Chitosan surface modification modulates the mucoadhesive, permeation and anti-angiogenic properties of gellan gum/bevacizumab nanoparticles.

Bevacizumab (BVZ) was the first monoclonal antibody approved by the FDA and has shown an essential advance in the antitumor therapy of colorectal cancer (CRC), however, the systemic action of BVZ administered intravenously can trigger several adverse effects. The working hypothesis of the study was to promote the modulation of the mucoadhesion properties and permeability of the BVZ through the formation of nanoparticles (NPs) with gellan gum (GG) with subsequent surface modification with chitosan (CS). NPs comprising BVZ and GG were synthesized through polyelectrolyte complexation, yielding spherical nanosized particles with an average diameter of 264.0 ± 2.75 nm and 314.0 ± 0.01 nm, polydispersity index of 0.182 ± 0.01 e 0.288 ± 0.01, and encapsulation efficiency of 29.36 ± 0.67 e 60.35 ± 0.27 mV, for NPs without (NP_BVZ) and with surface modification (NP_BVZ + CS). The results showed a good ability of nanoparticles with surface modification to modulate the NPs biological properties.

Multifunctional systems based on nano-in-microparticles as strategies for drug delivery: advances, challenges, and future perspectives.

INTRODUCTION: Innovative delivery systems are a promising and attractive approach for drug targeting in pharmaceutical technology. Among the various drug delivery systems studied, the association of strategies based on nanoparticles and microparticles, called nano-in-microparticles, has been gaining prominence as it allows targeting in a specific and personalized way, considering the physiological barriers faced in each disease. AREAS COVERED: This review proposes to discuss nano-in-micro systems, updated progress on the main biomaterials used in the preparation of these systems, preparation techniques, physiological considerations, applications and challenges, and possible strategies for drug administration. Finally, we bring future perspectives for advances in clinical and field translation of multifunctional systems based on nano-in-microparticles. EXPERT OPINION: This article brings a new approach to exploring the use of multifunctional systems based on nano-in-microparticles for different applications, in addition, it also emphasizes the use of biomaterials in these systems and their limitations. There is currently no study in the literature that explores this approach, making a review article necessary to address this association of strategies for application in pharmaceutical technology.

The role of hyaluronic acid in the design and functionalization of nanoparticles for the treatment of colorectal cancer.

Despite advances in new approaches for colorectal cancer (CRC) therapy, intravenous chemotherapy remains one of the main treatment options; however, it has limitations associated with off-target toxicity, tumor cell resistance due to molecular complexity and CRC heterogeneity, which lead to tumor recurrence and metastasis. In oncology, nanoparticle-based strategies have been designed to avoid systemic toxicity and increase drug accumulation at tumor sites. Hyaluronic acid (HA) has obtained significant attention thanks to its ability to target nanoparticles (NPs) to CRC cells through binding to cluster-determinant-44 (CD44) and hyaluronan-mediated motility (RHAMM) receptors, along with its efficient biological properties of mucoadhesion. This review proposes to discuss the state of the art in HA-based nanoparticulate systems intended for localized treatment of CRC, highlighting the importance of the mucoadhesion and active targeting provided by this polymer. In addition, an overview of CRC will be provided, emphasizing the importance of CD44 and RHAMM receptors in this type of cancer and the current challenges related to this disease, and important concepts about the physicochemical and biological properties of HA will also be addressed. Finally, this review aims to contribute to the advancement of accuracy treatment of CRC by the design of new platforms based on by HA.

Evaluation of photodynamic therapy on nanoparticles and films loaded-nanoparticles based on chitosan/alginate for curcumin delivery in oral biofilms.

