Understanding mucus modulation behavior of chitosan oligomers and dextran sulfate combining light scattering and calorimetric observations.

This study reports the fundamental understanding of mucus-modulatory strategies combining charged biopolymers with distinct molecular weights and surface charges. Here, key biophysical evidence supports that low-molecular-weight (Mw) polycation chitosan oligosaccharides (COSs) and high-Mw polyanion dextran sulfate (DS) exhibit distinct thermodynamic signatures upon interaction with mucin (MUC), the main protein of mucus. While the COS â†’ MUC microcalorimetric titrations released ~14 kcal/mol and ~60 kcal/mol, the DS â†’ MUC titrations released ~1200 and ~1450 kcal/mol at pH of 4.5 and 6.8, respectively. The MPT-2 titrations of COS â†’ MUC and DS â†’ MUC indicated a greater zeta potential variation at pH = 4.5 (relative variation = 815 % and 351 %, respectively) than at pH = 6.8 (relative variation = 282 % and 136 %, respectively). Further, the resultant binary (COS-MUC) and ternary (COS-DS-MUC) complexes showed opposite behavior (aggregation and charge inversion events) according to the pH environment. Most importantly, the results indicate that electrostatics could not be the driving force that governs COS-MUC interactions. To account for this finding, we proposed a two-level abstraction model. Macro features emerge collectively from individual interactions occurring at the molecular level. Therefore, to understand the outcomes of mucus modulatory strategy based on charged biopolymers it is necessary to integrate both visions into the same picture.

Immunomodulatory properties of nanostructured systems for cancer therapy.

Based on statistical data reported in 2020, cancer was responsible for approximately 10 million deaths. Furthermore, 17 million new cases were diagnosed worldwide. Nanomedicine and immunotherapy have shown satisfactory clinical results among all scientific and technological alternatives for the treatment of cancer patients. Immunotherapy-based treatments comprise the consideration of new alternatives to hinder neoplastic proliferation and to reduce adverse events in the body, thereby promoting immune destruction of diseased cells. Additionally, nanostructured systems have been proven to elicit specific immune responses that may enhance anti-tumor activity. A new generation of nanomedicines, based on biomimetic and bioinspired systems, has been proposed to target tumors by providing immunomodulatory features and by enabling recovery of human immune destruction capacity against cancer cells. This review provides an overview of the aspects and the mechanisms by which nanomedicines can be used to enhance clinical procedures using the immune modulatory responses of nanoparticles (NPs) in the host defense system. We initially outline the cancer statistics for conventional and new treatment approaches providing a brief description of the human host defense system and basic principles of NP interactions with monocytes, leukocytes, and dendritic cells for the modulation of antitumor immune responses. A report on different biomimetic and bioinspired systems is also presented here and their particularities in cancer treatments are addressed, highlighting their immunomodulatory properties. Finally, we propose future perspectives regarding this new therapeutic strategy, highlighting the main challenges for future use in clinical practice.

Nose-to-brain co-delivery of drugs for glioblastoma treatment using nanostructured system.

Mutations on the epidermal growth factor receptor (EGFR), induction of angiogenesis, and reprogramming cellular energetics are all biological features acquired by tumor cells during tumor development, and also known as the hallmarks of cancer. Targeted therapies that combine drugs that are capable of acting against such concepts are of great interest, since they can potentially improve the therapeutic efficacy of treatments of complex pathologies, such as glioblastoma (GBM). However, the anatomical location and biological behavior of this neoplasm imposes great challenges for targeted therapies. A novel strategy that combines alpha-cyano-4-hydroxycinnamic acid (CHC) with the monoclonal antibody cetuximab (CTX), both carried onto a nanotechnology-based delivery system, is herein proposed for GBM treatment via nose-to-brain delivery. The biological performance of Poly (D,L-lactic-co-glycolic acid)/chitosan nanoparticles (NP), loaded with CHC, and conjugated with CTX by covalent bonds (conjugated NP) were extensively investigated. The NP platforms were able to control CHC release, indicating that drug release was driven by the Weibull model. An ex vivo study with nasal porcine mucosa demonstrated the capability of these systems to promote CHC and CTX permeation. Blot analysis confirmed that CTX, covalently associated to NP, impairs EGRF activation. The chicken chorioallantoic membrane assay demonstrated a trend of tumor reduction when conjugated NP were employed. Finally, images acquired by fluorescence tomography evidenced that the developed nanoplatform was effective in enabling nose-to-brain transport upon nasal administration. In conclusion, the developed delivery system exhibited suitability as an effective novel co-delivery approaches for GBM treatment upon intranasal administration.

