Hydrogel nanoparticles in drug delivery

Hydrogel nanoparticles have gained considerable attention in recent years as one of the most promising nanoparticulate drug delivery systems owing to their unique potentials via combining the characteristics of a hydrogel system (e.g., hydrophilicity and extremely high water content) with a nanoparticle (e.g., very small size). Several polymeric hydrogel nanoparticulate systems have been prepared and characterized in recent years, based on both natural and synthetic polymers, each with its own advantages and drawbacks. Among the natural polymers, chitosan and alginate have been studied extensively for preparation of hydrogel nanoparticles and from synthetic group, hydrogel nanoparticles based on poly (vinyl alcohol), poly (ethylene oxide), poly (ethyleneimine), poly (vinyl pyrrolidone), and poly-N-isopropylacrylamide have been reported with different characteristics and features with respect to drug delivery. Regardless of the type of polymer used, the release mechanism of the loaded agent from hydrogel nanoparticles is complex, while resulting from three main vectors, i.e., drug diffusion, hydrogel matrix swelling, and chemical reactivity of the drug/matrix. Several crosslinking methods have been used in the way to form the hydrogel matix structures, which can be classified in two major groups of chemically- and physically-induced crosslinking.     

Liposomes and micro/nanoparticles as colloidal carriers for nasal drug delivery

The use of the nasal route for drug delivery has attracted much interest in recent years in the pharmaceutical field. Local and principally systemic drug delivery can be achieved by this route of administration. But the nasal route of delivery is not applicable to all drugs. Polar drugs and some macromolecules are not absorbed in sufficient concentration due to poor membrane permeability, rapid clearance and enzymatic degradation into the nasal cavity. Thus, alternative means that help overcome these nasal barriers are currently in development. Absorption enhancers such as phospholipids and surfactants are constantly used, but care must be taken in relation to their concentration. Drug delivery systems including liposomes, cyclodextrins, micro- and nanoparticles are being investigated to increase the bioavailability of drugs delivered intranasally. This review article discusses recent progress and specific development issues relating to colloidal drug delivery systems in nasal drug delivery.     

PEG-PLA nanoparticles as carriers for nasal vaccine delivery.

This report presents an overview of the potential of nanoparticles as nasal carriers for drug/vaccine administration. In addition, this report shows, for the first time, the efficacy of polylactic acid nanoparticles coated with a hydrophilic polyethyleneglycol coating (PEG-PLA nanoparticles) as carriers for the nasal transport of bioactive compounds. For this purpose, tetanus toxoid (TT), a high molecular weight protein (Mw 150,000 Da), was chosen as a model antigen and encapsulated in the PEG-PLA nano- and microparticles (200 nm and 1.5 microm respectively). These nanosystems were first characterized for their stability in the presence of lysozyme and also for their size, electrical charge, loading efficiency, in vitro release of antigenically active toxoid and afterwards, these formulations were administered intranasally to mice and the systemic and mucosal anti-tetanus responses were evaluated for up to 24 weeks. Additionally, PEG-PLA particles labeled with rhodamine 6G were administered intranasally to rats in order to visualize their interaction with the nasal mucosae by fluorescence microscopy. Their behavior was compared with that of the well known PLA nanoparticles (200 nm). The results showed that PLA nanoparticles suffered an immediate aggregation upon incubation with lysozyme, whereas the PEG-coated nanoparticles remained totally stable. The antibody levels elicited following i.n. administration of PEG-coated nanoparticles were significantly higher than those corresponding to PLA nanoparticles. Furthermore, PEG-PLA nanoparticles generated an increasing and a long lasting response. The qualitative fluorescence microscopy studies revealed that PEG-PLA particles are able to cross the rat nasal epithelium. These studies indicate that the PEG coating around the particles has a role in stabilizing PLA particles in mucosal fluids and that it facilitates the transport of the nanoencapsulated antigen, hence eliciting a high and long lasting immune response.     

Chitosan-based hydrogels for nasal drug delivery: from inserts to nanoparticles

Importance of the field: Chitosan represents a multifunctional polymer, featuring both mucoadhesive and permeation-enhancing properties and therefore is a widely studied excipient for mucosal drug delivery. As regards nasal administration, chitosans have been used for the preparation of gels, solid inserts, powders and nanoparticles in which a three-dimensional network can be recognized.

