Lipid-Based Nanocarriers for RNA Delivery

Author(s):

Hui Yi Xue, Pengbo Guo, Wu-Cheng Wen and Ho Lun WongPages 3140-3147 (8)

Abstract:

RNA-interference (RNAi) agents such as small-interfering RNA (siRNA) and micro-RNA (miRNA) have strong potential as therapeutic agents for the treatment of a broad range of diseases such as malignancies, infections, autoimmune diseases and neurological diseases that are associated with undesirable gene expression. In recent years, several clinical trials of RNAi therapeutics especially siRNAs have been conducted with limited success so far. For systemic administration of these poorly permeable and easily degradable macromolecules, it is obvious that a safe and efficient delivery platform is highly desirable. Because of high biocompatibility, biodegradability and solid track record for clinical use, nanocarriers made of lipids and/or phospholipids have been commonly employed to facilitate RNA delivery. In this article, the key features of the major sub-classes of lipid-based nanocarriers, e.g. liposomes, lipid nanoparticles and lipid nanoemulsions, will be reviewed. Focus of the discussion is on the various challenges researchers face when developing lipid-based RNA nanocarriers, such as the toxicity of cationic lipids and issues related to PEGylated lipids, as well as the strategies employed in tackling these challenges. It is hoped that by understanding more about the pros and cons of these most frequently used RNA delivery systems, the pharmaceutical scientists, biomedical researchers and clinicians will be more successful in overcoming some of the obstacles that currently limit the clinical translation of RNAi therapy.

Keywords:

Drug delivery, lipid, nanocarrier, RNA interference, small-interfering RNA.

Affiliation:

School of Pharmacy, Temple University, 3307 North Broad Street, Philadelphia, Pennsylvania, US 19140.

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Recent advances in the fundamental understanding of adhesive mixtures for inhalation

Author(s):

Floris Grasmeijer, Niels Grasmeijer, Paul Hagedoorn, Henderik Willem Frijlink and Anne Haaije de BoerPages 5900-5914 (15)

Abstract:

Adhesive mixtures for inhalation are the most widely used type of formulation in dry powder inhalation products. Although they have been the subject of active research, the relationships between properties of the starting materials, the mixing and dispersion processes, and the dispersion performance of this type of formulation are generally poorly understood. Interactions between relevant variables have been mentioned as an important cause. By reviewing the effects on mixture dispersion performance of the most widely studied formulation variables we try to find out whether or not the understanding of adhesive mixtures has improved in recent years. We furthermore propose an approach that may potentially accelerate the process of understanding. General conclusions concerning the effects of the variables considered cannot be drawn, because inconsistent findings are reported throughout the literature for all of them. These inconsistencies are indeed largely the result of interactions between variables of the formulation and dispersion processes. Mechanisms for most of the observed effects and interactions have been proposed, but they often remain unproven and, therefore, speculative. We have attempted to condense the knowledge from the literature into a theoretical framework that is intended to help explain the interplay between variables. According to this framework, only few mixture properties are key to understanding the effects of and interactions between formulation variables. Therefore, we suggest that the development or optimisation of techniques to accurately characterise these mixture properties could be an effective approach to further the fundamental understanding of adhesive mixtures for inhalation and enable their rational engineering.

Keywords:

Carrier particle size distribution, carrier surface roughness, cohesion-adhesion balance, drug content, fines, interactive mixtures, ordered mixtures, powder dispersion.

Affiliation:

University of Groningen, Department of Pharmaceutical Technology and Biopharmacy, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.

