Repellent active ingredients encapsulated in polymeric nanoparticles: potential alternative formulations to control arboviruses.

Dengue, yellow fever, Chinkungunya, Zika virus, and West Nile fever have infected millions and killed a considerable number of humans since their emergence. These arboviruses are transmitted by mosquito bites and topical chemical repellents are the most commonly used method to protect against vector arthropod species. This study aimed to develop a new generation of repellent formulations to promote improved arboviruses transmission control. A repellent system based on polycaprolactone (PCL)-polymeric nanoparticles was developed for the dual encapsulation of IR3535 and geraniol and further incorporation into a thermosensitive hydrogel. The physicochemical and morphological parameters of the prepared formulations were evaluated by dynamic light scattering (DLS), nano tracking analysis (NTA), atomic force microscopy (AFM). In vitro release mechanisms and permeation performance were evaluated before and after nanoparticles incorporation into the hydrogels. FTIR analysis was performed to evaluate the effect of formulation epidermal contact. Potential cytotoxicity was evaluated using the MTT reduction test and disc diffusion methods. The nanoparticle formulations were stable over 120 days with encapsulation efficiency (EE) of 60% and 99% for IR3535 and geraniol, respectively. AFM analysis revealed a spherical nanoparticle morphology. After 24 h, 7 ± 0.1% and 83 ± 2% of the GRL and IR3535, respectively, were released while the same formulation incorporated in poloxamer 407 hydrogel released 11 ± 0.9% and 29 ± 3% of the loaded GRL and IR3535, respectively. GRL permeation from PCL nanoparticles and PCL nanoparticles in the hydrogel showed similar profiles, while IR3535 permeation was modulated by formulation compositions. Differences in IR3535 permeated amounts were higher for PCL nanoparticles in the hydrogels (36.9 ± 1.1 mg/cm2) compared to the IR3535-PCL nanoparticles (29.2 ± 1.5 mg/cm2). However, both active permeation concentrations were low at 24 h, indicating that the formulations (PCL nanoparticles and PCL in hydrogel) controlled the bioactive percutaneous absorption. Minor changes in the stratum corneum (SC) caused by interaction with the formulations may not represent a consumer safety risk. The cytotoxicity results presented herein indicate the carrier systems based on poly-epsilon caprolactone (PCL) exhibited a reduced toxic effect when compared to emulsions, opening perspectives for these systems to be used as a tool to prolong protection times with lower active repellent concentrations.

Sericin based nanoformulations: a comprehensive review on molecular mechanisms of interaction with organisms to biological applications.

BACKGROUND: The advances in products based on nanotechnology have directed extensive research on low-cost, biologically compatible, and easily degradable materials. MAIN BODY: Sericin (SER) is a protein mainly composed of glycine, serine, aspartic acid, and threonine amino acids removed from the silkworm cocoon (particularly Bombyx mori and other species). SER is a biocompatible material with economic viability, which can be easily functionalized due to its potential crosslink reactions. Also, SER has inherent biological properties, which makes possible its use as a component of pharmaceutical formulations with several biomedical applications, such as anti-tumor, antimicrobials, antioxidants and as scaffolds for tissue repair as well as participating in molecular mechanisms attributed to the regulation of transcription factors, reduction of inflammatory signaling molecules, stimulation of apoptosis, migration, and proliferation of mesenchymal cells. CONCLUSION: In this review, the recent innovations on SER-based nano-medicines (nanoparticles, micelles, films, hydrogels, and their hybrid systems) and their contributions for non-conventional therapies are discussed considering different molecular mechanisms for promoting their therapeutic applications.

Evaluation of Budesonide-Hydroxypropyl-ß-Cyclodextrin Inclusion Complex in Thermoreversible Gels for Ulcerative Colitis.

