Design and biological evaluation of Repaglinide loaded polymeric nanocarriers for diabetes linked neurodegenerative disorder: QbD-driven optimization, in situ, in vitro and in vivo investigation.

Diabetes mellitus is a metabolic disorder characterized by inadequate insulin secretion and signaling dysfunction, leading to a vast spectrum of systemic complications. These complications trigger cascades of events that result in amyloid-beta plaque formation and lead to neurodegenerative disorders such as Alzheimer's. Repaglinide (REP) an insulinotropic agent, suppresses the down regulatory element antagonist modulator (DREAM) and enhances the ATF6 expression to provide neuroprotection following the DREAM/ATF6/apoptotic pathway. However, oral administration of REP for brain delivery becomes more complicated due to its physicochemical characteristics (high protein binding (>98%), low permeability, short half-life (∼1 h), low bioavailability). Therefore, to circumvent these problems, we develop a polymeric nanocarrier system (PNPs) by in-house synthesized di-block copolymer (PEG-PCL). PNPs were optimized using quality by design approach response surface methodology and characterized by particle size (112.53 ± 5.91 nm), PDI (0.157 ± 0.08), and zeta potential (-6.20 ± 0.82 mV). In vitro release study revealed that PNPs (∼70% in 48 h) followed the Korsmeyer-Peppas model with a Fickian diffusion release pattern, and in intestinal absorption assay PNPs showed increment of ∼1.3 folds compared of REP. Moreover, cellular studies confirmed that REP-loaded PNPs significantly enhance the cellular viability, uptake and reduce the peroxide-induced stress in neuroblastoma SHSY-5Y cells. Further, pharmacokinetic parameters of PNPs showed an increment in tmax (2.46-fold), and Cmax (1.25-fold) associated with REP. In the brain biodistribution study, REP loaded PNPs was sustained for 24 h whereas free REP sustained only for12 h. In DM induced neurodegenerative murine model, a significantly (p < 0.01) enhanced pharmacodynamic was observed in PNP treated group by estimating biochemical and behavioral parameters. Hence, oral administration of REP-loaded PNPs promotes efficient brain uptake and improved efficacy of REP in the diseased model.

Emerging innovations in cold plasma therapy against cancer: A paradigm shift.

Cancer is one of the major causes of mortality, accounting for ∼ 9.5 million deaths globally in 2018. The spectrum of conventional treatment for cancer includes surgery, chemotherapy and radiotherapy. Recently, cold plasma therapy surfaced as a novel technique in the treatment of cancer. The FDA approval of the first trial for the use of cold atmospheric plasma (CAP) in cancer therapy in 2019 is evidence of this. This review highlights the mechanisms of action of CAP. Additionally, its applications in anticancer therapy have been reviewed. In summary, this article will introduce the readers to the exciting field of plasma oncology and help them understand the current status and prospects of plasma oncology.

Revisiting techniques to evaluate drug permeation through skin.

INTRODUCTION: Investigating the transportation of a drug molecule through various layers of skin and determining the amount of drug retention in skin layers is of prime importance in transdermal and topical drug delivery. The information regarding drug permeation and retention in skin layers aids in optimizing a formulation and provides insight into the therapeutic efficacy of a formulation. AREAS COVERED: This perspective covers various methods that have been explored to estimate drug/therapeutics in skin layers using in vitro, ex vivo, and in vivo conditions. In vitro methods such as diffusion techniques, ex vivo methods such as isolated perfused skin models and in vivo techniques including dermato-pharmacokinetics employing tape stripping, and microdialysis are discussed. Application of all techniques at various stages of formulation development where various local and systemic effects need to be considered. EXPERT OPINION: The void in the existing methodologies necessitates improvement in the field of dermatologic research. Standardization of protocols, experimental setups, regulatory guidelines, and further research provides information to select an alternative for human skin to perform skin permeation experiments to increase the reliability of data generated through the available techniques. There is a need to utilize multiple techniques for appropriate dermato-pharmacokinetics evaluation and formulation's efficacy.

Emerging innovations in nano-enabled therapy against age-related macular degeneration: A paradigm shift.

Age-related macular degeneration (AMD), a degenerative eye disease, is the major cause of irreversible loss of vision among individuals aged 50 and older. Both genetic and environmental factors are responsible for the progressive damage to central vision. It is a multifactorial retinal disease with features such as drusen, hypopigmentation and/or hyperpigmentation of the retinal pigment epithelium, and even choroidal neovascularization in certain patients. AMD is of two major forms: exudative (wet) and atrophic (dry) with changes affecting the macula leading to impaired vision. Although the retina remains an accessible portion for delivering drugs, there are no current options to cure or treat AMD. The existing expensive therapeutics are unable to treat the underlying pathology but display several side effects. However, recent innovations in nanotherapeutics provide an optimal alternative of drug delivery to treat the neovascular condition. These new-age technologies in the nanometer scale would enhance bioactivity and improve the bioavailability of drugs at the site of action to treat AMD. The nanomedicine also provides sustained release of the drug with prolonged retention after penetrating across the ocular tissues. In this review, the insights into the cellular and molecular mechanisms associated with the pathophysiology of AMD are provided. It also serves to review the current progress in nanoparticle-based drug delivery systems that offer feasible treatments in AMD.

Evolving new-age strategies to transport therapeutics across the blood-brain-barrier.

A basic understanding of the blood-brain barrier (BBB) is essential for the novel advancements in targeting drugs specific to the brain. Neoplasm compromising the internal structure of BBB that results in impaired vasculature is called as blood tumor barrier (BTB). Besides, the BBB serves as a chief hindrance to the passage of a drug into the brain parenchyma. The small and hydrophilic drugs majorly display an absence of desired molecular characteristics required to cross the BBB. Furthermore, all classes of biologics have failed in the clinical trials of brain diseases over the past years since these biologics are large molecules that do not cross the BBB. Also, new strategies have been discovered that use the Trojan horse technology with the re-engineered biologics for BBB transport. Thus, this review delivers information about the different grades of tumors (I-IV) i.e. examples of BBB/BTB heterogenicity along with the different mechanisms for transporting the therapeutics into the brain tumors by crossing BBB. This review also provides insights into the emerging approaches of peptide delivery and the non-invasive and brain-specific molecular Trojan horse targeting technologies. Also, the several challenges in the clinical development of BBB penetrating IgG fusion protein have been discussed.

MicroRNAs as biological regulators in skin disorders.

microRNAs are being investigated as promising therapeutic targets and biomarkers for different disease conditions. miRNAs serve as essential regulators of cell differentiation, proliferation and survival. The involvement of miRNAs in the functioning and regulation of the skin cells and skin diseases is a rapidly advancing area in dermatological research. miRNAs have been identified to play a key role in the pathogenesis, diagnosis, and treatment of the skin diseases. Skin is one of the largest organs of the body, primarily functioning as the first line of defence against external insults including bacteria, virus and other pathogens. Various miRNAs have been identified to demonstrate significant effects in various skin inflammatory conditions such as wounds, cancer, psoriasis, scleroderma, dermatomyositis. The current review explores the possible roles of the miRNAs in skin disorders and reports relating to the clinical trials involving skin diseases and miRNAs. The review has also compiled the information of the databases available, which correlates the miRNAs with different diseases and give details about targeting interactions of miRNA.