Current Pharmaceutical Design - Volume 21, Issue 22, 2015

In recent decades, targeted nano-drug delivery systems have attracted extensive attention in cancer therapy for their efficient drug delivery and tumor site specificity. Tumor vasculature, including angiogenesis and vasculogenic mimicry is associated tightly with tumor growth, progression and metastasis. Therefore, nano-drug delivery systems targeting tumor vasculature are becoming a promising approach for tumor treatment. As complicated mechanisms and various factors are involved in the tumor vasculature, different ligands modified on the surface of nanocarriers acquire active targeting through binding to the receptors over-expressed by cancer cells or angiogenic endothelial cells. In this review, the tumor vasculature characteristics are briefly described and the recent advances and potential strategies in tumor vasculature targeted nano-drug delivery systems are introduced.

Tuberculosis (TB) is an airborne communicable disease, mainly caused by aerobic, non-motile, rodshaped, weakly gram-positive, acid-fast tubercular bacillus Mycobacterium tuberculosis (MTb). Mycobacterium has worsened the problem in humans by acquiring various types of resistances like Multi-drug resistance (MDR), Single-drug resistance (SDR), and Extensive drug resistance (XDR). Some clinical problems and challenges associated with conventional TB chemotherapy include poor patient compliance, longer duration of chemotherapy, lesser cell permeability, primary drug resistance, difficulty in maintaining higher drug concentrations at the infected site, and degradation of the drug before reaching the target site. Thus, newer micrometric or nanometric carriers drug delivery approaches are needed. Colloidal (vesicular and particulate) drug carriers offer numerous advantages over conventional therapy such as better systemic bioavailability, rapid onset of therapeutic action, avoidance of first-pass metabolism, providing sustained and controlled release, fewer dosing frequencies, desired pharmacokinetic profile and route of administration. This review article present updates and fabrication of drug delivery approaches for tuberculosis chemotherapy in order to improve patient compliance.

Hydrophilic polymers are the most common group of polymers used in the preparation of modifiedrelease drug delivery systems. This is due to their versatility, low cost, high production yield, as well as easy manufacturing and adequate in vitro/in vivo correlation. In normal physiological conditions, the matrix controls the release of the loaded drug over time through a process of diffusion and/or erosion of the matrix, depending on its physicochemical composition. This is particularly relevant when describing the pharmacokinetic profile of nanosized drug delivery systems (nanoparticles). The use of mathematical models became an important tool to characterize the pharmacokinetics of drugs loaded in nanoparticles to improve the drug bioavailability and to establish bioequivalence. Therefore, the drug release profile can be predicted by a minimum number of experimental studies, since the mathematical equations reveal the dissolution rate of the drug loaded in the hydrophilic matrix. The present paper discusses the use of mathematical models when developing modified-release drug delivery systems of nanometer size composed of hydrophilic polymers.

In recent years, advances in biotechnology and protein engineering have enabled the production of large quantities of proteins and peptides as important therapeutic agents. Various researchers have used biocompatible functional polymers to prepare oral dosage forms of proteins and peptides for chronic use and for easier administration to enhance patient compliance. However, there is a need to enhance their safety and effectiveness further. Most macromolecules undergo severe denaturation at low pH and enzymatic degradation in the gastrointestinal tract. The macromolecules’ large molecular size and low lipophilicity cause low permeation through the intestinal membrane. The major strategies that have been used to overcome these challenges (in oral drug carrier systems) can be classified as follows: enteric coating or encapsulation with pH-sensitive polymers or mucoadhesive polymers, co-administration of protease inhibitors, incorporation of absorption enhancers, modification of the physicochemical properties of the macromolecules, and site-specific delivery to the colon. This review attempts to summarize the various advanced oral delivery carriers, including nanoparticles, lipid carriers, such as liposomes, nano-aggregates using amphiphilic polymers, complex coacervation of oppositely charged polyelectrolytes, and inorganic porous particles. The particles were formulated and/or surface modified with functional polysaccharides or synthetic polymers to improve oral bioavailability of proteins and peptides. We also discuss formulation strategies to overcome barriers, therapeutic efficacies in vivo, and potential benefits and issues for successful oral dosage forms of the proteins and peptides.

