Receptor-Assisted Nanotherapeutics for Overcoming the Blood-Brain Barrier.

Blood-brain barrier (BBB) is a distinguishing checkpoint that segregates peripheral organs from neural compartment. It protects the central nervous system from harmful ambush of antigens and pathogens. Owing to such explicit selectivity, the BBB hinders passage of various neuroprotective drug molecules that escalates into poor attainability of neuroprotective agents towards the brain. However, few molecules can surpass the BBB and gain access in the brain parenchyma by exploiting surface transporters and receptors. For successful development of brain-targeted therapy, understanding of BBB transporters and receptors is crucial. This review focuses on the transporter and receptor-based mechanistic pathway that can be manoeuvred for better comprehension of reciprocity of receptors and nanotechnological vehicle delivery. Nanotechnology has emerged as one of the expedient noninvasive approaches for brain targeting via manipulating the hurdle of the BBB. Various nanovehicles are being reported for brain-targeted delivery such as nanoparticles, nanocrystals, nanoemulsion, nanolipid carriers, liposomes and other nanovesicles. Nanotechnology-aided brain targeting can be a strategic approach to circumvent the BBB without altering the inherent nature of the BBB.

Harnessing the potential of nanoengineered siRNAs carriers for target responsive glioma therapy: Recent progress and future opportunities.

Past scientific testimonials in the field of glioma research, the deadliest tumor among all brain cancer types with the life span of 10-15 months after diagnosis is considered as glioblastoma multiforme (GBM). Even though the availability of treatment options such as chemotherapy, radiotherapy, and surgery, are unable to completely cure GBM due to tumor microenvironment complexity, intrinsic cellular signalling, and genetic mutations which are involved in chemoresistance. The blood-brain barrier is accountable for restricting drugs entry at the tumor location and related biological challenges like endocytic degradation, short systemic circulation, and insufficient cellular penetration lead to tumor aggression and progression. The above stated challenges can be better mitigated by small interfering RNAs (siRNA) by knockdown genes responsible for tumor progression and resistance. However, siRNA encounters with challenges like inefficient cellular transfection, short circulation time, endogenous degradation, and off-target effects. The novel functionalized nanocarrier approach in conjunction with biological and chemical modification offers an intriguing potential to address challenges associated with the naked siRNA and efficiently silence STAT3, coffilin-1, EGFR, VEGF, SMO, MGMT, HAO-1, GPX-4, TfR, LDLR and galectin-1 genes in GBM tumor. This review highlights the nanoengineered siRNA carriers, their recent advancements, future perspectives, and strategies to overcome the systemic siRNA delivery challenges for glioma treatment.

ApoE3 Anchored Liposomal Delivery of Rivastigmine for Brain Delivery: Formulation, Characterization, and In Vivo Pharmacokinetic Evaluation.

Rivastigmine hydrogen tartrate (RHT) is an acetylcholinesterase (AChE) inhibitor used in the management of Alzheimer's disease (AD). RHT is a BCS class-I drug that undergoes significant first-pass metabolism. Permeating a hydrophilic drug through the brain remains a major challenge in brain delivery. In this study, the RHT was incorporated inside the hydrophilic core of liposomes (LPS) and then coated with the ApoE3. ApoE3-coated RHT-loaded liposomes (ApoE3-RHT-LPS) were fabricated through the thin film hydration method using DSPE-PEG. The coating of LPS with ApoE3 enhances brain uptake and improves Aß clearance. The results obtained from the physicochemical characterization demonstrated that ApoE3-RHT-LPS shows a particle size of 128.6 ± 2.16 nm and a zeta potential of 16.6 ± 1.19. The % entrapment efficiency and % drug loading were found to be 75% and 17.84%, respectively. The data obtained from TEM and SEM studies revealed that the particle size of the LPS was less than 200 nm. An in vitro AChE assay was performed, and the results demonstrated the AChE inhibitory potential of ApoE3-RHT-LPS. Through the intravenous route, an in vivo pharmacokinetic study of formulation displayed improved brain uptake of RHT by ~ 1.3-fold than pure RHT due to ApoE3 coating. In vivo, biodistribution studies in vital organs suggested that the biodistribution of RHT to the liver was significantly reduced (p < 0.001), signifying an increase in the drug's half-life and blood circulation time. All research findings suggested that ApoE3 coating and LPS strategy are proven effective for improving the brain uptake of RHT designed for the management of AD.

Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata.

Alopecia areata is a chronic hair loss disorder that involves autoimmune disruption of hair follicles by CD8+  T cells. Most patients present with patchy hair loss on the scalp that improves spontaneously or with topical and intralesional steroids, topical minoxidil, or topical immunotherapy. However, recurrence of hair loss is common, and patients with extensive disease may require treatment with oral corticosteroids or oral Janus kinase (JAK) inhibitors, both of which may cause systemic toxicities with long-term use. Itaconate is an endogenous molecule synthesized in macrophages that exerts anti-inflammatory effects. To investigate the use of itaconate derivatives for treating alopecia areata, we designed a prodrug of 4-methyl itaconate (4-MI), termed SCD-153, with increased lipophilicity compared to 4-MI (CLogP 1.159 vs. 0.1442) to enhance skin and cell penetration. Topical SCD-153 formed 4-MI upon penetrating the stratum corneum in C57BL/6 mice and showed low systemic absorption. When added to human epidermal keratinocytes stimulated with polyinosinic-polycytidylic acid (poly I:C) or interferon (IFN)γ, SCD-153 significantly attenuated poly I:C-induced interleukin (IL)-6, Toll-like receptor 3, IL-1ß, and IFNß expression, as well as IFNγ-induced IL-6 expression. Topical application of SCD-153 to C57BL/6 mice in the resting (telogen) phase of the hair cycle induced significant hair growth that was statistically superior to vehicle (dimethyl sulfoxide), the less cell-permeable itaconate analogues 4-MI and dimethyl itaconate, and the JAK inhibitor tofacitinib. Our results suggest that SCD-153 is a promising topical candidate for treating alopecia areata.

Anti-fibrotic effects of valproic acid: role of HDAC inhibition and associated mechanisms.

Tissue injuries and pathological insults produce oxidative stress, genetic and epigenetic alterations, which lead to an imbalance between pro- and anti-fibrotic molecules, and subsequent accumulation of extracellular matrix, thereby fibrosis. Various molecular pathways play a critical role in fibroblasts activation, which promotes the extracellular matrix production and accumulation. Recent reports highlighted that histone deacetylases (HDACs) are upregulated in various fibrotic disorders and play a central role in fibrosis, while HDAC inhibitors exert antifibrotic effects. Valproic acid is a first-line anti-epileptic drug and a proven HDAC inhibitor. This review provides the current research and novel insights on antifibrotic effects of valproic acid in various fibrotic conditions with an emphasis on the possible strategies for treatment of fibrosis.