Advances in using chitosan-based nanoparticles for in vitro and in vivo drug and gene delivery

Importance of the field: This review aims to provide an overview of state-of-the-art chitosan-based nanosized carriers for the delivery of therapeutic agents. Chitosan nanocarriers are smart delivery systems owing to the possibility of their property alterations with various approaches, which would confer them with the possibility of spatiotemporal delivery features.

Areas covered in this review: The focus of this review is principally on those aspects that have not often been addressed in other reviews. These include the influence of physicochemical properties of chitosan on delivery mechanisms and chitosan modification with a variety of ligand moieties specific for cell surface receptors to increase recognition and uptake of nanocarriers into cells through receptor-mediated endocytosis. Multiple examples that demonstrate the advantages of chitosan-based nanocarriers over other delivery systems of therapeutic agents are highlighted. Particular emphasis is given to the alteration of material properties by functionalization or combination with other polymers for their specific applications. Finally, structural and experimental parameters influencing transfection efficiency of chitosan-based nanocarriers are presented for both in vitro and in vivo gene delivery.

What the reader will gain: The readers will acquire knowledge of parameters influencing the properties of the chitosan-based nanocarriers for delivery of therapeutic agents (genetic material or drugs) in vitro and in vivo. They will get a better idea of the strategies to be adapted to tune the characteristics of chitosan and chitosan derivatives for specific delivery applications.

Take home message: Chitosan is prone to chemical and physical modifications, and is very responsive to environmental stimuli such as temperature and pH. These features make chitosan a smart material with great potential for developing multifunctional nanocarrier systems to deliver large varieties of therapeutic agents administrated in multiple ways with reduced side effects.     

Designer nanoparticles: incorporating size,shape and triggered release into nanoscale drug carriers

Importance of the field: Although significant progress has been made in delivering therapeutic agents through micro and nanocarriers, precise control over in vivo biodistribution and disease-responsive drug release has been difficult to achieve. This is critical for the success of next generation drug delivery devices, as newer drugs, designed to interfere with cellular functions, must be efficiently and specifically delivered to diseased cells. The chief constraint in achieving this has been our limited repertoire of particle synthesis methods, especially at the nanoscale. Recent developments in generating shape-specific nanocarriers and the potential to combine stimuli-responsive release with nanoscale delivery devices show great promise in overcoming these limitations.

Areas covered in this review: How recent advances in fabrication technology allow synthesis of highly monodisperse, stimuli-responsive, drug-carrying nanoparticles of precise geometries is discussed. How particle properties, specifically shape and stimuli responsiveness, affect biodistribution, cellular uptake and drug release is also reviewed.

What the reader will gain: The reader is introduced to recent developments in intelligent drug nanocarriers and new nanofabrication approaches that can be combined with disease-responsive biomaterials. This will provide insight into the importance of controlling particle geometry and incorporating stimuli-responsive materials into drug delivery.

Take home message: The integration of responsive biomaterials into shape-specific nanocarriers is one of the most promising avenues towards the development of next generation, advanced drug delivery systems.     

Nanostructured hyaluronic acid-based materials for active delivery to cancer

Importance of the field: Active targeting of bioactive molecules by physicochemical association with hyaluronic acid (HA) is an attractive approach in current nanomedicine because HA is biocompatible, non-toxic and non-inflammatory.

Areas covered in this review: This review focuses on synthesis, physicochemical characterization and biological properties of different nanoparticulate delivery systems that include HA in their structures. Chemically based approaches to the delivery of small molecule drugs, proteins and nucleic acids in which they become chemically or physically bound to hyaluronic acid are reviewed, including the use of molecular HA conjugates and nanocarriers. The systems are considered in terms of intracellular delivery to different cultured cells that express HA-specific receptors (hyaladherines) differently. The in vivo biodistribution and therapeutic effect of these systems are discussed.

What the reader will gain: Different synthetic methodologies for preparations of HA-based nanoparticles are presented extensively. HA nanoparticulate systems of various structures can be compared with respect to their in vitro assays and in vivo biodistribution.