BACKGROUND: New formulations for topical treatment of ulcerative colitis with budesonide inclusion complex (BUDHP-ß-CD) and poloxamers (PL) were developed for future clinical use. AIMS: This study evaluated the efficacy of such novel formulations in a rat model of colitis. METHODS: The PL-BUDHP-ß-CD systems were prepared by direct dispersion of the complex (BUD concentration 0.5 mg mL-1) in solutions with PL407 or PL403. Male Wistar rats underwent TNBS-induced colitis and were treated for 5 days by a rectal route, as follows: BUD 1: BUDHP-ß-CD + PL407 (18%); BUD 2: BUDHP-ß-CD + PL407 (20%); BUD 3: BUDHP-ß-CD + PL407 (18%) + PL403 (2%); BUD 4: plain BUD; BUD 5: BUDHP-ß-CD; C1: HP-ß-CD + PL407 (18%); C2: HP-ß-CD + PL407 (20%); C3: HP-ß-CD + PL407 (18%) + PL403 (2%); C4: saline. A negative control group without colitis was also used. Colitis was assessed via myeloperoxidase (MPO) activity, and macroscopic and microscopic damage score in colon tissues. Protein levels of TNF-α, IL-1ß, IL-10 and endogenous glucocorticoids were obtained using ELISA. RESULTS: BUDHP-ß-CD poloxamer formulations had similar MPO activity when compared with the negative control group. All formulations presented lower MPO activity than BUDHP-ß-CD and plain BUD (p < 0.001). BUD 2 produced lower microscopic score values than plain BUD and BUDHP-ß-CD (p < 0.01). All formulations with BUDHP-ß-CD poloxamers reduced TNF-α levels (p < 0.05). CONCLUSION: Novel budesonide inclusion complex formulations improved microscopic damage and reduced colonic MPO activity and TNF-α levels.

Changes in fertilization medium viscosity using hyaluronic acid impact bull sperm motility and acrosome status.

The female reproductive tract, in particular the composition of the uterine and oviduct fluids, is responsible, at least in part, for triggering sperm cell modifications, essential for the acquisition of fertilization ability. Hyaluronic acid (HA) is a glycosaminoglycan present in these fluids, and its role in the fertilization process and sperm functionality is still barely understood. This work was designed to (a) determine the rheological characteristics of the fertilization medium by the addition of HA and (b) determine the HA influence on sperm motility and functional status. To that end, the in vitro fertilization medium was supplemented with 4 doses of HA (6, 60, 600 and 6,000 µg/ml) and analysed for viscosity and adhesion strength characteristics. Then, thawed semen from 6 bulls were incubated in these media and assessed at 4 different moments for morphological and functional parameters (plasma and acrosomal membrane integrities, mitochondrial membrane potential, capacitation, acrosomal reaction, and motility). The rheological evaluation showed that the addition of HA was able to increase both the viscosity and the adhesion strength of the fertilization medium, especially in the 6,000 µg/ml group in which the effect was more pronounced. No influence of HA could be observed on mitochondrial potential, and acrosomal and plasma membrane integrities. However, HA supplementation, at lower doses, led to an increase in the number of reacted sperm, as well as changes in motility parameters, with increase in the number of motile, rapid and progressive spermatozoa. In conclusion, the addition of HA alters the rheological properties of the fertilization medium and leads to the improvement of the properties related to sperm motility and capacitation, without compromising other functional aspects of the cell.

Liposomal butamben gel formulations: toxicity assays and topical anesthesia in an animal model.

The aim of this study was to evaluate the in vitro cytotoxicity and the in vivo analgesic effect and local toxicity of the local anesthetic butamben (BTB) encapsulated in conventional or elastic liposomes incorporated in gel formulations. The results showed that both gel formulations of liposomal BTB reduced the cytotoxicity (p < 0.001; one-way ANOVA/Tukey's test) and increased the topical analgesic effect (p < 0.05; one-way ANOVA/Tukey's test) of butamben, compared to plain BTB gel. The gel formulations presented good rheological properties, and stability assays detected no differences in physicochemical stability up to 30 d after preparation. Moreover, histological assessment revealed no morphological changes in rat skin after application of any of the gel formulations tested.