Nanoparticles and nanoparticle-loaded films based on chitosan/sodium alginate with curcumin (CUR) are promising strategies to improve the efficacy of antimicrobial photodynamic therapy (aPDT) for the treatment of oral biofilms. This work aimed to develop and evaluate the nanoparticles based on chitosan and sodium alginate encapsulated with CUR dispersed in polymeric films associated with aPDT in oral biofilms. The NPs were obtained by polyelectrolytic complexation, and the films were prepared by solvent evaporation. The photodynamic effect was evaluated by counting Colony Forming Units (CFU/mL). Both systems showed adequate characterization parameters for CUR release. Nanoparticles controlled the release of CUR for a longer period than the nanoparticle-loaded films in simulated saliva media. Control and CUR-loaded nanoparticles showed a significant reduction of 3 log10 CFU/mL against S. mutans biofilms, compared to treatment without light. However, biofilms of S. mutans showed no photoinactivation effect using films loaded with nanoparticles even in the presence of light. These results demonstrate the potential of chitosan/sodium alginate nanoparticles associated with aPDT as carriers for the oral delivery of CUR, offering new possibilities to improve the treatment of dental caries and infections. This work will contribute to advances in the search for innovative delivery systems in dentistry.

Lyotropic liquid crystal mesophases as transdermal delivery systems for lipophilic drugs: A comparative study.

The present work aimed to evaluate different Liquid Crystal Mesophases (LCM) as transdermal drug delivery systems (TDDS) for nifedipine (NFD), a lipophilic drug model. The formulations composed of water, Citrus sinensis essential oil (CSEO), PPG-5-CETETH-20, and Olive oil ester PEG-7 were obtained and characterized by polarized light microscopy (PLM), rheology, small-angle x-ray scattering (SAXS), Fourier transform infrared coupled with an attenuated total reflection accessory (FTIR-ATR) and in vitro assays: bioadhesion, drug release, skin permeation, and retention tests. As a result, changes in component proportions led to several transparent viscous systems with an anisotropic profile. PLM and SAXS proved the presence of lamellar (S1), hexagonal (S3), and lamellar + hexagonal (S2) LCM, and rheology showed a high viscoelasticity profile. LCMs were able to adhere to the skin, and S2 achieved higher adhesion strength. NFD (5 mg/mL) has not modified the organization of LCMs. Results also showed that S3 promoted higher permeation and retention and higher disorganization of stratum corneum lipids, which is the main permeation-enhancing mechanism. Thus, the formulations obtained can carry and improve drug delivery through the skin and are promising TDDS for lipophilic drug administration, such as NFD.

An Updated Review on Properties, Nanodelivery Systems, and Analytical Methods for the Determination of 5-Fluorouracil in Pharmaceutical and Biological Samples.

5-Fluorouracil (5-FU) is an antimetabolite drug used for over 70 years as first-line chemotherapy to treat various types of cancer, such as head, neck, breast, and colorectal cancer. 5-FU acts mainly by inhibiting thymidylate synthase, thereby interfering with deoxyribonucleic acid (DNA) replication or by 5-FU incorporating into DNA, causing damage to the sequence of nucleotides. Being analogous to uracil, 5-FU enters cells using the same transport mechanism, where a is converted into active metabolites such as fluorouridine triphosphate (FUTP), fluorodeoxyuridine monophosphate (FdUMP), and fluorodeoxyuridine triphosphate (FdUTP). Currently, there are several nano delivery systems being developed and evaluated at the preclinical level to overcome existing limitations to 5-FU chemotherapy, including liposomes, polymeric nanoparticles, polymeric micelles, nanoemulsions, mesoporous silica nanoparticles, and solid lipid nanoparticles. Therefore, it is essential to choose and develop suitable analytical methods for the quantification of 5-FU and its metabolites (5- fluorouridine and 5-fluoro-2-deoxyuridine) in pharmaceutical and biological samples. Among the analytical techniques, chromatographic methods are commonly the most used for the quantification of 5-FU from different matrices. However, other analytical methods have also been developed for the determination of 5-FU, such as electrochemical methods, a sensitive, selective, and precise technique, in addition to having a reduced cost. Here, we first review the physicochemical properties, mechanism of action, and advances in 5-FU nanodelivery systems. Next, we summarize the current progress of other chromatographic methods described to determine 5- FU. Lastly, we discuss the advantages of electrochemical methods for the identification and quantification of 5- FU and its metabolites in pharmaceutical and biological samples.