Take home message: To make HA useful as an intravenous targeting carrier, strategies have to be devised to: reduce HA clearance from the blood; suppress the HA uptake by liver and spleen; and provide tumor-triggered mechanisms of release of an active drug from the HA carrier.     

Nanoparticle-mediated delivery of therapeutic genes: focus on miRNA therapeutics

Introduction: Micro RNAs (miRNA) are 21 – 23 nucleotides long and regulate the expression of coding genes by binding imperfectly with their 3′ UTR region. The miRNA profile is altered in pathological processes, making miRNAs good targets for drug therapy. Restoration of down-regulated miRNA or inhibition of overexpressed miRNA to return miRNA to its normal state is the basis of miRNA-based therapy. This review focuses on nanocarriers used for the delivery of miRNA that confer physical stability to the unstable RNA structure, protect the RNA from nuclease degradation and aid in effective silencing of target genes.

Areas covered: The necessity of the nanocarrier for the delivery of the miRNA is emphasized and the recent research on liposome-, metal- and polymer-mediated miRNA delivery for the inhibition or replacement of the disease-related miRNA is summarized.

Expert opinion: The size, charge and surface properties of nanocarriers have to be tuned to ensure effective and safe delivery of the miRNA in clinical practice. The immune responses related to the nanocarriers and the double-stranded nucleotide delivery remain to be addressed. Also, the binding of miRNAs to non-specific targets has to be studied in more detail because miRNAs have multiple targets due to partial binding unlike siRNA.     

Orally active-targeted drug delivery systems for proteins and peptides

Introduction: In the past decade, extensive efforts have been devoted to designing ‘active targeted’ drug delivery systems (ATDDS) to improve oral absorption of proteins and peptides. Such ATDDS enhance cellular internalization and permeability of proteins and peptides via molecular recognition processes such as ligand–receptor or antigen?antibody interaction, and thus enhance drug absorption.

Areas covered: This review focuses on recent advances with orally ATDDS, including ligand–protein conjugates, recombinant ligand–protein fusion proteins and ligand-modified carriers. In addition to traditional intestinal active transport systems of substrates and their corresponding receptors, transporters and carriers, new targets such as intercellular adhesion molecule-1 and β-integrin are also discussed.

Expert opinion: ATDDS can improve oral absorption of proteins and peptides. However, currently, no clinical studies on ATDDS for proteins and peptides are underway, perhaps due to the complexity and limited knowledge of transport mechanisms. Therefore, more research is warranted to optimize ATDDS efficiency.     

Nanoparticle-based vaginal drug delivery systems for HIV prevention

Importance of the Field: Several strategies are being investigated for the prevention of heterosexual transmission of HIV. Of these, topical vaginal drug delivery systems, microbicides, are being actively pursued. HIV prevention by means of a topical microbicide has several drug delivery challenges. These challenges include the vaginal mucosal barriers and potential degradation of the drugs in the vaginal lumen due to pH and enzymes present. Also, new drugs being evaluated as microbicides have specific mechanisms of action, which in some cases require drug targeting to a specific site of action. Nanoparticles provide a delivery strategy for targeted or controlled delivery to the vagina which can be applied in the field of HIV prevention.

Areas covered in the review: This review summarizes nanoparticulate systems and their use in mucosal delivery to date. The sexual transmission of HIV along with the various targets to prevent transmission are discussed as well as the potential opportunities, challenges and advantages in using a nanoparticle-based approach for microbicidal drug delivery.

What the reader will gain: This review provides a general understanding of vaginal drug delivery, its challenges, and nanoparticulate delivery systems. Additionally, insight will be gained as to the limited existing application of this technology to the field of HIV prevention.

Take home message: To date, few studies have been published that exploit nanoparticle-based microbicidal delivery to the vagina. The use of nanoparticles for vaginal drug delivery provides an approach to overcome the existing barriers to success.     

Micro- and nanocarrier-mediated lung targeting

Importance of the field: Drug delivery to lungs appears to be an attractive proposition on account of the large surface area of the alveolar region; it provides tremendous opportunities to improve drug therapies both systemically and locally using new drug delivery systems. Administration of drugs directly to the lungs is the most appropriate route in the treatment of asthma and other pulmonary diseases such as tuberculosis, chronic obstructive pulmonary disease and lung cancer.