Areas covered in this review: This review provides a discussion of the different nasal dosage forms based on chitosan hydrogels. In the first section intranasal delivery is discuss as a useful tool for non-invasive administration of drugs intended for local or systemic treatments. Then chitosan-based hydrogels are described with a focus on their mucoadhesive and permeation-enhancing ability as well as their capacity of controlled drug release. Finally, a detailed discussion regarding several examples of the different nasal dosage forms is reported, including considerations on in vitro, ex vivo and in vivo studies.

What the reader will gain: Summary and discussion of recent data on the different pharmaceutical forms based on chitosan hydrogels could be of interest to researchers dealing with nasal drug delivery.

Take home message: The aim of this review is to stimulate further investigations in order to achieve the collection of harmonized data and concrete clinical perspectives.     

Albumin nanoparticles carrying cyclodextrins for nasal delivery of the anti-Alzheimer drug tacrine

Peroral administration of tacrine, the first acetylcholinestearse inhibitor licensed for the treatment of Alzheimer's disease, is associated with low bioavailability, due to an extended first-pass methabolism, short elimination half-life and hepatotoxicity. Nasal drug delivery may reduce the degree of these problems. Tacrine hydrochloride nasal delivery is here investigated by means of albumin nanoparticles carrying beta cyclodextrin and two different beta cyclodextrin derivatives (hydroxypropyl beta cyclodextrin and sulphobutylether beta cyclodextrin). Bovine serum albumin nanoparticles were obtained using a coacervation method, followed by thermal cross-linking, starting from protein solution at alkaline pH. After preparation, nanoparticles were loaded by soaking from solutions of tacrine hydrochloride and lyophilised. Thermal analysis (differential scanning calorimetry and thermogravimetric analysis) supported by Fourier Transform Infrared Spectroscopy were performed in order to confirm protein cross-linking in nanosphere structure and possible drug/carrier interaction occurred after the loading process. Moreover, size, polydispersity, zeta potential and morphology of the nanoparticles were investigated as well as drug loading, mucoadhesion properties and ex-vivo drug permeation ability. Results indicate that all the nanoparticles presented a mean size and a polydispersity lower than 300nm and 0.33nm, respectively, were spherical shaped and negatively charged even after drug loading. Moreover, the presence of the different beta cyclodextrins in the polymeric network affected drug loading and could differently modulate nanoparticle mucoadhesiveness and drug permeation behaviour.     

Prodrugs for nasal drug delivery

Recently, the delivery of xenobiotics via the nasal route has received increasing attention as this offers several advantages, i.e. high systemic availability, rapid onset of action. Both charged and uncharged forms of drugs can be transported across the nasal epithelium. This mucosa is rich in various metabolizing enzymes such as aldehyde dehydrogenase, glutathione transferases, epoxide hydrolases, cyt-P450-dependent monooxygenases. The presence of these enzymes may make it possible for pharmaceutical scientists to design prodrugs for better absorption and high systemic availability. Recent advances in peptide nasal delivery through prodrug modification has been thoroughly discussed in this paper. Finally, nasally delivered therapeutic agents targeted to various disease states have been examined.     

Non-degradable polymer nanocomposites for drug delivery

INTRODUCTION: The need to optimize therapeutic outcomes while minimizing side effects is a major driving force for research and development in the controlled drug delivery field. Polymer nanocomposites (NCs) are an emerging class of materials with remarkable potential for controlled drug delivery. There are a range of release mechanisms that characterize polymer NC systems, and these may be perturbed not only by the addition of nanofillers, but also by the type of drug and the interactions of the drug with the components of the system. AREAS COVERED: The focus of this review is on non-degradable polymer NC systems. In particular, the types of drug delivery approach from these polymer NCs and the theoretical models developed to describe those approaches are discussed. The importance of component interactions and factors affecting drug delivery from polymer NCs is also addressed. EXPERT OPINION: Despite the remarkable potential and extensive research being conducted on polymer NCs for use in drug delivery, commercialization and large-scale production are limited by the cost and difficulty in consistently producing fully exfoliated NCs. A continuing challenge for the field is to understand better the key interactions and structure-property relationships arising from different polymer, filler and drug combinations.     

