Current Drug Discovery Technologies (v.8, #3)

Over the past few decades, micro and nanomaterials for drug delivery applications have received tremendous experimentalattraction in almost every field of biosciences. These materials hold great promise in biomedical applications for earlydiagnostics,noninvasive imaging and targeting delivery of therapeutics, as well as combined multifunctions and simultaneoustherapy and monitoring of the diseases (theranostics). More than ever there are combined efforts from many scientists all overthe World with different backgrounds to develop efficient and promising drug delivery systems (DDS) for the future. Currently,the field of drug delivery and biomaterials is a rather interdisciplinary and rapidly growing one. For example, efficient drugdelivery, targeting and diagnostics can be achieved by employing advanced natural and synthetic biopolymers, new generationof lipid-based formulations (e.g. solid lipid nanoparticles) and even by using outstanding inorganic materials, such as poroussilica- and silicon-based materials. These biomaterials are produced by novel technologies based on top-down and bottom-upapproaches.It is well recognized that many of the new developed drug molecules encompass potent biological activity, but still exhibitpoor pharmacokinetic properties that hinder their effective delivery to the intended site of action. These problems can be overcomeby means of DDS. The great advantage of these systems is that in most cases they are non-toxic and biodegradable,which render them great promising in the future when moving from pre-clinical to clinical trials. In addition, the incorporationof therapeutic compounds in DDS enables not only the improvement of the dissolution rate, solubility and bioavailability of thecompounds and the drug formulation stability, but also to effectively and selectively carrier the therapeutics to the specific sitein a controlled manner. The DDS are also expected to be suitable to the specific application (e.g. biodegradable and pHsensitive)and attain a particular degree of drug loading and release kinetics (e.g. slow or fast). Importantly, the tissue/cellmaterialinteractions have to be carefully considered to ensure the biocompatibility of DDS. It is well-known that there aremany factors affecting the biofate of the drug carriers when in contact with cell/tissues, e.g. their surface chemistry, topology,and biocompatibility. The biodistribution, accumulation and cellular uptake of biomaterial-based delivery systems may alsooccur through several different pathways depending on the properties of the DDS, such as particle size, shape, surface charge,etc. Therefore, the safety of novel DDS requires a total understanding of the physicochemical properties that account for adversebiological responses before coming to clinical trials.In this special issue of Current Drug Discovery Technologies several examples of innovative technologies for drug deliveryapplications will be illustrated, ranging from biopolymers, nanocapsules, liposomes, solid nanoparticles, to inorganic siliconandsilica-based materials. Eight review papers and one original research article will highlight and describe in more detail someof the most recent innovative technologies and strategies used to design different DDS and demonstrate their potential in biomedicalapplications. The introductory review paper by Andrade et al. describes the recent potentialities and advantages of chitosan-based pharmaceutical dosage forms used in the development of formulations for therapeutic proteins, as well as their interactionwith biological moieties and the effect on protein absorption pathways. Besides chitosan, other biodegradable polymersused for preparing nanocapsules are considered in the review paper by Rong et al., which also presents the most commonmethods of preparation of polymeric nanocapsules and also describes the applications of polymeric nanocapsules as carriers oftherapeutics. In the subsequent review paper, Hirsjarvi et al. presents several nanocarrier systems based on polymer micelles,nanoparticles/polymer-drug conjugates and liposomes used for passive and active tumor targeting. Similarly, the review paperby Kolhatkar et al. further discusses the in vitro binding and in vivo pharmacokinetics of dendrimers, copolymers andliposomes modified with folic acid, integrin and transferring for targeting delivery applications. In addition, the review paper byKeck et al. reviews the 20 years work on solid lipid nanoparticles, including the state of production, regulatory aspects, the importantquestions of nanotoxicity, the different administration routes, as well as presents the potential of solid lipid nanoparticlesfor optimized delivery and pharmaceutical product developments. The subsequent review paper by Santos et al. highlightsthe potential applications of porous silicon materials in biomedical applications and presents examples on the most recent invitro and in vivo studies, including the biocompatibility of these materials, their potential as carriers for delivery of therapeuticsand as platforms for drug targeting and noninvasive imaging. A similar approach continues in the review paper by Simovic etal. which describes the most recent milestones in the research of silica-based materials for controlled drug delivery, emphasizinge.g. their fabrication processes, biocompatibility aspects, their anticancer therapy and stimuli-responsive applications. Thereview paper by Cheng and Lo continues presenting the current application of silica-based materials, gold and iron oxide asnanodelivery systems, in particular for enhanced photodynamic cancer treatment. The last article, an original research paper bySandri et al., presents the results of an in situ gelling formulation based on Poloxamer 407 and sodium alginate, and demonstratesthat such formulation is a suitable extemporaneous vehicle to deliver platelet lysate on buccal mucosa to treat oral mucositis.The reports presented here highlight great potential of the described DDS for safety, controlled, and targeted delivery oftherapeutics and emphasize that more advanced or modified systems will emerge in the future with multifunctional applicationstowards the clinical trials. By taking advantage of the valuable properties of the DDS, such as increased surface area, improved solubility of therapeutics, possibility to encapsulate and protect therapeutics from degradation with reduced immunogenic potentialand toxicological effect, new tuneable and targeted drug delivery technologies can be development to improve the clinicalarsenal for numerous diseases. Moreover, many references can be found at the end of the individual reviews, which makethis thematic issue useful to a wide range of scientists working in various fields of research, thus emphasizing the high scientificstanding of the issue. All together, this issue will hopefully provide knowledge on the advances in DDS, biomaterials, andbio-nanotechnology, as well as demonstrate that they can be used for improving and/or delivery of therapeutics, potentiallyleading to new and effective DDS in the very near future. Finally, I would like to express my grateful thanks, as the Guest Editorof the special issue of Current Drug Discovery Technologies, to all the contributing authors and reviewers for their efforts inputting together this special issue.