Design of chitosan-based particle systems: A review of the physicochemical foundations for tailored properties.

Chitosan-based particles are widely proposed as biocompatible drug delivery systems with mucoadhesive and permeation enhancing properties. However, strategies on how to modulate the intended biological responses are still scarce. Considering that particle properties affect the biological outcome, the rational design of the synthesis variables should be proposed to engineer drug delivery systems with improved biological performance. The purpose of this review is to establish a deeper understanding of possible correlations between these variables and the particle properties from theoretical and experimental perspectives. The fundamental physicochemical knowledge of chitosan-based polyelectrolyte complexation and surface modification is discussed focusing on chitosan-TPP, polyelectrolyte complexes, and chitosan-surface modified PLGA or lipid particles. A set of design considerations is proposed to enable future investigation in the development of chitosan particles with modulated properties. The approach presented here contributes to the rational design of chitosan-based particles that meet different requirements for biological activities.

Modulating chitosan-PLGA nanoparticle properties to design a co-delivery platform for glioblastoma therapy intended for nose-to-brain route.

Nose-to-brain delivery is a promising approach to target drugs into the brain, avoiding the blood-brain barrier and other drawbacks related to systemic absorption, and enabling an effective and safer treatment of diseases such as glioblastoma (GBM). Innovative materials and technologies that improve residence time in the nasal cavity and modulate biological interactions represent a great advance in this field. Mucoadhesive nanoparticles (NPs) based on poly(lactic-co-glycolic acid) (PLGA) and oligomeric chitosan (OCS) were designed as a rational strategy and potential platform to co-deliver alpha-cyano-4-hydroxycinnamic acid (CHC) and the monoclonal antibody cetuximab (CTX) into the brain, by nasal administration. The influence of formulation and process variables (O/Aq volume ratio, Pluronic concentration, PLGA concentration, and sonication time) on the properties of CHC-loaded NPs (size, zeta potential, PDI and entrapment efficiency) was investigated by a two-level full factorial design (24). Round, stable nano-sized particles (213-875 nm) with high positive surface charge (+ 33.2 to + 58.9 mV) and entrapment efficiency (75.69 to 93.23%) were produced by the emulsification/evaporation technique. Optimal process conditions were rationally selected based on a set of critical NP attributes (258 nm, + 37 mV, and 88% EE) for further conjugation with CTX. The high cytotoxicity of CHC-loaded NPs and conjugated NPs was evidenced for different glioma cell lines (U251 and SW1088). A chicken chorioallantoic membrane assay highlighted the expressive antiangiogenic activity of CHC-loaded NPs, which was enhanced for conjugated NPs. The findings of this work demonstrated the potential of this nanostructured polymeric platform to become a novel therapeutic alternative for GBM treatment. Graphical abstract.

A novel strategy for glioblastoma treatment combining alpha-cyano-4-hydroxycinnamic acid with cetuximab using nanotechnology-based delivery systems.