Areas covered in this review: This review focuses on the utilization of nano- and microcarriers such as microspheres, nanoparticles, liposomes, niosomes and dendrimers for targeted delivery of bioactive molecules to lungs.

What the reader will gain: This review sheds light on the current status of nano- and microcarrier-mediated lung targeting of bioactive compounds.

Take home message: The literature review shows that carriers could supplement sustained drug delivery to the lungs, extended duration of action, reduced therapeutic dose, improved patient compliance, and reduced adverse effects of highly toxic drugs. There is still a need to identify more specific receptors that are present exclusively in the lungs. The identification of such receptors may also facilitate drug targeting to further specific parts of the lungs, such as bronchioles and alveoli.     

Cellular delivery of siRNA and antisense oligonucleotides via receptor-mediated endocytosis

Introduction: There is great potential for antisense and siRNA oligonucleotides to become mainstream therapeutic entities thanks to their high specificity and wide therapeutic target space compared with small molecules. Despite this potential, the pharmacological targets within the cells are less accessible to oligonucleotides that are hydrophilic and often charged. Oligonucleotides access their intracellular targets mainly by means of endocytosis, but only a fraction of them reach their targets, as delivery requires functional synergy of cellular uptake and intracellular trafficking.

Areas covered: This review provides an update on the progress of receptor-targeted delivery of oligonucleotides over the last 15 years and summarizes various targeting moieties for oligonucleotide delivery and coupling strategies. To inspire new strategies that can lead to oligonucleotides in the clinic, this review highlights how oligonucleotides successfully reach their intracellular targets by means of receptor-mediated endocytosis.

Expert opinion: Understanding the mechanisms of oligonucleotide internalization has led to greater cellular uptake and superior endosomal release through the rational design of receptor-targeted delivery systems. Further improvements will again depend on a better understanding of the intracellular trafficking of oligonucleotides.     

Challenges and advances in the development of inhalable drug formulations for cystic fibrosis lung disease

Introduction: Cystic fibrosis (CF) is a multisystem genetic disorder, which usually results in significant respiratory dysfunction. At present there is no cure for CF, but advances in pharmacotherapy have gradually increased the life expectancy of CF patients. As many drugs used in the therapy of CF are delivered by inhalation, the demand for effective and convenient inhalational CF drug formulations will grow as CF patients live longer. Knowledge of the current limitations in inhalational CF drug delivery is critical in identifying new opportunities and designing rational delivery strategies.

Areas covered: This review discusses current and emerging therapeutic agents for CF therapy, selected physiological challenges to effective inhalational medication delivery, and various approaches to overcoming these challenges. The reader will find an integrated view of the known inhalational drug delivery challenges and the rationales for recent investigational inhalational drug formulations.

Expert opinion: An ideal drug/gene delivery system to CF airways should overcome the tenacious sputum, which presents physical, chemical and biological barriers to effective transport of therapeutic agents to the targets and various cellular challenges.     

Advances in quantitative structure–activity relationship models of antimalarials

Importance of the field: Malaria still remains one of the deadliest infectious diseases having a tremendous morbidity and mortality impact in the developing world. Computational tools such as quantitative structure–activity relationship (QSAR) studies help medicinal chemists to understand the consistent relationship between antimalarial activity and molecular properties, and design new potent and selective ligands that may act on different classes of antimalarial drug targets so that these compounds may eventually be synthesized and assayed.

Area covered in this review: In the present review, we focus on the current knowledge of QSARs and pharmacophore models of different classes of antimalarial drugs. In this context, we also review the reported docking studies of antimalarial compounds acting on different targets to explore the interaction pattern at the molecular level.

What the reader will gain: The reader will gain an overview of advances of QSAR and related theoretical models of antimalarial drug compounds.

Take home message: This review infers that most of the reported QSAR models are analog based QSARs with a limited applicability domain, but QSAR models based on diverse chemical structures acting on a particular target have been reported in very few cases.     