Chitosan Formulations as Carriers for Therapeutic Proteins by Fernanda Andrade, Filipa Antunes, Ana Vanessa Nascimento, Sara Baptista da Silva, Jose das Neves, Domingos Ferreira, Bruno Sarmento (157-172).
Protein drugs represent a significant part of the new pharmaceuticals coming on the market every year and arenow widely spread in therapy to treat or relief symptomatology related to many metabolic and oncologic diseases. The deliveryof therapeutic proteins is still a major drawback against their maximum pharmacodynamic due to their physicochemicalproperties, poor stability, permeability and biodistribution. Despite the fact that the parenteral route remains theprimary route of protein administration, research continues on non-parenteral delivery routes. However, the high molecularweight of proteins, combined with their hydrophilic and charged nature, renders transport through membranes very difficult.In this regard, the biopolymer chitosan exhibits several favorable biological properties, such as biocompatibility,biodegradability, low-toxicity and mucoadhesiveness, which made it a promising candidate for the formulation of proteindrugs. The success of a protein formulation depends not only on the stability of the delivery system but also on their abilityto maintain the native structure and activity of the protein during preparation and the delivery, as well as during longtermstorage of the formulation. Chitosan-based delivery systems have been proposed as valid approaches to provide suchprotective conditions. The development of novel protein delivery systems based on chitosan is a rising subject irrespectiveof the intended route of administration. In this review, the different approaches recently exploited to formulate and delivertherapeutic proteins are underlined.

Applications of Polymeric Nanocapsules in Field of Drug Delivery Systems by Xinyu Rong, Yinghua Xie, Xiaomei Hao, Tao Chen, Yingming Wang, Yuanyuan Liu (173-187).
Drug-loaded polymeric nanocapsules have exhibited potential applications in the field of drug delivery systemsin recent years. This article entails the biodegradable polymers generally used for preparing nanocapsules, which includeboth natural polymers and synthetic polymers. Furthermore, the article presents a general review of the different preparationmethods: nanoprecipitation method, emulsion-diffusion method, double emulsification method, emulsioncoacervationmethod, layer-by-layer assembly method. In addition, the analysis methods of nanocapsule characteristics,such as mean size, morphology, surface characteristics, shell thickness, encapsulation efficiency, active substance release,dispersion stability, are mentioned. Also, the applications of nanocapsules as carriers for use in drug delivery systems arereviewed, which primarily involve targeting drug delivery, controlled/sustained release drug delivery systems, transdermaldrug delivery systems and improving stability and bioavailability of drugs. Nanocapsules, prepared with different biodegradablepolymers, have received more and more attention and have been regarded as one of the most promising drug deliverysystems.

