic responses with nonspecific targeting actions. To overcome such issues, the use of nanomedicines, including liposomes, nanoparticles, micelles, hybrid nanoparticles, etc., has gained wider attention in the treatment of BC. Smaller dimensional nanomedicine (especially 50-200 nm) exhibited improved in vivo effectiveness, such as better tissue penetration and more effective tumor suppression through enhanced retention and permeation, as well as active targeting of the drug. Additionally, nanotechnology, which further extended and developed theranostic nanomedicine by incorporating diagnostic and imaging agents in one platform, has been applied to BC. Furthermore, hybrid and theranostic nanomedicine has also been explored for gene delivery as anticancer therapeutics in BC. Moreover, the nanocarriers' size, shape, surface charge, chemical compositions, and surface area play an important role in the nanocarriers' stability, cellular absorption, cytotoxicity, cellular uptake, and toxicity. Additionally, nanomedicine clinical translation for managing BC remains a slow process. However, a few cases are being used clinically, and their progress with the current challenges is addressed in this Review. Therefore, this Review extensively discusses recent advancements in nanomedicine and its clinical challenges in BC.

Innate Immune Response and Inflammasome Activation During SARS-CoV-2 Infection.

The novel coronavirus SARS-CoV-2, responsible for the COVID-19 outbreak, has become a pandemic threatening millions of lives worldwide. Recently, several vaccine candidates and drugs have shown promising effects in preventing or treating COVID-19, but due to the development of mutant strains through rapid viral evolution, urgent investigations are warranted in order to develop preventive measures and further improve current vaccine candidates. Positive-sense-single-stranded RNA viruses comprise many (re)emerging human pathogens that pose a public health problem. Our innate immune system and, in particular, the interferon response form an important first line of defense against these viruses. Flexibility in the genome aids the virus to develop multiple strategies to evade the innate immune response and efficiently promotes their replication and infective capacity. This review will focus on the innate immune response to SARS-CoV-2 infection and the virus' evasion of the innate immune system by escaping recognition or inhibiting the production of an antiviral state. Since interferons have been implicated in inflammatory diseases and immunopathology along with their protective role in infection, antagonizing the immune response may have an ambiguous effect on the clinical outcome of the viral disease. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin-domain-containing 3 (NLRP3) inflammasome pathway, and release of its products including the pro-inflammatory cytokines IL-6, IL-18, and IL-1ß. This predictive view may aid in designing an immune intervention or preventive vaccine for COVID-19 in the near future.