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Evolving Drug Delivery Strategies to Overcome the Blood Brain Barrier

Author(s):

David S. Hersh, Aniket S. Wadajkar, Nathan B. Roberts, Jimena G. Perez, Nina P. Connolly, Victor Frenkel, Jeffrey A. Winkles, Graeme F. Woodworth and Anthony J. KimPages 1177-1193 (17)

Abstract:

The blood-brain barrier (BBB) poses a unique challenge for drug delivery to the central nervous system (CNS). The BBB consists of a continuous layer of specialized endothelial cells linked together by tight junctions, pericytes, nonfenestrated basal lamina, and astrocytic foot processes. This complex barrier controls and limits the systemic delivery of therapeutics to the CNS. Several innovative strategies have been explored to enhance the transport of therapeutics across the BBB, each with individual advantages and disadvantages. Ongoing advances in delivery approaches that overcome the BBB are enabling more effective therapies for CNS diseases. In this review, we discuss: (1) the physiological properties of the BBB, (2) conventional strategies to enhance paracellular and transcellular transport through the BBB, (3) emerging concepts to overcome the BBB, and (4) alternative CNS drug delivery strategies that bypass the BBB entirely. Based on these exciting advances, we anticipate that in the near future, drug delivery research efforts will lead to more effective therapeutic interventions for diseases of the CNS.

Keywords:

Central Nervous System (CNS), Blood-Brain Barrier (BBB), nanotechnology, ultrasound, immunotherapy.

Affiliation:

Department of Neurosurgery, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201., Departments of Neurosurgery and Pharmaceutical Sciences, University of Maryland, Baltimore, 655 W. Baltimore Street, Baltimore, MD 21201.

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The Therapeutic Aspects of the Endocannabinoid System (ECS) for Cancer and their Development: From Nature to Laboratory

Author(s):

Mohammed I. Khan, Anna A. Sobocińska, Anna M. Czarnecka, Magdalena Król, Bruno Botta and Cezary SzczylikPages 1756-1766 (11)

Abstract:

The endocannabinoid system (ECS) is a group of neuromodulatory lipids and their receptors, which are widely distributed in mammalian tissues. ECS regulates various cardiovascular, nervous, and immune system functions inside cells. In recent years, there has been a growing body of evidence for the use of synthetic and natural cannabinoids as potential anticancer agents. For instance, the CB1 and CB2 receptors are assumed to play an important role inside the endocannabinoid system. These receptors are abundantly expressed in the brain and fatty tissue of the human body. Despite recent developments in molecular biology, there is still a lack of knowledge about the distribution of CB1 and CB2 receptors in the human kidney and their role in kidney cancer. To address this gap, we explore and demonstrate the role of the endocannabinoid system in renal cell carcinoma (RCC). In this brief overview, we elucidate the therapeutic aspects of the endocannabinoid system for various cancers and explain how this system can be used for treating kidney cancer. Overall, this review provides new insights into cannabinoids’ mechanisms of action in both in vivo and in vitro models, and focuses on recent discoveries in the field.

Keywords:

CB1 and CB2 receptors, Cannabinoids, Endocannabinoid system, Renal cell carcinoma.

Affiliation:

Molecular Oncology Laboratory, Department of Oncology, Military Institute of Medicine, ul. Szaserów 128, 04-141 Warsaw, Poland

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Therapeutic Targets for Management of Periodontitis and Diabetes

Author(s):

Corneliu Sima and Thomas E. Van DykePages 2216-2237 (22)

Abstract:

The increasing incidence of diabetes mellitus (DM) and chronic periodontitis (CP) worldwide imposes a rethinking of individualized therapy for patients with both conditions. Central to bidirectional links between DM and CP is deregulated systemic inflammation and dysfunctional immune responses to altered-self and non-self. Control of blood glucose levels and metabolic imbalances associated with hyperglycemia in DM, and disruption of pathogenic subgingival biofilms in CP are currently the main therapeutic approaches for these conditions. Mounting evidence suggests the need to integrate immune modulatory therapeutics in treatment regimens that address the unresolved inflammation associated with DM and CP. The current review discusses the pathogenesis of DM and CP with emphasis on deregulated inflammation, current therapeutic approaches and the novel pro-resolution lipid mediators derived from -3 polyunsaturated fatty acids.

Keywords:

Diabetes mellitus, periodontitis, inflammation, lipid mediators, pro-resolution therapeutics.

Affiliation:

Corneliu Sima, 245 First Street, Room 5145, Cambridge, MA, 02142, USA.

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