Current Pharmaceutical Design - Volume 26, Issue 27, 2020

Lipid drug conjugates (LDCs) are the chemical entities, which are commonly referred to as lipoidal prodrug. They contain the bioactive molecules, covalently or non-covalently linked with lipids like fatty acids, glycerides or phospholipids. Lipid drug conjugates are fabricated with the aim of increasing drug payload. It also prevents leakage of a highly polar bioactive(s) from the lipophilic matrix. Conjugating lipidic moieties to bioactive molecules improves hydrophobicity. It also modifies other characteristics of bioactive(s). These conjugates possess numerous merits encompassing enhanced tumor targeting, lymphatic system targeting, systemic bioavailability and decreased toxicity. Different conjugation approaches, chemical linkers and spacers can be used to synthesize LDCs based on the chemical behaviour of lipidic moieties and bioactive(s). The factors such as coupling/ conjugation methods, the linkers etc. regulate and control the release of bioactive(s) from the LDCs. It is considered as a crucial parameter for the better execution of the LDCs. The purpose of this review is to explore widely the potential of LDCs as an approach for improving the therapeutic indices of bioactive(s). In this review, the conjugation methods, various lipids used for preparing LDCs, and advantages of using LDCs are summarized. Though LDCs might be administered without using a carrier; however, majority of them are incorporated in an appropriate nanocarrier system. In the conjugates, the lipidic component may considerably improve the loading of lipoidal bioactive(s) in the lipid compartments. This results in high % drug entrapment in nanocarriers with greater stability. Several nanometric carriers such as polymeric nanoparticles, micelles, liposomes, emulsions and lipid nanoparticles, which have been explored, are reviewed here.

Solid lipid nanoparticles (SLNs) have shown potential as a novel lipid-based drug delivery system for the topical applications of innumerable therapeutic compounds. However, the mechanisms governing the absorption and cellular uptake of SLNs through topical route, along with the mechanism of drug release from SLNs are still ambiguous, and require further investigation. In addition, the selection of an appropriate dosage form/formulation base is essential for ease of application of SLNs and to enhance dermal and transdermal delivery. Upscaling and regulatory approvals are other challenges that may impede the clinical translation of SLNs. Therefore, this review focusses on different mechanisms involved in skin penetration and cellular uptake of SLNs. This is followed by a comprehensive discussion on the physicochemical properties of SLNs including various formulation and dosage form factors, which might influence the absorption of SLNs through the skin. Finally, translational status with respect to scale-up and regulatory aspects are also discussed. This review will be useful to researchers with an interest in topical applications of SLNs for the efficient delivery of drugs and cosmetics.

Cancer is the second leading cause of death globally, with every sixth death being attributable to cancer. Nevertheless, the efficacy of conventional chemotherapeutic drugs is often limited due to their poor solubility, unfavorable pharmacokinetic profile, and lack of tumor selectivity. The use of nanotechnology provides an opportunity to enhance the efficacy of a chemotherapeutic drug by improving its bioavailability and pharmacokinetic profile while facilitating preferential accumulation at the tumor tissue. To date, a variety of platforms have been investigated as nanocarriers in oncology, which include lipid-based, polymer-based, inorganic materials, and even viruses. Among different nanocarriers, lipid-based delivery systems have been extensively used in oncology because of their biocompatibility, biodegradability, ability to encapsulate diverse drug molecules, high temporal and thermal stability, and offer prolonged and controlled drug release. This review discusses the current status of the lipid-based nanocarriers and their applications in cancer treatment as well as an overview of the different liposomal formulations commercially available for cancer therapy.

Potential short interfering RNAs (siRNA) modulating gene expression have emerged as a novel therapeutic arsenal against a wide range of maladies and disorders containing cancer, viral infections, bacterial ailments and metabolic snags at the molecular level. Nanogel, in the current medicinal era, displayed a comprehensive range of significant drug delivery prospects. Biodegradation, swelling and de-swelling tendency, pHsensitive drug release and thermo-sensitivity are some of the renowned associated benefits of nanogel drug delivery system. Global researches have also showed that nanogel system significantly targets and delivers the biomolecules including DNAs, siRNA, protein, peptides and other biologically active molecules. Biomolecules delivery via nanogel system explored a wide range of pharmaceutical, biomedical engineering and agro-medicinal application. The siRNAs and DNAs delivery plays a vivacious role by addressing the hitches allied with chronic and contemporary therapeutic like generic possession and low constancy. They also incite release kinetics approach from slow-release while mingling to rapid release at the targets will be beneficial as interference RNAs delivery carriers. Therefore, in this research, we focused on the latest improvements in the delivery of siRNA loaded nanogels by enhancing the absorption, stability, sensitivity and combating the hindrances in cellular trafficking and release process.

