Fernanda S. Poletto

An algorithm to determine the mechanism of drug distribution in lipid-core nanocapsule formulations

Aqueous solutions of lipid-core nanocapsules are interesting drug delivery systems for passive drug targeting. In this study, we hypothesized that the drug distribution mechanisms in lipid-core nanocapsule formulations could be categorized into six different types. To experimentally determine the type of drug distribution in these formulations, we proposed the use of an algorithm as an innovative strategy. The approach is shown to be a valuable tool to optimize and select formulations intended for drug delivery. The best physico-chemical parameter in terms of predicting the type of distribution was the log D value. In conclusion, the use of the algorithm developed in this study represents a simple and rapid approach through which it was possible to experimentally determine the drug distribution in colloidal formulations for eight drug models.

Polymeric Nanocapsules: Concepts and Applications

This chapter presents an overview of polymeric nanocapsules for dermatological and cosmetic applications, including their preparation methods, physicochemical characterization and models of supramolecular structures. Polymeric nanocapsules are advantageous because of their ability to control the release rate and the penetration/permeation of drugs and active ingredients in the skin. These properties can be modulated through manipulating the qualitative and quantitative compositions of formulations. The chemical nature of raw materials can define the supramolecular structures of the nanocapsule core and surface. In addition, polymeric nanocapsules protect the encapsulated drug or active ingredient from degradation by acting as reservoirs. Aqueous suspensions of polymeric nanocapsules are directly applied on the skin or used as intermediate products for semisolid formulations, such as hydrogels and emulgels. The rheological characteristics of semisolid formulations can be modified by the presence of nanocapsules. Polymeric nanocapsules are valuable devices for skin applications and represent a promising research field in terms of providing products to be explored by industry.

Lipid-core nanocapsules increase the oral efficacy of quercetin in cutaneous leishmaniasis

New oral treatments are needed for all forms of leishmaniasis. Here, the improved oral efficacy of quercetin (Qc) and its penta-acetylated derivative (PQc) was evaluated in cutaneous leishmaniasis after encapsulation in lipid-core nanocapsules (LNCs) of poly(ε-caprolactone). Leishmania amazonensis-infected BALB/c mice were given 51 daily oral doses of free drugs (16 mg kg-1) or LNC-loaded drugs (0·4 mg kg-1). While treatment with free Qc reduced the lesion sizes and parasite loads by 38 and 71%, respectively, LNC-Qc produced 64 and 91% reduction, respectively. The antileishmanial efficacy of PQc was similar but not as potently improved by encapsulation as Qc. None of the treatments increased aspartate aminotransferase, alanine aminotransferase or creatinine serum levels. These findings indicate that when encapsulated in LNC, Qc and, to a lesser extent, PQc can safely produce an enhanced antileishmanial effect even at a 40-fold lower dose, with implications for the development of a new oral drug for cutaneous leishmaniasis.

Smart Polymers: Synthetic Strategies, Supramolecular Morphologies, and Drug Loading

Smart polymers are a relatively new type of material that is attracting attention from considerable attention from polymer scientists due to their promising applications in several high-tech industry fields. The properties of the smart polymers can change in various ways due to the action of a number of triggers such as temperature, pH, enzymes, ionic strength, and light intensity. The design of the polymer architecture is a key factor to obtain structures with the desired properties. The advent of controlled radical polymerization techniques has led to the development of a variety of polymers with controlled characteristics. Functionalization of these polymers has been successfully used to synthesize numerous structures with desired architectures creating unprecedented opportunities for the design of advanced materials with stimuli-responsive properties. In this chapter, recent advances in this fascinating research field will be presented highlighting new controlled living polymerization methods. Some concepts will also be introduced regarding drug loading and types of morphologies of self-assembled supramolecular structures derived from smart polymers.

Stimuli-responsive polymeric hydrogels and nanogels for drug delivery applications

Abstract Polymeric hydrogels are three-dimensional networks formed by cross-linked polymer chains that are swollen by a large amount of water. The high affinity of the network to aqueous solutions, the biocompatibility of the polymers, and the possibility of functionalization of these systems open remarkable opportunities for biomedical applications. Nanoparticles with hydrogel-like structure, commonly named nanogels, show advantages similar to those from bulk hydrogels and, in addition, they can also be targeted to intended sites of action in the organism. The development of responsive hydrogels and nanogels is a new trend to reach exceptional control of the biological response. This is in tune with the idea of precision medicine at molecular and supramolecular levels aiming better therapeutic results. Smart hydrogels and nanogels should release drugs only in the presence of triggers reducing adverse effects. Different stimuli, such as pH, temperature, glucose concentration, and redox environment can be proposed as triggers. In this chapter, these concepts are explored, merging the chemical and the biochemical aspects of triggered responses of hydrogels and nanogels in the organism. The main concepts and current techniques used to characterize the systems are also mentioned.