Neurological disorders represent one of the major health concerns worldwide. Yet currently employed treatment strategies have not been very successful in the treatment of many of these disorders. One of the root causes of this lack of success is that many pharmaceutically active compounds are unable to reach their target sites of action inside the body. The delivery of substances from systemic circulation to the desired site of action, namely central nervous system (CNS), is hindered by CNS extracellular and intracellular barriers. One promising approach to circumvent these barriers is the use of nanoscaled drug delivery systems. These nanosized drug carriers display various advantages over other conventional drug delivery methods such as high drug loading capacity, targeted action, reduced toxicity, and increased therapeutic effect. Nano-neuroscience is thereby emerging as an exciting field of study and a promising future direction for the delivery of therapeutics to their targeted site of action inside the CNS for the treatment of various neurological and psychiatric disorders. Here, we will first discuss the general pharmacokinetics of therapeutics depending on the route of administration, drawbacks of conventional drug delivery systems and challenges for CNS drug delivery, namely CNS barriers. Next, a short overview of the strategies to circumvent these barriers will be given. Finally, nanotechnology and its emerging use as drug delivery systems will be discussed. This includes the advantages of nanoparticles over other conventional drug delivery systems; production of nanoparticles and their designing as an effective drug carrier; various types of nanoparticles; and some examples of their efficient use in the delivery of bioactive substances, and in the treatment of neurological disorders mainly Alzheimer’s disease, brain tumors and neuroAIDS. Lastly, a future perspective on the use of nanotechnology in CNS drug delivery will be highlighted.

Low water solubility of drug products causes delivery problems such as low bioavailability. The reduced particle size and increased surface area of nanocrystals lead to the increasing of the dissolution rate. The formulation of drug nanocrystals is a robust approach and has been widely applied to drug delivery system (DDS) due to the significant development of nanoscience and nanotechnology. It can be used to improve drug efficacy, provide targeted delivery and minimize side-effects. Crystallization is the main and efficient unit operation to produce nanocrystals. Both traditional crystallization methods such as reactive crystallization, anti-solvent crystallization and new crystallization methods such as supercritical fluid crystallization, high-gravity controlled precipitation can be used to produce nanocrystals. The current mini-review outlines the main crystallization methods addressed in literature. The advantages and disadvantages of each method were summarized and compared.

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.

Nano drug delivery systems are considered as useful means to remedy the problems of drugs of poor solubility, permeability and bioavailability, which became one of the most troublesome questions of the pharmaceutical industry. Different types of nanosized drug delivery systems have been developed and investigated for oral administration, providing auspicious solutions for drug development. In this paper nanosized drug delivery systems intended for oral administration are discussed based on the chemical nature of the carrier of drug molecules. Lipid nanoparticles comprising solid lipid nanoparticles, improved nanostructured lipid carriers and nanostructured silica- lipid hybrid particles have become popular in the formulation of lipophilic drugs of poor oral bioavailability. Polymeric nanoparticles including nanospheres and nanocapsules and polymeric fibrous systems have also emerged as potential drug delivery systems owing to their unique structure. The feasibility of surface functionalization of mesoporous materials and gold nanoparticles enables high level of control over particle characteristics making inorganic nanoparticles an exceptional formulation approach. The authors paid particular attention to the functionality-related stability of the reviewed delivery systems.

In recent years, combination of different types of therapies using nanoparticles has emerged as an advanced strategy for cancer treatment. Most of all, combination of chemotherapeutic drug and siRNA in nanoformulation has shown a great potential, because siRNA-mediated specific gene silencing can compensate for the incomplete anti-cancer actions of chemotherapy. In this article, nanoparticle-based combination therapy for cancer treatment is introduced to be focused on the therapeutic chemical and siRNA combination. It is classified into 3 groups: 1) general chemotherapy combined with siRNA carrying nanoparticle, 2) co-delivery of chemical and siRNA therapeutics within a single nanoparticle, and 3) Use of multiple nanoparticles for chemical and siRNA therapeutics. The purpose of the combination and the mechanisms of anti-cancer action was described according to the categories. Examples of some recent developments of nanotechnology-based chemo- and siRNA- therapeutics combination therapy are summarized for better understanding of its practical application.