Combination therapy that uses multiple drugs against different molecular targets should be considered as interesting alternatives for treating complex diseases such as glioblastoma (GBM). Drugs like alpha-cyano-4-hydroxycinnamic acid (CHC) and the monoclonal antibody cetuximab (CTX) are already explored for their capacity to act against different hallmarks of cancer. Previous reports suggest that the simultaneous use of these drugs, as a novel combining approach, might result in additive or synergistic effects. Therefore, advances in nanotechnology-based delivery systems will inevitably bring nano-mediated therapeutic gains to the proposed combination since they enable the association of different drugs into a single carrier. The current study provides indications that the new dual therapeutic strategy proposed, in association with nanotechnology, provides significative improvements when compared to the use of isolated drugs. Nanotechnological tools were employed by developing polymeric nanoparticles based on poly(lactic-co-glycolic acid) and chitosan for CHC encapsulation. Furthermore, these structures were conjugated with CTX by supramolecular forces. In summary, the encapsulation of the CHC drug into the nanoparticles increased its individual therapeutic capacity. In addition, conjugation with CTX seemed to enhance therapeutic efficacy, especially for U251 GBM cells. In conclusion, developed nanostructured delivery systems exhibited a set of favorable attributes and potential to be applied as a promising new alternative for GBM treatment. Graphical abstract .

Structural and Thermal Behavior of Meglumine-Based Supra-Amphiphiles in Bulk and Assembled in Water.

Supra-amphiphiles are a new class of building blocks that are fabricated by means of noncovalent forces. In this work, we studied the formation of supra-amphiphiles by combining hydrophilic meglumine (MEG) with hydrophobic maleated castor oils (MACO). Spectroscopic analysis demonstrated that ionic interactions are the main driving force in the fabrication of these materials. Subsequently, supra-amphiphile/water systems were examined for their structure and water behavior by polarized optical microscopy (POM), small-angle X-ray scattering (SAXS), and differential scanning calorimetry (DSC). Micellar and lamellar liquid crystalline phases were observed. Finally, we observed that the supra-amphiphiles produced using an excess of MEG retain a large amount of water. As bound water plays an important role in biointerfacial interactions, we anticipate that these materials will display a pronounced potential for biomedical applications.

Kinetic parameters for thermal decomposition of supramolecular polymers derived from diclofenac-meglumine supramolecular adducts.

Meglumine is an aminocarbohydrate able to form supramolecular adducts with organic acids. The recognition is based on hydrogen bonds and the structures resulting from the complexation have high solubility in water. This property has been exploited by the pharmaceutical industry in the improvement of existing drugs, and the successful example of this approach involves the poorly soluble non-steroidal anti-inflammatory drugs (NSAIDs). Investigation of the thermal behavior of adduct obtained from meglumine and the NSAID diclofenac revealed that a polymer-like material is formed from the self-assembly of diclofenac-meglumine adducts in the melt. This polymer showed a high molecular weight around 2.0×10(5)kDa. The kinetic parameters for the thermal decomposition step of the polymer were determined by the Capela-Ribeiro non-linear isoconversional method. From data for the TG curves in nitrogen atmosphere and heating rates of 5, 10, 15 and 20°Cmin(-1), the E(α) and B(α) terms could be determined, and consequently the pre-exponential factor, A(α), as well as the kinetic model, g(α).

A discriminating dissolution method for glimepiride polymorphs.

Glimepiride, an oral antidiabetic drug, is practically insoluble in water and exists in two polymorphic forms, I and II, of which form II has higher solubility in water. Because the dissolution rate of drugs can depend on the crystal form, there is a need to develop discriminating dissolution methods that are sensitive to changes in polymorphic forms. In this work, a dissolution method for the assessment of 4 mg glimepiride tablets was developed and validated. The optimal dissolution conditions were 1000 mL of phosphate buffer (pH 6.8) containing 0.1% (w/v) of sodium dodecyl sulfate as the dissolution medium and a stirring speed of 50 rpm using a paddle apparatus. The results demonstrated that all the data meet the validation acceptance criteria. Subsequently, tablets containing forms I and II of glimepiride were prepared and subjected to dissolution testing. A significant influence of polymorphism on the dissolution properties of glimepiride tablets was observed. These results suggested that the raw material used to produce glimepiride tablets must be strictly controlled because they may produce undesirable and unpredictable effects.