Artificial cerium-based proenzymes confined in lyotropic liquid crystals: synthetic strategy and on-demand activation

Inorganic nanoparticles that mimic the activity of enzymes are promising systems for biomedical applications. However, they cannot distinguish between healthy and damaged tissues, which could cause undesired effects. Natural enzymes avoid this drawback via activation triggered by specific biochemical events in the body. Inspired by this strategy, we proposed an artificial cerium-based proenzyme system that could be activated to a superoxide dismutase-like form using H2O2 as the trigger. To achieve this goal, an innovative and easy strategy to synthesize Ce(OH)3 nanoparticles as artificial proenzymes was developed using a lyotropic liquid crystal composed of phytantriol, which was essential to maintain their stability at physiological pH. The transmission electron microscopy measurements showed that the Ce(OH)3 nanoparticles were as small as 2 nm. The nanoparticles were fitted into the tiny aqueous channels of the liquid crystal matrix, which presented a Pn3m space group. X-ray absorption near edge structure measurements were used to determine the Ce(iii) fraction of the proenzyme-like nanoparticles, which was around 85%. The Ce(iii) fraction dramatically dropped to around 5% after contact with H2O2 because of the conversion of Ce(OH)3 to CeO(2-x) nanoparticles. The CeO(2-x) nanoparticles showed superoxide dismutase-like activity in contrast to the inactive Ce(OH)3 form. The proof of concept presented in this work opens up new possibilities for using nanoparticles as artificial proenzymes that are activated by a biochemical trigger in vivo.

Monoolein-based nanoparticles for drug delivery to the central nervous system: A platform for lysosomal storage disorder treatment

&NA; Lysosomal Storage Disorders (LSDs) are characterized by an abnormal accumulation of substrates within the lysosome and comprise more than 50 genetic disorders with a frequency of 1:5000 live births. Nanotechnology may be a promising way to circumvent the drawbacks of the current therapies for lysosomal diseases. The blood circulation time and bioavailability of the enzymes or drugs could be improved by inserting them in nanocarriers, which could decrease and/or avoid the need of frequent intravenous infusions along with the minimization or elimination of associated immunogenic responses. Considering the exposed, we aimed to build monoolein‐based nanoparticles stabilized by polysorbate 80 as a smart platform able to reach the central nervous system (CNS) to deliver drugs or enzymes inside lysosomes. We developed and characterized the nanoparticles by dynamic light scattering (DLS), small‐angle X‐ray scattering (SAXS) and cryogenic transmission electron microscopy (Cryo‐TEM). The nanoparticles showed a diameter of 115 nm, which is compatible with in vivo application. The SAXS patterns of the formulations displayed a single broad correlation peak that was fitted to the Teubner‐Strey model confirming that disordered bicontinuous structures were obtained. Cryo‐TEM images corroborated this finding and showed nanoparticles with size values that are similar to those determined by DLS. Furthermore, the nanoparticles did not present cytotoxicity when they were incubated with human fibroblasts, and demonstrated hemolytic activity proportional to the negative control, proving to be safe for parenteral administration. Through the use of a fluorescent dye to track the nanoparticles inside the cell, we demonstrated that they reached lysosomes after 1 h of treatment. More interestingly, the fluorescent dye was detected in the CNS of mice just after 3 h of treatment. The nanoparticles show great potential to improve the treatment of LSDs with brain impairment, acting as a smart platform to targeted delivery of drugs or enzymes. Graphical abstract Figure. No caption available.

Oxidative Imbalance, Nitrative Stress, and Inflammation in C6 Glial Cells Exposed to Hexacosanoic Acid: Protective Effect of N-acetyl-l-cysteine, Trolox, and Rosuvastatin

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder caused by disfunction of the ABCD1 gene, which encodes a peroxisomal protein responsible for the transport of the very long-chain fatty acids from the cytosol into the peroxisome, to undergo β-oxidation. The mainly accumulated saturated fatty acids are hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in tissues and body fluids. This peroxisomal disorder occurs in at least 1 out of 20,000 births. Considering that pathophysiology of this disease is not well characterized yet, and glial cells are widely used in studies of protective mechanisms against neuronal oxidative stress, we investigated oxidative damages and inflammatory effects of vesicles containing lecithin and C26:0, as well as the protection conferred by N-acetyl-l-cysteine (NAC), trolox (TRO), and rosuvastatin (RSV) was assessed. It was verified that glial cells exposed to C26:0 presented oxidative DNA damage (measured by comet assay and endonuclease III repair enzyme), enzymatic oxidative imbalance (high catalase activity), nitrative stress [increased nitric oxide (NO) levels], inflammation [high Interleukin-1beta (IL-1β) levels], and induced lipid peroxidation (increased isoprostane levels) compared to native glial cells without C26:0 exposure. Furthermore, NAC, TRO, and RSV were capable to mitigate some damages caused by the C26:0 in glial cells. The present work yields experimental evidence that inflammation, oxidative, and nitrative stress may be induced by hexacosanoic acid, the main accumulated metabolite in X-ALD, and that antioxidants might be considered as an adjuvant therapy for this severe neurometabolic disease.

Liquid Crystalline Nanostructured Polymer Blends

Polymeric materials presenting liquid crystalline domains are attracting increasing attention from academia and industry due to their unique properties, particularly for optical applications and as components of high-strength fibers. Polymer liquid crystals (PLC) present remarkable characteristics because they feature properties of polymers with those of liquid crystals. The PCL materials usually contain relatively rigid and flexible sequences in the polymer chain. The rigid element in the chain is called mesogen, which is responsible for inducing self-assembly of the same mesophases found in low molecular mass liquid crystals under suitable temperature, pressure, and concentration conditions. The mesogen can be placed in the main chain, or in side chains, or in both. The position of the mesogen in the chain is strongly related to the resulting properties exhibited by the polymeric material. The ordered arrangement from the polymer network at the nanoscale size range can also be tailored by blending. Several polymer liquid crystals have been blended with many thermoplastics improving the characteristics of the material. In addition, some polymers containing mesogen sequences can act as compatibilizers for other polymers. Considering this, basic science aspects of polymer liquid crystals and their polymeric blends will be discussed with current examples of technological applications in different areas.