Cancer has been described as one of the major and leading causes of death worldwide. By the year 2030, it has been postulated that over 21.4 million new cases of cancer could be expected, 17 million cancer deaths yearly and a total of 75 million people will be living with cancer within five years of diagnosis. Chemotherapy is the main therapeutic intervention for treating people living with SCC. However, drug resistance has rendered it inefficient and ineffective in combating the disease even after combination chemotherapy. Many peptides and proteins have been investigated to possess biological activities that mark them as potential anti-cancer agents. Targeting peptides are conjugated with other functional peptides or nanoparticles to augment drug delivery both in vitro and in vivo assays. The current identification of tumor-homing peptides through phage display technology has opened a new strategy for targeted therapy in SCC diseases. Despite the advances in cancer nanomedicine, targeted approaches in the delivery of therapeutics for the treatment of squamous cell carcinoma related tumours have not been well established. In this review, current drugs employed in cancer nanomedicine are highlighted, possible rate limiting factors for the application of polymeric materials in cancer nanomedicine are elucidated and functionalized nano-constructs using receptor ligands and homing peptides as targeted moieties are discussed. The combinatorial strategy of attaching both homing peptides and receptor ligands as dual moieties on nano-cargos should further strengthen the advantages of each technology in cancer targeted therapy.

DNA origami technique was first introduced in 2006 by Rothemund, it has gained widespread research interest and led to explosive achievements, in which long single-stranded DNA (ssDNA) is folded into a designed nanostructure, in either two dimensions (2D) or three dimensions (3D), with the aid of many shorter staple strands. A series of methods for new design principles for DNA origami nanostructures have already been proposed, ranging from the preparation of scaffold to the folding mechanisms. After that, novel strategies in functionalizing DNA origami nanostructures and their practical applications are gradually becoming research hotspots. This review focuses on the development in the new scaffold design approaches, folding conditions, various nano objects functionalized on DNA origami nanostructures, and their applications as drug carriers in the recent five years. We anticipate more exploratory and extendible work developed based on the summary of progress obtained previously.

Knocking down expression by small interfering RNA (siRNA) has shown high affinity, specificity and potency in silencing target gene sites. For effective endogenous RNA interference (RNAi), proper siRNA delivery vehicles are essential, to take the siRNA inside cells and protect them during the circulation. Carbon nanomaterials (CNMs) have been successfully applied in biomedicine and biosensor based on their ultra-high surface functionalization and nucleic acid molecular loading capacity. Recently, CNMs have drawn considerable research interest and expectation as potential non-viral vectors for siRNA delivery. Here we reviewed the recent application of CNMs in gene delivery for RNAi, mainly about fullerenes, carbon nanotubes (CNTs) and graphene.

Plant proteins have been drawing increasing attention owing to their safety, abundance and relatively low cost in comparison with animal proteins. The development of plant protein-based delivery vehicles may lead to the provision of novel pharmaceutical products to patients. Zein is a class of alcohol-soluble prolamine proteins present in maize endosperm that was approved as a generally recognised as safe excipient in 1985 by the US FDA for use in pharmaceutical film coatings. Over the past few decades, numerous studies have been carried out to illustrate zein’s potential for novel applications in the biomedical field. This paper reviews the present status of zein-based nanofibres, with emphasis on their fabrication and biomedical applications, particularly for drug delivery. Their benefits and limitations are also discussed to provide further insight into zein’s potential as a promising biomaterial.

Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. Solid tumor tissue is characterized by high density of vascular bed however; the vast majority of these blood vessels are not functioning. The vast majority of solid tumors can be described as poorly perfused with blood; and anticancer agents need to penetrate/distribute avascularly within solid tumor micro-milieu. Classic pharmacokinetic parameters correlate drug status within central compartment (blood) to all perfused body tissues according to their degree of perfusion. Yet, these classic pharmacokinetic parameters cannot fully elucidate the intratumoral drug penetration/distribution status of anticancer drugs due to the great discrepancies in perfusion between normal and solid tumor tissues. Herein, we will discuss the recently proposed pharmacokinetic parameters that might accurately portray the distribution of anticancer agents within solid tumor micro-milieu. In addition, we will present the new challenges attributed to these new pharmacokinetic parameters towards designing nanobiomaterial drug delivery system.

Nano graphene oxide (nGO) is a member of graphene family, which is a novel, one-atom-thickness, two-dimensional carbon nanomaterial. In comparison with graphene, nGO contains much higher extent of reactive chemical functionalities such as hydroxyl, carbonyl, carboxyl, and epoxy group, so as to enable its easier biochemo-functionalization, higher biocompatibility, and greater potentials of applications in biomedicine fields. Up to now, nGO has attracted extensive research interests in nanomedicine and drug delivery systems for cancer imaging and therapy due to its unique biochemical and in vivo properties. This review generally describes the preparation, functionalization, and toxicity of nGO firstly, and then focuses on the studies of biomedical applications for cancer imaging and drug delivery.

Symptomatic distresses associated with common ophthalmic infections and their persistence, have remained a tribulation with repeated occurrences. Although being a directly accessible organ, traditional therapeutic strategies exhibiting seemingly fruitful outcome in treatment and prognosis of eye disorders call for improvement in disease intervention. This is due to frequent challenges presented by the ophthalmic environment. Contemporary research has addressed these challenges by applying nanotechnology as a central concept in designing more proficient diagnostic and therapeutic systems for eye ailments. Within such nanosystems (dendrimers, aptamers, metal nanoparticles, etc.), bioactive agents, drugs and genetic materials can be entrapped and these form the key elements that act at the biomolecular stage and bestow a high level of efficacy towards eradication of disease causatives and specificity for recognition and capture aiding diagnostic processes. In the current review, we present researched and patented nanocentric technologies as promising tools in detection and treatment of ophthalmic ailments.

Electrohydrodynamic atomization (EHDA) enabling platform technologies have gathered significant momentum over the last two decades. Utilisation of the underpinning jetting process in tandem with desired materials (including polymers, ceramics, metals and even naturally occurring compounds such as peptides, DNA and cells) provides the basis for novel engineered therapies. Through EHDA processes, the generation of a variety of nano-meter and micro-meter scaled structures with control on surface and encapsulation features is attainable in a single step. While a host of adaptable EHDA techniques have evolved (e.g. printing and template patterning), there are two main processes that continue to dominate: electrospraying (ESy) and electrospinning (ESp). Although ESp has drawn considerable researcher interest for nanofibre applications, ESy is an important and timely process for nano- and micro-particle fabrication. Thus, an appropriate evaluation of ESy is vital. This short review focuses on key developments in the ESy field in relation to nanotechnologies with potential healthcare applications using metals, polymers and ceramics. An insight into the process of particle formation (during EHDA spraying or ESy), process parameters and materials specifications, is provided. Emerging biomedical and other healthcare research through nanotechnologies are highlighted

Adeno-associated virus (AAV) vectors are promising human gene delivery vehicles due to their ability to establish long-term gene expression in a wide variety of target tissues; however, the broad native viral tropism raises concerns over the feasibility and safety of their systemic administration. To overcome this issue, much effort has been made to redirect AAVs toward specific tissues. This review presents several design strategies that have been applied to generate AAVs that target specific tissues and cells while inhibiting the transduction of non-target tissues. Multiple methods of vector capsid engineering have shown promise in vitro, including indirect targeting by adaptor systems and direct targeting by the insertion of antibodies or receptor-specific small peptide motifs. Other strategies, including creating mosaic or chimeric capsids and directed evolution, have also been used to successfully retarget AAV vectors. This research will further expand the clinical applications of AAV vectors by enhancing the control over tissue-specific gene delivery.