The pilosebaceous unit is the triad comprising of hair follicle, arrector pilli muscle, and sebaceous gland. Drug delivery to and through the hair follicles has garnered much attention of the researchers and the hair follicles represent an attractive target site via topical applications. They are bordered by capillaries and antigenpresenting cells, connected to the sebaceous glands and the bulge region of the hair follicle anchors the stem cells. The nano lipid carriers have the propensity to penetrate through the skin via transcellular route, intracellular route and follicular route. It has been established that nano lipid carriers have the potential for follicular drug delivery and provide some advantages over conventional pathways, including improved bioavailability, enhanced penetration depth, fast transport into the skin, tissue targeting and form a drug reservoir for prolonged release. This review describes the pilosebaceous unit (PSU) and related diseases and the recent lipid-based nanotechnology approaches for drug delivery to the follicular unit as well as related issues. Different types of nano lipid carriers, including ethosomes, liposomes, nanoparticles, solid lipid nanoparticles (SLNs), and nano lipid carriers (NLCs) have been reported for follicular drug delivery. Targeted drug delivery with nano-lipid carriers has the potential to augment the efficacy of drugs/bioactives to treat diseases of PSU. This review systematically introduces the activities of different formulations and the use of nano lipid carriers in treating PSU related disorders like alopecia, acne, and hirsutism.

NLC is a next-generation lipid nanocarrier, which holds many advantages over other colloidal lipid carrier systems like higher drug loading, better and controlled release and enhanced stability. Owing to the unique structural composition, i.e. crystallized solid and liquid lipid blend, it offers excellent biocompatibility and higher permeation across physiological membranes like BBB. Moreover, the surface of NLC can easily be modified with target-specific ligands, proteins, peptides, etc. which makes it a potential candidate for brain targeting of CNS acting drugs. NLC has found various applications for the treatment of various CNS disorders including Alzheimer’s disease, Parkinson’s disease, schizophrenia, epilepsy, migraine, cerebral ischemia, etc. Among these, the application of NLC towards the treatment of AD has been well-explored in the past two decades. In this piece of work, we have discussed the types of NLC, its composition, fabrication techniques, characterization, stability profile and application in the treatment of AD.

Background: Alzheimer's is the primary cause of death in the various countries that affect wide strata of the population. The treatment of it is restricted to a few conventional oral medications that act only superficially. It is evident that the delivery of a drug to the brain across the blood-brain barrier is challenging as the BBB is armed with several efflux transporters like the P-glycoprotein as well as nasal mucociliary clearance adds up leading to decreased concentration and reduced therapeutic efficacy. Considering these, the intranasal IN route of drug administration is emerging as an alternative route for the systemic delivery of a drug to the brain. The intranasal (IN) administration of lipid nanoparticles loaded with cerebroactive drugs showed promise in treating various neurodegenerative diseases, since the nasal route allows the direct nose to brain delivery by means of solid lipid nanoparticles (SLN’s). The tailoring of intranasal lipid particulate drug delivery systems is a pleasing approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when a free drug has poor pharmacokinetics/ biodistribution (PK/BD) or significant off-site toxicities. Objectives: 1) In this review, key challenges and physiological mechanisms regulating intranasal brain delivery in Alzheimer’s disease, ex vivo studies, pharmacokinetics parameters including brain uptake and histopathological studies are thoroughly discussed. 2) A thorough understanding of the in vivo behaviour of the intranasal drug carriers will be the elusive goal. 3) The article emphasizes to drag the attention of the research community working in the intranasal field towards the challenges and hurdles of the practical applicability of intranasal delivery of cerebroactive drugs. Method: Various electronic databases, journals like nanotechnology and nanoscience, dove press are reviewed for the collection and compilation of data. Results: From in vivo biodistribution studies, pharmacokinetics parameters, and gamma scintigraphy images of various drugs, it is speculated that intranasal lipid particulates drug delivery system shows better brain targeting efficiency for various CNS disorders in comparison to other routes. Conclusion: Various routes are explored for the delivery of drugs to increase bioavailability in the brain for CNS disorders but the intranasal route shows better results that pave the way for success in the future if properly explored.

Cubosome is a biocompatible, thermodynamically stable and bioadhesive drug carrier that is prepared from certain amphiphilic lipids and surfactants when mixed in a definite ratio. Structurally, they are selfassembled nano-constructed liquid crystalline particles comprising three-dimensionally arranged bicontinuous as well as nonintersecting lipid bilayers that give them a honeycomb-like appearance. Morphological characterization through SAXS (small-angle X-ray scattering) and cryo-TEM (cryo-transmission electron microscopy) revealed that they are square and round shaped particles in the nanometer range. These carriers have two separate aqueous regions and a large interfacial area that allow them to carry a variety of bioactive molecules having hydrophobic, hydrophilic or amphiphilic behavior. One of either two strategies i.e., top-down or bottom-up methods can be adopted to prepare these cubic structures. A number of dispersion techniques like sonication, spray drying, high-pressure homogenization or spontaneous emulsification can be adopted to prepare cubosomes. Their characteristics and benefits like multicompartmental structure, high drug loading, simple and convenient method of preparation, use of biodegradable lipids such as glycerol monooleate, encapsulation of hydrophilic, hydrophobic and amphiphilic moieties, targeted and controlled release make them versatile bioactive carriers that can be administered through multiple biological routes like topical, transdermal, parenteral, and oral. Cubosomes have appreciable applications in various fields especially in the pharmaceutical industry where they are used as potential bioactive carriers. Molecules like paclitaxel, oligonucleotide, δ-amino-levulinic acid, bovine serum albumin, etc. can be easily delivered through this system. This article provides a detailed note on the structure of cubosomes, ingredients and techniques used for their preparation, mechanism of drug release, applications and routes of drug administration, their formulations, patent review and market scenario.