New insights into physicochemical aspects involved in the formation of polyelectrolyte complexes based on chitosan and dextran sulfate.

Polyelectrolyte complexation is a technique based on interactions between polyelectrolytes of opposite charges driven by supramolecular interactions. Although many studies address the formation of polyelectrolyte complexes (PECs), few explore strategies and tools to select the best working conditions and are often based on empirical choices. This study evaluates the influence of pH, molecular weight, and polymeric proportion on the formation of PECs based on chitosan:dextran sulfate. In addition, it assesses the approaches that study the influence of pH on the zeta potential of polymeric dispersions as a tool in the design of PECs. Results showed that nanoparticles with an excess of polycation formed aggregates, while an excess of dextran sulfate reduced the size of the particles. The graph of zeta potential as a function of pH proved to be a promising tool in the choice of polymers and a better pH condition in the development of PECs.

Oral delivery of micro/nanoparticulate systems based on natural polysaccharides for intestinal diseases therapy: Challenges, advances and future perspectives.

Colon-targeted oral delivery of drugs remains as an appealing and promising approach for the treatment of prevalent intestinal diseases (ID), such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). Notwithstanding, there are numerous challenges to effective drug delivery to the colon, which requires the design of advanced strategies. Micro- and nanoparticles have received great attention as colon-targeted delivery platforms due to their reduced size and structural composition that favors the accumulation and/or residence time of drugs at the site of action and/or absorption, contributing to localized therapy. The choice by natural polysaccharides imparts key properties and advantages to the nano-in-microparticulate systems to effective colon-specific oral delivery. This review proposes to discuss the physiological barriers imposed by the gastrointestinal tract (GIT) against oral administration of drugs, as well as pathological factors and challenges of the ID for oral delivery of colon-targeted systems. We then provide an updated progress about polysaccharides-based colon-targeted drug delivery systems, including microparticulate, nanoparticulate and nano-in-microparticulate systems, highlighting their key properties, advantages and limitations to achieving targeted delivery and efficacious therapy within the colon. Lastly, we provide future perspectives, towards advances in the field and clinical translation of colon-targeted oral delivery systems for ID therapy.

Understanding the role of colon-specific microparticles based on retrograded starch/pectin in the delivery of chitosan nanoparticles along the gastrointestinal tract.

The encapsulation of nanoparticles within microparticles designed for specific delivery to the colon is a relevant strategy to avoid premature degradation or release of nanoparticles during their passage through the stomach and upper gastrointestinal tract (GIT), allowing the targeted delivery of chemotherapeutics to the colon after oral administration. Here, we designed an oral multiparticulate system to achieve targeted release in the colon. In this sense, chitosan nanoparticles (CS NPs) encapsulated with 5-fluorouracil (5-FU) and incorporated into retrograded starch and pectin (RS/P) microparticles were developed and their in vivo distribution along the mouse GIT after oral administration was monitored using multispectral optical imaging. In vitro release studies revealed that the encapsulation of CS NPs into RS/P microparticles promoted greater control of 5-FU release rates, with a significant reduction (53%) in acid media that might replicate that found in the stomach following oral administration. The evaluation of the in vivo biodistribution of the CS NPs in mice showed a faster clearance in the distribution pattern along the mouse GIT, i.e., a shorter transit time of CS NPs compared to CS NPs-loaded RS/P microparticles. Additionally, CS NPs alone showed non-specific absorption into the blood-stream with associated kidney accumulation, while for the CS NPs-loaded RS/P microparticles no significant accumulation was observed in blood or major clearance organs. This suggests the specific degradability of RS/P by the colon microbiota appears to have been decisive in the higher protection of the CS NPs along the GIT until release in the colon, preventing unwanted absorption into the bloodstream and major organs following oral administration. Our findings represent a proof of concept for the use of RS/P microparticles as potential carriers for delivering drug-loaded nanoparticles to the colon and this work will contribute to the development of oral-systems for colorectal cancer therapy.