Liposomal lidocaine gel for topical use at the oral mucosa: characterization, in vitro assays and in vivo anesthetic efficacy in humans.

OBJECTIVE: To characterize liposomal-lidocaine formulations for topical use on oral mucosa and to compare their in vitro permeation and in vivo anesthetic efficacy with commercially available lidocaine formulations. MATERIALS AND METHODS: Large unilamellar liposomes (400 nm) containing lidocaine were prepared using phosphatidylcholine, cholesterol, and α-tocoferol (4:3:0.07, w:w:w) and were characterized in terms of membrane/water partition coefficient, encapsulation efficiency, size, polydispersity, zeta potential, and in vitro release. In vitro permeation across pig palatal mucosa and in vivo topical anesthetic efficacy on the palatal mucosa in healthy volunteers (double-blinded cross-over, placebo controlled study) were performed. The following formulations were tested: liposome-encapsulated 5% lidocaine (Liposome-Lido5); liposome-encapsulated 2.5% lidocaine (Liposome-Lido2.5); 5% lidocaine ointment (Xylocaina®), and eutectic mixture of lidocaine and prilocaine 2.5% (EMLA®). RESULTS: The Liposome-Lido5 and EMLA showed the best in vitro permeation parameters (flux and permeability coefficient) in comparison with Xylocaina and placebo groups, as well as the best in vivo topical anesthetic efficacy. CONCLUSION: We successfully developed and characterized a liposome encapsulated 5% lidocaine gel. It could be considered an option to other topical anesthetic agents for oral mucosa.

Recombinant scFv-Fc Anti-kallikrein 7 Antibody-Loaded Thermosensitive Hydrogels Against Skin Desquamation Disorders.

Human tissue kallikrein-related peptidase 7 (KLK7) is a serine protease implicated in the physiology of skin desquamation, and its uncontrolled activity can lead to chronic diseases such as psoriasis, atopic dermatitis, and Netherton syndrome. For this reason, kallikrein 7 has been identified as a potential therapeutic target. This work aimed to evaluate Pluronic (PL) hydrogels as topical carriers of four specific scFv-Fc antibodies to inhibit KLK7. The hydrogels comprised PL F127 (30% w/v) alone and a binary F127/P123 (28-2% w/v) system. Each formulation was loaded with 1 µg/mL of each antibody and characterized by physicochemical and pharmaceutical techniques, considering antibody-micelle interactions and hydrogel behavior as smart delivery systems. Results showed that the antibodies were successfully loaded into the PL-based systems, and the sol-gel transition temperature was shifted to high values after the P123 addition. The antibodies released from the gels preserved their rheological properties (G' > G'', 35- to 41-fold) and inhibitory activity against KLK7, even after 24 h. This work presented potential agents targeting KLK7 that may provide strategies for treating skin abnormalities.

Tricalcium phosphate-loaded injectable hydrogel as a promising osteogenic and bactericidal teicoplanin-delivery system for osteomyelitis treatment: An in vitro and in vivo investigation.