Liposomal cancer therapy: exploiting tumor characteristics

Importance of the field: More than 10 million people worldwide are diagnosed with cancer each year, and the development of effective cancer treatments is consequently of great significance. Cancer therapy is unfortunately hampered by severe dose-limiting side effects that reduce the efficacy of cancer treatments. In the search for more effective cancer treatments, nanoparticle-based drug delivery systems, such as liposomes, that are capable of delivering their drug payload selectively to cancer cells are among the most promising approaches.

Areas covered in this review: This review provides an overview of current strategies for improving the different stages of liposomal cancer therapy, which involve transporting drug-loaded liposomes through the bloodstream, increasing tumor accumulation, and improving drug release and cancer cell uptake after accumulation at the tumor target site.

What the reader will gain: The review focuses on strategies that exploit characteristic features of solid tumors, such as abnormal vasculature, overexpression of receptors and enzymes, as well as acidic and thiolytic characteristics of the tumor microenvironment.

Take home message: It is concluded that the design of new liposomal drug delivery systems that better exploit tumor characteristic features is likely to result in more efficacious cancer treatments.     

Glycobiology of the Leishmania parasite and emerging targets for antileishmanial drug discovery

Importance of the field: Parasitic diseases that pose a threat to human life include leishmaniasis – caused by protozoa of Leishmania species. Existing drugs have limitations due to deleterious side effects like teratogenicity and factors like cost and drug resistance, thus furthering the need to develop this area of research.

Areas covered in this review: We came across drug targets, very recently characterised, cloned and validated by genomics and bioinformatics. We bring these promising drug targets into focus so that they can be explored to their fullest.

What the reader will gain: In an effort to bridge the gaps between existing knowledge and future prospects of drug discovery, we found interesting studies validating drug targets and paving the way for better experiments to be designed. In a few cases, novel pathways have been characterized, while in others, well established pathways when probed further, led to the discovery of new drug targets.

Take home message: The review constitutes a comprehensive report on upcoming drug targets, with emphasis on glycosylphosphatidylinositol (GPI)-anchored glycoconjugates along with related biochemistry of enolase, glycosome and purine salvage pathways, as we strive to bring ourselves a step closer to being able to combat this deadly disease.     

Potential of polymeric nanoparticles in AIDS treatment and prevention

Importance of the field: Acquired immunodeficiency syndrome (AIDS) remains one of the greatest challenges in public health. The AIDS virus is now responsible for > 2.5 million new infections worldwide each year. Despite significant advances in understanding the mechanism of viral infection and identifying effective treatment approaches, the search for optimum treatment strategies for AIDS remains a major challenge. Recent advances in the field of drug delivery have provided evidence that engineered nanosystems may contribute to the enhancement of current antiretroviral therapy.

Areas covered in this review: This review describes the potential of polymeric nanoparticle-based drug delivery systems in the future treatment of AIDS. Polymeric nanoparticles have been developed to improve physicochemical drug characteristics (by increasing drug solubility and stability), to achieve sustained drug release profile, to provide targeting to the cellular and anatomic human immunodeficiency virus (HIV) latent reservoirs and to be applied as an adjuvant in anti-HIV vaccine formulations.

What the reader will gain: The insight that will be gained is knowledge about the progress in the development of polymeric nanoparticle-based drug delivery systems for antiretroviral drugs as alternative for AIDS treatment and prevention.

Take home message: The advances in the field of targeted drug delivery can result in more efficient strategies for AIDS treatment and prevention.     

Low-frequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs

Importance of the field: Transdermal delivery of macromolecules provides an attractive alternative route of drug administration when compared to oral delivery and hypodermic injection because of its ability to bypass the harsh gastrointestinal tract and deliver therapeutics non-invasively. However, the barrier properties of the skin only allow small, hydrophobic permeants to traverse the skin passively, greatly limiting the number of molecules that can be delivered via this route. The use of low-frequency ultrasound for the transdermal delivery of drugs, referred to as low-frequency sonophoresis (LFS), has been shown to increase skin permeability to a wide range of therapeutic compounds, including both hydrophilic molecules and macromolecules. Recent research has demonstrated the feasibility of delivering proteins, hormones, vaccines, liposomes and other nanoparticles through LFS-treated skin. In vivo studies have also established that LFS can act as a physical immunization adjuvant. LFS technology is already clinically available for use with topical anesthetics, with other technologies currently under investigation.