Background: In recent decades, the incidence of obesity has been rising globally. Obesity can often cause various inflammatory reactions, resulting in several diseases that threaten public health. The purpose of this review is to explore the role of long non-coding RNAs in metabolic obesity and find new targets for the prevention and treatment of metabolic diseases. Methods: We described the relationship between obesity and inflammation, reviewed several signaling pathways in metabolic inflammation, and summarized some of the long non-coding RNAs and their targets associated with metabolic inflammation. The related studies were retrieved through a systematic search of the PubMed database. Result: Metabolic stress during obesity can cause inflammation through several metabolic pathways. Many long non-coding RNAs can affect the progression of metabolic inflammation by affecting different pathways. Conclusion: Downregulation or antagonization of long non-coding RNAs in metabolic pathways may provide new ideas and therapeutic targets for the prevention and treatment of metabolic inflammation.

Background: Considering a consistent body of evidence has been showing that schizophrenia patients have had an increased risk of developing dementia. The hypothesis that dementia and schizophrenia share a complex link, is emerging. It is highly discussed that dysregulations related to Ca2+ signalling, e.g., an increase of the intracellular concentration of Ca2+, could link both diseases, in addition to cAMP signalling pathways. Objective: Thus, revealing this interplay between schizophrenia and dementia may provide novel insights into the pathogenesis of these diseases. Methods: Publications involving Ca2+ and cAMP signalling pathways, dementia and schizophrenia (alone or combined) were collected by searching PubMed and EMBASE. Results: Both Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling) control the release of neurotransmitters/ hormones and neuronal death, and dysregulations of these cellular processes may be involved in both diseases. Conclusion: Bearing in mind the experience of our group in this field, this article debated the involvement of Ca2+/cAMP signalling in this link between schizophrenia and dementia, including its pharmacological implications.

Background: Cerebral ischemia-reperfusion injury is an extremely complicated pathological process that is clinically characterized by high rates of disability and mortality. It is imperative to explore some effective neuroprotective agents for its treatment. Ulinastatin is a protease inhibitor with anti-inflammatory and antioxidant activity. For the past few years, new studies of ulinastatin for the treatment of ischemic brain injury have emerged. Objective: We conducted a review to summarize the mechanisms of ulinastatin and analyze its neuroprotective action against cerebral ischemia–reperfusion injury. Methods: We reviewed and summarized pertinent reports published between 1993 and 2019 from PubMed, Web of Science, and Embaseby searching for the scientific terms ulinastatin, cerebral ischemia–reperfusion injury, neuroprotective, stroke, cardiac arrest, and brain edema. Results: The protective mechanisms of ulinastatin in the key steps of cerebral ischemia–reperfusion injury include inhibition of inflammatory response, oxidative stress, neuronal apoptosis, neuronal autophagy, and aquaporin- 4 expression as well as improvement in blood–brain barrier permeability. In addition, we provide a perspective on potential research directions and clinical safety. Conclusion: Ulinastatin seems to have the potential to alleviate cerebral ischemia–reperfusion injury. These findings may be valuable to further promote the research and development of drug candidates and provide novel and reliable references for rational drug use.

Introduction: Diabetes mellitus (DM) due to its increasing prevalence and associated morbidity and mortality has become a serious public health problem. In DM, HDL may lose its beneficial features and become proatherogenic due to its altered biological activity thus increasing cardiovascular risk. The aim of this study was to assess the influence of the presence of diabetes mellitus type 2 and its duration on the distribution of HDL subfractions. Moreover, the effect of statin treatment on HDL subfraction share was analysed in this study. Methods: The study group consisted of 50 patients with newly diagnosed DM and 50 persons with DM for longer than 10 years while the control group consisted of 50 healthy volunteers. HDL subfractions were analysed with the use of Lipoprint. Results: We demonstrated progressive worsening of heart functioning and impairment of its structure in the course of diabetes mellitus. Moreover, we observed that HDL-6 subfraction and intermediate HDL fraction are lowest in the group with advanced DMt2 compared to the group with newly diagnosed DM and a healthy control group. Finally, the results of our study indicated the effect of statin treatment on HDL subfractions that seems not to be advantageous. Conclusion: It seems that in patients with diabetes mellitus compromised antiatherogenic properties of HDL, as a result of oxidative modification and glycation of the HDL protein as well as the transformation of the HDL proteome into a proinflammatory protein, increase cardiovascular risk.