Osteomyelitis is an inflammation of bone tissue usually caused by pyogenic bacteria. The most recurrent clinical approach consists of bone debridement followed by parenteral administration of antibiotics. However, systemic antibiotic treatment has limitations regarding absorption rate and bioavailability over time. The main challenge of osteomyelitis treatment consists of coupling the persistent infection treatment with the regeneration of the bone debrided. In this work, we developed an injectable drug delivery system based on poloxamer 407 hydrogel containing undoped Mg, Zn-doped tricalcium phosphate (ß-TCP), and teicoplanin, a broad-spectrum antibiotic. We evaluated how the addition of teicoplanin and ß-TCP affected the micellization, gelation, particle size, and surface charge of the hydrogel. Later, we studied the hydrogel degradation and drug delivery kinetics. Finally, the bactericidal, biocompatibility, and osteogenic properties were evaluated through in vitro studies and confirmed by in vivo Wistar rat models. Teicoplanin was found to be encapsulated in the corona portions of the hydrogel micelles, yielding a bigger hydrodynamics radius. The encapsulated teicoplanin showed a sustained release over the evaluated period, enough to trigger antibacterial properties against Gram-positive bacteria. Besides, the formulations were biocompatible and showed bone healing ability and osteogenic properties. Finally, in vivo studies confirmed that the proposed locally injected formulations yielded osteomyelitis treatment with superior outcomes than parenteral administration while promoting bone regeneration. In conclusion, the presented formulations are promising drug delivery systems for osteomyelitis treatment and deserve further technological improvements.

Analgesic Effect of Sulforaphane: A New Application for Poloxamer-Hyaluronic Acid Hydrogels.

Sulforaphane (SFN) has shown potential as an antioxidant and anti-inflammatory agent. To improve its druggability, we developed new analgesic formulations with sulforaphane-loaded hyaluronic acid (HA)-poloxamer (PL) hydrogel. This study evaluated the pre-clinical safety and effectiveness of these formulations. Effectiveness was tested on Wistar rats divided into groups (n = 15) receiving (IM, 10 mg/kg) SFN formulations or control groups (without SFN). This study used a hind paw incision postoperative pain model to evaluate mechanical hypersensitivity with von Frey filaments. TNF-α, IL-1ß, substance P, and CGRP levels verified anti-inflammatory activity in the hind paw tissue. Histopathology of tissues surrounding the injection site was assessed after 2 and 7 days post-treatment. To corroborate drug safety, cell viability of 3T3 and RAW 264.7 cultures was assessed. Additionally, RAW 264.7 cultures primed with carrageenan evaluated nitric oxide (NO) levels. All animals exhibited post-incisional hypersensitivity, and F2 (PL 407/338 (18/2%) + HA 1% + SFN 0.1%) showed a longer analgesic effect (p < 0.05). F2 reduced TNF-α, IL-1ß, and CGRP levels (p < 0.05). Histopathological evaluation showed mild to moderate inflammatory reactions after the formulations' injections. F2 produced no significant difference in cell viability (p > 0.05) but reduced NO production (p < 0.05). Thus, our results highlight the biocompatibility and effectiveness of F2.

Transdermal delivery of butamben using elastic and conventional liposomes.

Gel formulations containing the local anesthetic butamben (BTB) encapsulated in either conventional (BTBLUV) or elastic (BTBLUV-EL) liposomes were prepared and characterized, and then evaluated in terms of their skin permeability. Parameters measured included vesicle size and surface charge, BTB fluorescence anisotropy, encapsulation efficiency, partition coefficient and liposomal membrane organization. Encapsulation efficiencies and membrane/water partition coefficients were determined using a phase separation. The partition coefficients of the elastic and conventional formulations were 2025 ± 234 and 1136 ± 241, respectively. The sizes of the elastic and conventional liposomes did not change significantly (p > 0.05) following incorporation of the anesthetic. As expected, the elastic liposomes presented order parameters that were lower than those of the conventional liposomes, as determined by electron paramagnetic resonance with a 5-stearic acid nitroxide probe incorporated into the bilayer. After 8 h, the fluxes into the receiving solution (µg/cm(2)/h) were 6.95 ± 1.60 (10% BTB), 23.17 ± 6.09 (10% BTBLUV) and 29.93 ± 6.54 (10% BTBLUV-EL). The corresponding time lags (h) were 1.90 ± 0.48, 1.23 ± 0.28 and 1.57 ± 0.38, respectively. The permeability coefficients (10(-3 )cm/h) were 1.02 ± 0.23, 2.96 ± 0.77 and 4.14 ± 0.9, for 10% BTB, 10% BTBLUV and 10% BTBLUV-EL, respectively. The results demonstrate that anesthetic access through the skin can be considerably enhanced using liposomal gel formulations, compared to plain gel formulations.