Areas covered in this review: This review provides an overview of mechanisms associated with LFS-mediated transdermal delivery, followed by an in-depth discussion of the current applications of LFS technology for the delivery of hydrophilic drugs and macromolecules, including its use in clinical applications.

What the reader will gain: The reader will gain an insight into the field of LFS-mediated transdermal drug delivery, including how the use of this technology can improve on more traditional drug delivery methods.

Take home message: Ultrasound technology has the potential to impact many more transdermal delivery platforms in the future due to its unique ability to enhance skin permeability in a controlled manner.     

Emerging concepts and approaches for chemokine-receptor drug discovery

Importance of the field: Chemokine receptors are most noted for their role in cell migration. However, inappropriate utilization or regulation of these receptors is implicated in many inflammatory diseases, cancer and HIV, making them important drug targets.

Areas covered in this review: Allostery, oligomerization and ligand bias are presented as they pertain to chemokine receptors and their associated pathologies. Specific examples of each are described from the recent literature and their implications are discussed in terms of drug discovery efforts targeting chemokine receptors.

What the reader will gain: Insight into the expanding view of the multitude of pharmacological variables that need to be considered or that may be exploited in chemokine receptor drug discovery.

Take home message: Since 2007, two drugs targeting chemokine receptors have been approved by the FDA, Maraviroc for preventing HIV infection and Mozobil^? for hematopoietic stem cell mobilization. While these successes permit optimism for chemokine receptors as drug targets, only recently has the complexity of this system begun to be appreciated. The concepts of allosteric inhibitors, biased ligands and functional selectivity raise the possibility that drugs with precisely-defined properties can be developed. Other complexities such as receptor oligomerization and tissue-specific functional states of receptors also offer opportunities for increased target and response specificity, although it will be more challenging to translate these ideas into approved therapeutics compared to traditional approaches.     

Micro and nanosystems for delivering local anesthetics

Introduction: One of the most common strategies for pain control during and after surgical procedures is the use of local anesthetics. Prolonged analgesia can be safely achieved with drug delivery systems suitably chosen for each local anesthetic agent.

Areas covered: This review considers drug delivery formulations of local anesthetics designed to prolong the anesthetic effect and decrease toxicity. The topics comprise the main drug delivery carrier systems (liposomes, biopolymers, and cyclodextrins) for infiltrative administration of local anesthetics. A chronological review of the literature is presented, including details of formulations as well as the advantages and pitfalls of each carrier system. The review also highlights pharmacokinetic data on such formulations, and gives an overview of the clinical studies published so far concerning pain control in medicine and dentistry.

Expert opinion: The design of novel drug delivery systems for local anesthetics must focus on how to achieve higher uploads of the anesthetic into the carrier, and how to sustain its release. This comprehensive review should be useful to provide the reader with the current state-of-art regarding drug delivery formulations for local anesthetics and their possible clinical applications.     

Metallic nanoparticles: technology overview & drug delivery applications in oncology

Importance of the field: The targeted delivery of therapeutic agents to tumour cells is a challenge because most of the chemotherapeutic agents distribute to the whole body, which results in general toxicity and poor acceptance by patients and sometimes discontinuation of the treatment. Metallic nanoparticles have been used for a huge number of applications in various areas of medical treatment. Metallic nanoparticles are emerging as new carrier and contrast agents in cancer treatment. These metallic nanoparticles have been used for imaging of tumour cells by means of active and passive targeting. Recent advances have opened the way to site-specific targeting and drug delivery by these nanoparticles.

Areas covered in this review: This review summarizes the mechanisms of passive and active targeted drug delivery by metallic nanoparticles and their potential use in cancer theranostics.

What the reader will gain: The reader will gain information on the development of tumour cells, advantages of modern methods of cancer treatment over the traditional method, targeted delivery of anticancer agents using nanoparticles, influence of nanotechnology on the quality and expectancy of life, and challenges, implications and future prospects of metallic nanoparticles as probes in cancer treatment.