Absorption enhancers for nasal drug delivery

This paper describes the basic concepts for the transmucosal delivery of drugs, and in particular the use of the nasal route for delivery of challenging drugs such as polar low-molecular-weight drugs and peptides and proteins. Strategies for the exploitation of absorption enhancers for the improvement of nasal delivery are discussed, including consideration of mechanisms of action and the correlation between toxic effect and absorption enhancement. Selected enhancer systems, such as cyclodextrins, phospholipids, bioadhesive powder systems and chitosan, are discussed in detail. Examples of the use of these enhancers in preclinical and clinical studies are given. Methods for assessing irritancy and damage to the nasal membrane from the use of absorption enhancers are also described. Finally, the mucosal use of absorption enhancers (chitosan) for the improved nasal delivery of vaccines is reported with reference to recent phase I/II clinical studies.     

Low molecular weight chitosan nanoparticles as new carriers for nasal vaccine delivery in mice.

High molecular weight (Mw) chitosan (CS) solutions have already been proposed as vehicles for nasal immunization. The aim of the present work was to investigate the potential utility of low Mw CS in the form of nanoparticles as new long-term nasal vaccine delivery vehicles. For this purpose, CS of low Mws (23 and 38 kDa) was obtained previously by a depolymerization process of the commercially available CS (70 kDa). Tetanus toxoid (TT), used as a model antigen, was entrapped within CS nanoparticles by an ionic cross-linking technique. TT-loaded nanoparticles were first characterized for their size, electrical charge, loading efficiency and in vitro release of antigenically active toxoid. The nanoparticles were then administered intranasally to conscious mice in order to study their feasibility as vaccine carriers. CS nanoparticles were also labeled with FITC-BSA and their interaction with the rat nasal mucosa examined by confocal laser scanning microcopy (CLSM). Irrespective of the CS Mw, the nanoparticles were in the 350 nm size range, and exhibited a positive electrical charge (+40 mV) and associated TT quite efficiently (loading efficiency: 50-60%). In vitro release studies showed an initial burst followed by an extended release of antigenically active toxoid. Following intranasal administration, TT-loaded nanoparticles elicited an increasing and long-lasting humoral immune response (IgG concentrations) as compared to the fluid vaccine. Similarly, the mucosal response (IgA levels) at 6 months post-administration of TT-loaded CS nanoparticles was significantly higher than that obtained for the fluid vaccine. The CLSM images indicated that CS nanoparticles can cross the nasal epithelia and, hence, transport the associated antigen. Interestingly, the ability of these nanoparticles to provide improved access to the associated antigen to the immune system was not significantly affected by the CS Mw. Indeed, high and long-lasting responses could be obtained using low Mw CS molecules. Furthermore, the response was not influenced by the CS dose (70-200 microg), achieving a significant response for a very low CS dose. In conclusion, nanoparticles made of low Mw CS are promising carriers for nasal vaccine delivery.     

Anthrax vaccine powder formulations for nasal mucosal delivery

Anthrax remains a serious threat worldwide as a bioterror agent. A second-generation anthrax vaccine currently under clinical evaluation consists of a recombinant Protective Antigen (rPA) of Bacillus anthracis. We have previously demonstrated that complete protection against inhalational anthrax can be achieved in a rabbit model, by intranasal delivery of a powder rPA formulation. Here we describe the preformulation and formulation development of such powder formulations. The physical stability of rPA was studied in solution as a function of pH and temperature using circular dichroism (CD), and UV-visible absorption and fluorescence spectroscopies. Extensive aggregation of rPA was observed at physiological temperatures. An empirical phase diagram, constructed using a combination of CD and fluorescence data, suggests that rPA is most thermally stable within the pH range of 6-8. To identify potential stabilizers, a library of GRAS excipients was screened using an aggregation sensitive turbidity assay, CD, and fluorescence. Based on these stability profiles, spray freeze-dried (SFD) formulations were prepared at pH 7-8 using trehalose as stabilizer and a CpG-containing oligonucleotide adjuvant. SFD formulations displayed substantial improvement in storage stability over liquid formulations. In combination with noninvasive intranasal delivery, such powder formulations may offer an attractive approach for mass biodefense immunization.     