Liposomal-benzocaine gel formulation: correlation between in vitro assays and in vivo topical anesthesia in volunteers.

The aim of the present study was to characterize a liposome-based benzocaine (BZC) formulation designed for topical use on the oral mucosa and to evaluate its in vitro retention and permeation using the Franz-type diffusion cells through pig esophagus mucosa. To predict the effectiveness of new designed formulations during preclinical studies, a correlation between in vitro assays and in vivo efficacy was performed. Liposomal BZC was characterized in terms of membrane/water partition coefficient, encapsulation efficiency, size, polydispersity, zeta potential, and morphology. Liposomal BZC (BL10) was incorporated into gel formulation and its performances were compared to plain BZC gel (B10) and the commercially available BZC gel (B20). BL10 and B10 presented higher flux and retention on pig esophagus mucosa with a shorter lag time, when compared to B20. BZC flux was strongly correlated with in vivo anesthetic efficacy, but not with topical anesthesia duration. The retention studies did not correlate with any of the in vivo efficacy parameters. Thus, in vitro permeation study can be useful to predict anesthetic efficacy during preclinical tests, because a correlation between flux and anesthetic efficacy was observed. Therefore, in vitro assays, followed by in vivo efficacy, are necessary to confirm anesthetic performance.

Topical Drug Delivery: Innovative Controlled Release Systems.

One of the most innovative strategies for administrating bioactive molecules is the design of adequate drug delivery systems [...].

Poloxamer-based nanogels as delivery systems: how structural requirements can drive their biological performance?

Poloxamers or Pluronics®-based nanogels are one of the most used matrices for developing delivery systems. Due to their thermoresponsive and flexible mechanical properties, they allowed the incorporation of several molecules including drugs, biomacromolecules, lipid-derivatives, polymers, and metallic, polymeric, or lipid nanocarriers. The thermogelling mechanism is driven by micelles formation and their self-assembly as phase organizations (lamellar, hexagonal, cubic) in response to microenvironmental conditions such as temperature, osmolarity, and additives incorporated. Then, different biophysical techniques have been used for investigating those structural transitions from the mechanisms to the preferential component's orientation and organization. Since the design of PL-based pharmaceutical formulations is driven by the choice of the polymer type, considering its physico-chemical properties, it is also relevant to highlight that factors inherent to the polymeric matrix can be strongly influenced by the presence of additives and how they are able to determine the nanogels biopharmaceuticals properties such as bioadhesion, drug loading, surface interaction behavior, dissolution, and release rate control. In this review, we discuss the general applicability of three of the main biophysical techniques used to characterize those systems, scattering techniques (small-angle X-ray and neutron scattering), rheology and Fourier transform infrared absorption spectroscopy (FTIR), connecting their supramolecular structure and insights for formulating effective therapeutic delivery systems. Supplementary Information: The online version contains supplementary material available at 10.1007/s12551-023-01093-2.

Protamine-mediated efficient transcellular and transmucosal delivery of proteins.

Proteins and peptides often require frequent needle-based administrations. Here, we report a non-parenteral delivery method for proteins through physical mixing with protamine, an FDA-approved peptide. Protamine was shown to promote tubulation and rearrangement of cellular actin, leading to enhanced intracellular delivery of proteins compared to poly(arginine)8 (R8). While the R8-mediated delivery resulted in significant lysosomal accumulation of the cargo, protamine directed the proteins to the nuclei with little lysosomal uptake. Intranasal delivery of insulin mixed with protamine effectively reduced blood glucose levels in diabetic mice 0.5 h after administration and the effect lasted for ∼6 h, comparable to subcutaneously injected insulin at the same dose. In mice, protamine was shown to overcome mucosal and epithelial barriers and modulate adherens junctions, promoting insulin penetration to the lamina propria layer for systemic absorption.