Passive and Active Tumour Targeting with Nanocarriers by Samuli Hirsjarvi, Catherine Passirani, Jean-Pierre Benoit (188-196).
Nanocarriers can penetrate the tumour vasculature through its leaky endothelium and, in this way, accumulatein several solid tumours. This is called the enhanced permeation and retention (EPR) effect. Together with nanocarrierswhose surface is tailored for prolonged blood circulation times, the concept is referred to as passive targeting. Targetingligands, which bind to specific receptors on the tumour cells and endothelium, can be attached on the nanocarrier surface.This active targeting increases the selectivity of the delivery of drugs. Passive and active drug targeting with nanocarriersto tumours reduce toxic side-effects, increase efficacy, and enhance delivery of poorly soluble or sensitive therapeuticmolecules. In this review, currently studied and used passive and active targeting strategies in cancer therapy are presented.

Active Tumor Targeting of Nanomaterials Using Folic Acid, Transferrin and Integrin Receptors by Rohit Kolhatkar, Asawari Lote, Hiren Khambhati (197-206).
Folic acid, transferrin and integrin alpha v beta 3 (αvβ3) receptors are overexpressed in various cancer cell lines.Ligands having high affinity for these receptors are often conjugated to nanocarriers to facilitate the tumor localization oftherapeutic agents. In this review the use of these ligands for targeted delivery using liposomes, dendrimers and (N-(2-hydroxypropyl) methacrylamide) (HPMA) copolymers is discussed. Emphasis is placed on discussing drug delivery systemsthat have been optimized for in-vitro binding as well as in-vivo pharmacokinetics. Our aim is to understand the variousfactors influencing the targeting ability of nanocarriers.

20 Years of Lipid Nanoparticles (SLN & NLC): Present State of Development & Industrial Applications by Rainer H. Muller, Ranjita Shegokar, Cornelia M. Keck (207-227).
In 1990, the lipid nanoparticles were invented in the laboratories, the first patent filings took place in 1991. Thelipid nanoparticles were developed as alternative to traditional carriers such as polymeric nanoparticles and liposomes. After20 years of lipid nanoparticles, the present state of development is reviewed - academic progress but also the developmentstate of pharmaceutical products for the benefit of patients. Meanwhile many research groups are active worldwide,their results are reviewed which cover many different administration routes: dermal and mucosal, oral, intravenous/parenteral, pulmonary but also ocular. The lipid nanoparticles are also used for peptide/protein delivery, in genetherapy and various miscellaneous applications (e.g. vaccines). The questions of large scale production ability, acceptedregulatory status of excipients, and - important for the public perception - lack of nanotoxicity are discussed, importantpre-requisites for the use of each nanocarrier in products. Identical to the liposomes, the lipid nanoparticles entered firstthe cosmetic market, product examples are presented. Presently the pharmaceutical product development focuses on productsfor unmet needs and on niche products with lower development costs (e.g. ocular delivery), which can be realizedalso by smaller companies. A pharmaceutical perspective for the future is given, but also outlined the opportunities fornon-pharmaceutical use, e.g. in nutraceuticals.