Cyclodextrins in nasal drug delivery

Nasal drug delivery is an attractive approach for the systemic delivery of high potency drugs with a low oral bioavailability due to extensive gastrointestinal breakdown and high hepatic first-pass effect. For lipophilic drugs nasal delivery is possible if they can be dissolved in the dosage form. Peptide and protein drugs often have a low nasal bioavailability because of their large size and hydrophilicity, resulting in poor transport properties across the nasal mucosa. Cyclodextrins are used to improve the nasal absorption of these drugs by increasing their aqueous solubility and/or by enhancing their nasal absorption. With several cyclodextrins very efficient nasal drug absorption has been reported, but also large interspecies differences have been found. Studies concerning the safety of cyclodextrins in nasal drug formulations demonstrate the non-toxicity of the cyclodextrins and also clinical data show no adverse effects. Therefore, some cyclodextrins can be expected to become effective and safe excipients in nasal drug delivery.     

Exploiting M cells for drug and vaccine delivery

The specialised antigen sampling M cells represent an efficient portal for mucosal drug and vaccine delivery. Delivery may be achieved using synthetic particulate delivery vehicles including poly(DL-lactide-co-glycolide) microparticles and liposomes. M cell interaction of these delivery vehicles is highly variable, and is determined by the physical properties of both particles and M cells. Delivery may be enhanced by coating with reagents including appropriate lectins, microbial adhesins and immunoglobulins which selectively bind to M cell surfaces. Live attenuated microorganisms are also suitable as vaccines and mucosal vectors and many, including Salmonella typhimurium, innately target to M cells. After cell surface adhesion, delivery vehicles are rapidly transported across the M cell cytoplasm to underlying lymphoid cells and may subsequently disseminate via the lymphatics. Further definition of M cell development and function should permit exploitation of their high transcytotic capacity for safe and reliable mucosal delivery.     

Inorganic nanoparticles for hydrophobic anticancer drug delivery

OBJECTIVE Many drug candidates identified from natural products are poorly water-soluble.The surfactants used to disperse the hydrophobic anticancer drugs in water may cause a serious of acute hypersensitivity reactions.Nanotechnology provides an alternative strategy for delivery of anticancer drugs.In the present study,different inorganic nanoparticles are utilized as hydrophobic anticancer drug carriers.METHODS Different inorganic superparamagnetic iron oxide,platinum and gold nanoparticles were synthesized.The hydrophobic anticancer drugs such as curcumin,gambogic acid and doxorubicin(DOX)base were loaded into the porous area or onto the surface of the nanoparticles.Cellular uptake and biocompatibility of nanoparticles were studied in human glioblastoma U-87 MG cells.The anticancer effect of drug loaded nanoparticles was compared with that of free drugs.Photothermal conversion of platinum and gold nanoparticles was studied by irradiation of nanoparticles with a near-infrared laser.RESULTS The synthesized nanoparticles are readily internalized by U-87 MG cells,and the internalized nanoparticles are mainly localized in endosomes/lysosomes in cells.The nanoparticle-based drug carrier provides the aqueous dispersions of the hydrophobic drugs.In endosomes/lysosomes mimicking buffers with a pH of 4.5-5.5,pH-dependent drug release was observed from drug loaded nanoparticles.The intracellular drug content and cytotoxicity are significantly higher for drug loaded nanoparticles than free drug.Photothermal treatment has a synergistic effect on drug′s anticancer activity.CONCLUSION These results suggested inorganic nanoparticles is a promising intracellular carrier for hydrophobic anticancer drugs.     

Solid lipid nanoparticles for ocular drug delivery

Ocular drug delivery remains challenging because of the complex nature and structure of the eye. Conventional systems, such as eye drops and ointments, are inefficient, whereas systemic administration requires high doses resulting in significant toxicity. There is a need to develop novel drug delivery carriers capable of increasing ocular bioavailability and decreasing both local and systemic cytotoxicity. Nanotechnology is expected to revolutionize ocular drug delivery. Many nano-structured systems have been employed for ocular drug delivery and yielded some promising results. Solid lipid nanoparticles (SLNs) have been looked at as a potential drug carrier system since the 1990s. SLNs do not show biotoxicity as they are prepared from physiological lipids. SLNs are especially useful in ocular drug delivery as they can enhance the corneal absorption of drugs and improve the ocular bioavailability of both hydrophilic and lipophilic drugs. SLNs have another advantage of allowing autoclave sterilization, a necessary step towards formulation of ocular preparations. This review outlines in detail the various production, characterization, sterilization, and stabilization techniques for SLNs. In-vitro and in-vivo methods to study the drug release profile of SLNs have been explained. Special attention has been given to the nature of lipids and surfactants commonly used for SLN production. A summary of previous studies involving the use of SLNs in ocular drug delivery is provided, along with a critical evaluation of SLNs as a potential ocular delivery system.     