Pluronic® triblock copolymer-based nanoformulations for cancer therapy: A 10-year overview.

This paper provides a review of the literature on the use of Pluronic® triblock copolymers for drug encapsulation over the last 10 years. A special focus is given to the progress of drug delivery systems (e.g., micelles, liposomes, micro/nanoemulsions, hydrogels and nanogels, and polymersomes and niosomes); the beneficial aspects of Pluronic® triblock copolymers as biological response modifiers and as pharmaceutical additives, adjuvants, and stabilizers, are also discussed. The advantages and limitations encountered in developing site-specific targeting approaches based on Pluronic-based nanostructures in cancer treatment are highlighted, in addition to innovative examples for improving tumor cytotoxicity while reducing side effects.

Local neurotoxicity and myotoxicity evaluation of cyclodextrin complexes of bupivacaine and ropivacaine.

BACKGROUND: Bupivacaine (BVC) and ropivacaine (RVC) are local anesthetics widely used in surgical procedures. In previous studies, inclusion complexes of BVC or RVC in hydroxypropyl-ß-cyclodextrin (HP-ß-CD) increased differential nervous blockade, compared to the plain anesthetic solutions. In this study we evaluated the local neural and muscular toxicity of these new formulations containing 0.5% BVC or RVC complexed with HP-ß-CD (BVC(HP-ß-CD) and RVC(HP-ß-CD)). METHODS: Schwann cell viability was assessed by determination of mitochondrial dehydrogenase activity, and histopathological evaluation of the rat sciatic nerve was used to identify local neurotoxic effects (48 hours and 7 days after the treatments). Evaluations of serum creatine kinase levels and the histopathology of rat gastrocnemius muscle (48 hours after treatment) were also performed. RESULTS: Schwann cell toxicity evaluations revealed no significant differences between complexed and plain local anesthetic formulations. However, use of the complexed local anesthetics reduced serum creatine kinase levels 5.5-fold, relative to the plain formulations. The differences were significant at P < 0.05 (BVC) and P < 0.01 (RVC). The histopathological muscle evaluation showed that differences between groups treated with local anesthetics (BVC or RVC) and their respective complexed formulations (BVC(HP-ß-CD) or RVC(HP-ß-CD)) were significant (P < 0.05). CONCLUSIONS: We concluded that the new formulations presented a lower myotoxicity and a similar cytotoxic effect when compared to plain local anesthetic solutions.

Crosstalk between incretin hormones, Th17 and Treg cells in inflammatory diseases.

Intestinal epithelial cells constantly crosstalk with the gut microbiota and immune cells of the gut lamina propria. Enteroendocrine cells, secrete hormones, such as incretin hormones, which participate in host physiological events, such as stimulating insulin secretion, satiety, and glucose homeostasis. Interestingly, evidence suggests that the incretin pathway may influence immune cell activation. Consequently, drugs targeting the incretin hormone signaling pathway may ameliorate inflammatory diseases such as inflammatory bowel diseases, cancer, and autoimmune diseases. In this review, we discuss how these hormones may modulate two subsets of CD4 + T cells, the regulatory T cells (Treg)/Th17 axis important for gut homeostasis: thus, preventing the development and progression of inflammatory diseases. We also summarize the main experimental and clinical findings using drugs targeting the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1) signaling pathways and their great impact on conditions in which the Treg/Th17 axis is disturbed such as inflammatory diseases and cancer. Understanding the role of incretin stimulation in immune cell activation and function, might contribute to new therapeutic designs for the treatment of inflammatory diseases, autoimmunity, and tumors.

Silk Fibroin/Poly(vinyl Alcohol) Microneedles as Carriers for the Delivery of Singlet Oxygen Photosensitizers.