Recent advances in hydrogels as strategy for drug delivery intended to vaginal infections.

Vaginal infections represent a clear women health problem due to the several issues as high recurrence rate, drug resistence and emergence of persistent strains. However, achieving improvements in therapeutic efficacy by using conventional formulations intended to vaginal drug delivery remains as a challenge due to anatomy and physiology of the vagina, since the secretion and renewal of vaginal fluids contribute to the removal of the dosage form. Hydrogels have been widely exploited aiming to achieve drug delivery directly into vaginal mucosa for local therapy due to their attractive features as increased residence time of the drug at the action site and control of drug release rates. Some polymers can aggregate specific properties to hydrogels as mucoadhesive, stimuli-responsive and antimicrobial, improving their interaction with the biological interface and therapeutic response. In this review, we highlight the advances, advantages and challenges of the hydrogels as drug and/or nanocarrier vehicles intended to the treatment of vaginal infections, emphasizing also the polymers and their properties more explored on the design these systems to improve the therapeutic effect on the vaginal tissue. In addition, this review can contribute for better exploitation these systems in search of new local treatments for bacterial vaginosis, candidiasis and trichomoniasis.

Advances and challenges in nanocarriers and nanomedicines for veterinary application.

To ensure success in the development and manufacturing of nanomedicines requires forces of an interdisciplinary team that combines medicine, engineering, chemistry, biology, material and pharmaceutical areas. Numerous researches in nanotechnology applied to human health are available in the literature. Althought, the lack of nanotechnology-based pharmaceuticals products for use exclusively in veterinary pharmacotherapy creates a potential area for the development of innovative products, as these animal health studies are still scarce when compared to studies in human pharmacotherapy. Nano-dosage forms can ensure safer and more effective pharmacotherapy for animals and can more be safer for the consumers of livestock products, once they can offer higher selectivity and smaller toxicity associated with lower doses of the drugs. In addition, the development and production of nanomedicines may consolidate the presence of pharmaceutical laboratories in the global market and can generate greater profit in a competitive business environment. To contribute to this scenario, this article provides a review of the main nanocarriers used in nanomedicines for veterinary use, with emphasis on liposomes, nanoemulsions, micelles, lipid nanoparticles, polymeric nanoparticles, mesoporous silica nanoparticles, metallic nanoparticles and dendrimers, and the state of the art of application of these nanocarriers in drug delivery systems to animal use. Finnaly, the major challenges involved in research, scale-up studies, large-scale manufacture, analytical methods for quality assessment, and regulatory aspects of nanomedicines were discussed.

Effect of in situ modification of bacterial cellulose with carboxymethylcellulose on its nano/microstructure and methotrexate release properties.

Bacterial cellulose/carboxymethylcelullose (BC/CMC) biocomposites with different DS-CMC (DS from 0.7 to 1.2) were developed in order to evaluate their impact as a drug delivery system. Biocomposites were loaded with methotrexate (MTX) as an alternative for the topical treatment of psoriasis. Scanning electron microscopy and atomic force microscopy showed that the CMC coated the cellulose nanofibers, leading to the decrease of the elastic modulus as the DS of CMC increased. BC/CMC0.9 exhibited the lower liquid uptake (up to 11 times lower), suggesting that the more linear structure of the intermediate substitute CMC grade (0.9) was able to interact more strongly with BC, resulting in a denser structure. All samples showed a typical burst release effect in the first 15min of test, however the BC/CMC0.9 biocomposite promoted a slight lowering of MTX release rates, suggesting that the DS of CMC can be considered the key factor to modulate the BC properties.

Trans-resveratrol-loaded nonionic lamellar liquid-crystalline systems: structural, rheological, mechanical, textural, and bioadhesive characterization and evaluation of in vivo anti-inflammatory activity.