Take home message: The development of metallic nanoparticles is rapid and multidirectional, and the improved practical potential of metallic nanoparticle highlights their potency as new tools for future cancer therapeutics modalities.     

Drug delivery using multifunctional dendrimers and hyperbranched polymers

Importance of the field: The review presents the design strategy and synthesis of multifunctional dendrimers and hyperbranched polymers with the objective to develop effective drug delivery systems.

Areas covered in this review: Well-characterized, commercially available dendritic polymers were subjected to functionalization for preparing drug delivery systems of low toxicity, high loading capacity, ability to target specific cells and transport through their membranes. This has been achieved by surface targeting ligands, which render the carriers specific to certain cells and polyethylene glycol groups, securing water solubility, stability and prolonged circulation. Moreover, transport agents facilitate transport through cell membranes while fluorescent probes detect their intracellular localization. A common feature of surface groups is multivalency, which considerably enhances their binding strength with complementary cell receptors. To these properties, one should also add the property of attaining high loading of active ingredients coupled with controlled and/or triggered release.

What the reader will gain: Readers will be exposed to the strategy of synthesizing multifunctional polymers, aimed at the development of effective drug delivery systems.

Take home message: Multifunctional systems upgrade the therapeutic potential of drugs and, in certain cases, may even lead to the application of new bioactive compounds that would otherwise not be feasible.     

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics

Introduction: Genetically engineered biomaterials are useful for controlled delivery owing to their rational design, tunable structure–function, biocompatibility, degradability and target specificity. Silk-elastin-like proteins (SELPs), a family of genetically engineered recombinant protein polymers, possess these properties. Additionally, given the benefits of combining semi-crystalline silk-blocks and elastomeric elastin-blocks, SELPs possess multi-stimuli-responsive properties and tunability, thereby becoming promising candidates for targeted cancer therapeutics delivery and controlled gene release.

Areas covered: An overview of SELP biomaterials for drug delivery and gene release is provided. Biosynthetic strategies used for SELP production, fundamental physicochemical properties and self-assembly mechanisms are discussed. The review focuses on sequence–structure–function relationships, stimuli-responsive features and current and potential drug delivery applications.

Expert opinion: The tunable material properties allow SELPs to be pursued as promising biomaterials for nanocarriers and injectable drug release systems. Current applications of SELPs have focused on thermally-triggered biomaterial formats for the delivery of therapeutics, based on local hyperthermia in tumors or infections. Other prominent controlled release applications of SELPs as injectable hydrogels for gene release have also been pursued. Further biomedical applications that utilize other stimuli to trigger the reversible material responses of SELPs for targeted delivery, including pH, ionic strength, redox, enzymatic stimuli and electric field, are in progress. Exploiting these additional stimuli-responsive features will provide a broader range of functional biomaterials for controlled therapeutics release and tissue regeneration.     

Exploitation of lipid-polymeric matrices at nanoscale for drug delivery applications

ABSTRACT

Introduction: Progress in drug delivery and a better quality of life for patients, relies on the development of new and suitable drug carrier systems, with unequivocal therapeutic benefits, low systemic toxicity and reduced side effects. Lipid-polymeric nanoparticles have been explored to produce nanocarriers due to their features and applications such as high drug entrapment, physical-chemical stability and controlled release properties.

Areas covered: In this review, we describe several hybrid nanoparticles obtained from mixing a polymer with a lipid matrix. This association can potentiate the efficacy of drug delivery systems, due to the enhancement of encapsulation efficiency and loading capacity, tailoring the drug release according to the therapeutic purpose, and improving the drug uptake by targeting it to specific receptors. Contrary to lipid nanoparticles, these hybrid nanoparticles can decrease the initial burst release and promote a more sustained and localized release of the drug.

Expert Opinion: Lipid-polymeric nanoparticles are versatile vehicles for drug delivery by different administration routes in the treatment of multiple diseases. Different solid lipids, polymers, surfactants and techniques for producing these carriers have been investigated, revealing the importance of their composition to achieve optimal characteristics to drug delivery.