Multifunctional Porous Silicon for Therapeutic Drug Delivery and Imaging by Helder A. Santos, Luis M. Bimbo, Vesa-Pekka Lehto, Vesa-Pekka Lehto, Anu J. Airaksinen, Jarno Salonen, Jouni Hirvonen (228-249).
Major challenges in drug formulation are the poor solid state stability of drug molecules, poor dissolution/solubility and/or poor pharmacokinetic properties (bioavailability), which may lead to unreliable in vitro-in vivo(IVIV) correlation. To improve current therapeutical strategies, novel means to deliver poorly water soluble active pharmaceuticalingredients, as well as to target them to specific sites or cells in the body are needed. Biomedical applicationsof porous silicon (PSi) have been actively investigated during the last 10 years, especially in the areas of drug delivery andimaging, due to the biocompatibility and biodegradability of PSi materials, which makes them a potential candidate forcontrolled drug release. In addition, the unique pore sizes and easily functionalized surface properties of PSi materials allowhigh drug payloads and controlled kinetics from the drug release formulations. Modification of the PSi surface propertiesalso facilitates biofunctionalization of the surface and the possibility to attach targeting moieties (e.g., antibodiesand peptides), thus enabling effective targeting of the payload. In this review, we briefly address the production methodologiesof PSi, and we will mainly present and discuss several examples about the biocompatibility of PSi, the most recentin vitro and in vivo applications of PSi as a carrier in drug/protein/peptide delivery and tissue engineering, as well as PSias a platform for drug targeting and imaging.

Silica Materials in Drug Delivery Applications by Spomenka Simovic, Nasrin Ghouchi-Eskandar, Aw Moom Sinn, Dusan Losic, Clive A. Prestidge (250-268).
In this review article we collect and analyse preparation, chemistry and properties of silica materials relevantfor drug delivery applications. We review some of the most relevant milestones in the research of silica materials for implantable,oral, intravenous and dermal drug delivery systems. Preparation, chemistry and drug delivery characteristics offumed silica nanoparticles (oral and dermal delivery route), silica xerogels (implant delivery), mesoporous silica materials(implant and oral delivery) and mesoporous silica spheres (intravenous delivery) with particular emphasis on their role inanticancer therapy and the design of stimuli responsive drug delivery systems are analysed. Recent progress in the researchof silica materials for controlled drug delivery, namely, biocompatibility aspects, research on hybrid materials,anticancer and stimuli-responsive mesoporous silica materials are particularly emphasized.

Inorganic Nanoparticles for Enhanced Photodynamic Cancer Therapy by Shih-Hsun Cheng, Leu-Wei Lo (269-276).
Photodynamic therapy (PDT) in cancer treatment uses photosensitizers to generate singlet oxygen followed byphotoirradiation. The efficacy of PDT is greatly determined by the dosimetry of activation light and the photosensitizer(PS), modulating the photodynamic reaction at depth in diseased tissue. Development of nano-formulated photosensitizerhas emerged as a promising field because of the biocompatibility and the accessibility for multi-functionalization ofnanoparticles. In this review, we summarize the contemporary progress in use of inorganic nanoparticles for improvementof PDT in cancer therapeutics.

An In Situ Gelling Buccal Spray Containing Platelet Lysate for the Treatment of Oral Mucositis by Giuseppina Sandri, Maria Cristina Bonferoni, Franca Ferrari, Silvia Rossi, Claudia Del Fante, Cesare Perotti, Angelo Gallanti, Carla Caramella (277-285).
Oral mucositis is an inflammatory disease of the mucosa lining oral cavity which leads to atrophy of the epitheliumand to its ulceration to form chronic lesions. Many studies, both in vitro and in vivo, have disclosed the effectivenessof growth factors derived from platelets to enhance cell proliferation, differentiation, chemotaxis, angiogenesis and extracellularmatrix synthesis involved in the healing of tissues. Despite potential usefulness of growth factors, animalderivedor genetically engineered ones are currently scarcely available for regenerative therapies.The aim of the present work was to study an in situ gelling formulation to be delivered by a spraying device to the oralcavity affected by mucositis. A vehicle based on Poloxamer 407 (F127) and sodium alginate (LVG) was developed. Anextemporaneous loading of the vehicle with PL was achieved.The formulation was able to quickly thermogelify at 34-35°C with a viscosity at 8°C suitable for spraying; moreover itwas characterized by good mucoadhesive properties.ELISA assay evidenced that at time zero the growth factor PDGF AB was compatible with the vehicle. The in vitrowound healing test showed that the formulation enhanced cell growth as PL alone even after 72 h of contact without cellapoptosis.The overall results indicate that PL loaded in the in situ gelling F127 and LVG vehicle can be profitably employed to treatbuccal mucositis.