Resveratrol (Res) is a common phytoalexin present in a few edible materials, such as grape skin, peanuts, and red wine. Evidence has shown the beneficial effects of Res on human health, which may be attributed to its anti-inflammatory activity. However, the poor aqueous solubility of Res limits its therapeutic effectiveness. Therefore, the use of nanostructured delivery systems for Res, such as liquid-crystalline systems, could be beneficial. In this study, we aimed to develop, characterize, and determine the in vivo effectiveness of Res-loaded liquid-crystalline systems. Systems containing copaiba balsam oil, polyethylene glycol-40 hydrogenated castor oil, and water were designed. Results of polarized light microscopy, small-angle X-ray scattering, texture-profile analysis, and flow-rheology analysis showed that the Res-loaded liquid-crystalline system had a lamellar structure, textural and mechanical (hardness, compressibility, and adhesiveness) properties, and behaved as a non-Newtonian fluid, showing pseudoplastic behavior upon skin application. Furthermore, all liquid-crystalline systems presented bioadhesive properties that may have assisted in maintaining the anti-inflammatory activity of Res, since the topical application of the Res-loaded lamellar mesophase liquid crystals resulted in edema inhibition in a carrageenan-induced paw-inflammation mouse model. Therefore, Res-loaded lamellar mesophases represent a promising new therapeutic approach for inhibition of skin inflammation.

Computational and experimental approaches for development of methotrexate nanosuspensions by bottom-up nanoprecipitation.

Development of nanosuspensions offers a promising tool for formulations involving poorly water-soluble drugs. In this study, methotrexate (MTX) nanosuspensions were prepared using a bottom-up process based on acid-base neutralization reactions. Computational studies were performed to determine structural and electronic properties for isolated molecules and molecular clusters in order to evaluate the mechanism of MTX nanoparticle formation. Computational results indicated that the clusters in zwitterionic and cationic states presented larger dimensions and higher energies of interaction between MTX molecules, which favored aggregation. In contrast, the clusters in the anionic state exhibited lower energies of interaction, indicating aggregation was less likely to occur. Experimental results indicated that the higher the HCl proportion during drug precipitation, the greater the particle size, resulting in micrometric particles (2874-7308nm) (cationic and zwitterionic forms). However, MTX nanoparticles ranging in size from 132 to 186nm were formed using the lowest HCl proportion during drug precipitation (anionic form). In vitro release profiles indicated that the drug release rate from nanosuspension was increased (approximately 2.6 times) over that of the raw material. Overall, computational modeling and experimental analysis were complementary and assisted in the rational design of the nanosuspension based on acid-base reactions.

Design, characterization, and biological evaluation of curcumin-loaded surfactant-based systems for topical drug delivery.

From previous studies, it has been found that curcumin exhibits an anti-inflammatory activity and is being used for the treatment of skin disorders; however, it is hydrophobic and has weak penetrating ability, resulting in poor drug transport through the stratum corneum. The aim of this study was to develop liquid crystalline systems for topical administration of curcumin for the treatment of inflammation. These liquid crystalline systems were developed from oleic acid, polyoxypropylene (5) polyoxyethylene (20) cetyl alcohol, and water as the surfactant, oil phase, and aqueous phase, respectively. These systems were characterized, and polarized light microscopy showed anisotropy with lamellar mesophases (Formulation 1) and hexagonal mesophases (Formulations 2 and 3), which were confirmed by the peak ratio measured using small-angle X-ray scattering. In addition, rheological tests revealed that the formulations exhibited gel-like behavior (G'>G″), as evidenced by the increased G' values that indicate structured systems. Texture profile analysis showed that hexagonal mesophases have high values of hardness, adhesiveness, and compressibility, which indicate structured systems. In vitro studies on bioadhesion revealed that the hexagonal mesophases increased the bioadhesiveness of the systems to the skin of the pig ear. An in vivo inflammation experiment showed that the curcumin-loaded hexagonal mesophase exhibited an anti-inflammatory activity as compared to the positive control (dexamethasone). The results suggest that this system has a potential to be used as a bioadhesive vehicle for the topical administration of curcumin. Therefore, it is possible to conclude that these systems can be used for the optimization of drug delivery systems to the skin.