Photodynamic therapy (PDT) is a medical treatment in which a combination of a photosensitizing drug and visible light produces highly cytotoxic reactive oxygen species (ROS) that leads to cell death. One of the main drawbacks of PDT for topical treatments is the limited skin penetration of some photosensitizers commonly used in this therapy. In this study, we propose the use of polymeric microneedles (MNs) prepared from silk fibroin and poly(vinyl alcohol) (PVA) to increase the penetration efficiency of porphyrin as possible applications in photodynamic therapy. The microneedle arrays were fabricated from mixtures in different proportions (1:0, 7:3, 1:1, 3:7, and 0:1) of silk fibroin and PVA solutions (7%); the polymer solutions were cast in polydimethylsiloxane (PDMS) molds and dried overnight. Patches containing grids of 10 × 10 microneedles with a square-based pyramidal shape were successfully produced through this approach. The polymer microneedle arrays showed good mechanical strength under compression force and sufficient insertion depth in both Parafilm M and excised porcine skin at different application forces (5, 20, 30, and 40 N) using a commercial applicator. We observe an increase in the cumulative permeation of 5-[4-(2-carboxyethanoyl) aminophenyl]-10,15,20-tris-(4-sulphonatophenyl) porphyrin trisodium through porcine skin treated with the polymer microneedles after 24 h. MNs may be a promising carrier for the transdermal delivery of photosensitizers for PDT, improving the permeation of photosensitizer molecules through the skin, thus improving the efficiency of this therapy for topical applications.

Defining the molecular basis of tumor metabolism: a continuing challenge since Warburg's discovery.

Cancer cells are the product of genetic disorders that alter crucial intracellular signaling pathways associated with the regulation of cell survival, proliferation, differentiation and death mechanisms. The role of oncogene activation and tumor suppressor inhibition in the onset of cancer is well established. Traditional antitumor therapies target specific molecules, the action/expression of which is altered in cancer cells. However, since the physiology of normal cells involves the same signaling pathways that are disturbed in cancer cells, targeted therapies have to deal with side effects and multidrug resistance, the main causes of therapy failure. Since the pioneering work of Otto Warburg, over 80 years ago, the subversion of normal metabolism displayed by cancer cells has been highlighted by many studies. Recently, the study of tumor metabolism has received much attention because metabolic transformation is a crucial cancer hallmark and a direct consequence of disturbances in the activities of oncogenes and tumor suppressors. In this review we discuss tumor metabolism from the molecular perspective of oncogenes, tumor suppressors and protein signaling pathways relevant to metabolic transformation and tumorigenesis. We also identify the principal unanswered questions surrounding this issue and the attempts to relate these to their potential for future cancer treatment. As will be made clear, tumor metabolism is still only partly understood and the metabolic aspects of transformation constitute a major challenge for science. Nevertheless, cancer metabolism can be exploited to devise novel avenues for the rational treatment of this disease.

Poly(lactide-co-glycolide) nanocapsules containing benzocaine: influence of the composition of the oily nucleus on physico-chemical properties and anesthetic activity.

PURPOSE: The aim of this work was to investigate the influence of the oily nucleus composition on physico-chemical properties and anesthetic activity of poly (lactide-co-glycolide) nanocapsules with benzocaine. METHODS: Nanocapsules containing benzocaine were prepared with three different oily nucleus composition and characterized by mean diameter, polydispersivity, zeta potential, pH and stability were investigated as a function of time. In vitro release kinetics were performed in a system with two compartments separated by a cellulose membrane. Intensity and duration of analgesia were evaluated in rats by sciatic nerve blockade. RESULTS: The greatest stability, slower release profile and improvement in the local anesthetic activity of BZC were obtained with the formulation using USP mineral oil as component. CONCLUSIONS: Results from our study provide useful perspectives on selection of the primary materials needed to produce suspensions of polymeric nanocapsules able to act as carriers of BZC, with potential future application in the treatment of pain.