Solid lipid nanoparticles for parenteral drug delivery

This review describes the use of nanoparticles based on solid lipids for the parenteral application of drugs. Firstly, different types of nanoparticles based on solid lipids such as "solid lipid nanoparticles" (SLN), "nanostructured lipid carriers" (NLC) and "lipid drug conjugate" (LDC) nanoparticles are introduced and structural differences are pointed out. Different production methods including the suitability for large scale production are described. Stability issues and drug incorporation mechanisms into the particles are discussed. In the second part, the biological activity of parenterally applied SLN and biopharmaceutical aspects such as pharmacokinetic profiles as well as toxicity aspects are reviewed.     

Penetratin-functionalized PEG-PLA nanoparticles for brain drug delivery

Nanoparticulate drug delivery system possesses distinct advantages for brain drug delivery. However, its amount that reach the brain is still not satisfied. Cell-penetrating peptides (CPPs), short peptides that facilitate cellular uptake of various molecular cargo, would be appropriate candidates for facilitating brain delivery of nanoparticles. However, such effect could be deprived by the rapid systemic clearance of CPPs-functionalized nanoparticles due to their positive surface charge. Penetratin (CPP with relatively low content of basic amino acids) was here functionalized to poly(ethylene glycol)-poly(lactic acid) nanoparticles (NP) to achieve desirable pharmacokinetic and biodistribution profiles for brain drug delivery. The obtained penetratin-NP showed a particle size of 100nm and zeta potential of -4.42mV. The surface conjugation of penetratin was confirmed by surface chemical compositions analysis via X-ray photo electron spectroscopy. In MDCK-MDR cell model, penetratin-NP presented enhanced cellular accumulation via both lipid raft-mediated endocytosis and direct translocation processes with the involvement of Golgi apparatus, lysosome and microtubules. In vivo pharmacokinetic and biodistribution studies showed that penetratin-NP exhibited a significantly enhanced brain uptake and reduced accumulation in the non-target tissues compared with low-molecular-weight protamine (CPP with high arginine content)-functionalized nanoparticles. These data strongly implicated that penetratin-NP might represent a promising brain-targeting drug delivery system. The findings also provided an important basis for the optimization of brain drug delivery systems via surface charge modulation.     

Multi-functional polymeric nanoparticles for tumour-targeted drug delivery

The use of nanoparticles as drug delivery vehicles for anticancer therapeutics has great potential to revolutionise the future of cancer therapy. As tumour architecture causes nanoparticles to preferentially accumulate at the tumour site, their use as drug delivery vectors results in the localisation of a greater amount of the drug load at the tumour site; thus improving cancer therapy and reducing the harmful nonspecific side effects of chemotherapeutics. In addition, formulation of these nanoparticles with imaging contrast agents provides a very efficient system for cancer diagnostics. Given the exhaustive possibilities available to polymeric nanoparticle chemistry, research has quickly been directed at multi-functional nanoparticles, combining tumour targeting, tumour therapy and tumour imaging in an all-in-one system, providing a useful multi-modal approach in the battle against cancer. This review will discuss the properties of nanoparticles that allow for such multiple functionality, as well as recent scientific advances in the area of multi-functional nanoparticles for cancer therapeutics.     

pH-sensitive Eudragit nanoparticles for mucosal drug delivery

Drug delivery via vaginal epithelium has suffered from lack of stability due to acidic and enzymatic environments. The biocompatible pH-sensitive nanoparticles composed of Eudragit S-100 (ES) were developed to protect loaded compounds from being degraded under the rigorous vaginal conditions and achieve their therapeutically effective concentrations in the mucosal epithelium. ES nanoparticles containing a model compound (sodium fluorescein (FNa) or nile red (NR)) were prepared by the modified quasi-emulsion solvent diffusion method. Loading efficiencies were found to be 26% and 71% for a hydrophilic and a hydrophobic compound, respectively. Both hydrophilic and hydrophobic model drugs remained stable in nanoparticles at acidic pH, whereas they are quickly released from nanoparticles upon exposure at physiological pH. The confocal study revealed that ES nanoparticles were taken up by vaginal cells, followed by pH-responsive drug release, with no cytotoxic activities. The pH-sensitive nanoparticles would be a promising carrier for the vaginal-specific delivery of various therapeutic drugs including microbicides and peptides/proteins.