Development and Characterization of PLGA Nanoparticles Containing 17-DMAG, an Hsp90 Inhibitor
Leishmaniasis is a spectrum of neglected tropical diseases and its cutaneous form (CL) is characterized by papillary or ulcerated skin lesions that negatively impact patients’ quality of life. Current CL treatments suffer limitations, such as severe side effects and high cost, making the search for new therapeutic alternatives an imperative. In this context, heat shock protein 90 (Hsp90) could present a novel therapeutic target, as evidence suggests that Hsp90 inhibitors, such as 17-Dimethylaminoethylamino-17 Demethoxygeldanamycin (17-DMAG), may represent promising chemotherapeutic agents against CL. As innovative input for formulation development of 17-DMAG, nano-based drug delivery systems could provide controlled release, targeting properties, and reduced drug toxicity. In this work, a double emulsion method was used to develop poly (lactic-co-glycolic acid) (PLGA) nanoparticles
containing 17-DMAG. The nanoparticle was developed using two distinct protocols: Protocol 1 (P1) and Protocol 2 (P2), which differed concerning the organic solvent (acetone or dichloromethane, respectively) and procedure used to form doubleemulsions (Ultra-Turrax® homogenization or sonication, respectively). The nanoparticles produced by P2 were comparatively smaller (305.5 vs. 489.0 nm) and more homogeneous polydispersion index (PdI) (0.129 vs. 0.33) than the ones made by P1. Afterward, the P2 was optimized and the best composition consisted of 2mg of 17-DMAG, 100mg of PLGA, 5% of polyethylene glycol (PEG 8000), 1.5mL of the internal aqueous phase, 1% of polyvinyl alcohol (PVA), and 4mL of the organic phase. Optimized P2 nanoparticles had a particle size of 297.2 nm (288.6–304.1) and encapsulation efficacy of 19.35%(15.42–42.18) by the supernatant method and 31.60% (19.9–48.79) by the filter/column method. Release kinetics performed at 37◦C indicated that ∼16% of the encapsulated 17-DMAG was released about to 72 h. In a separate set of experiments, a cell uptake assay employing confocal fluorescence microscopy revealed the internalization by macrophages of P2-optimized rhodamine B labeled nanoparticles at 30min, 1, 2, 4, 6, 24, 48, and 72 h. Collectively, our results indicate the superior performance of P2 concerning the parameters used to assess nanoparticle
development. Therefore, these findings warrant further research to evaluate optimized 17-DMAG-loaded nanoparticles (NP2-17-DMAG) for toxicity and antileishmanial effects in vitro and in vivo.
CRUZ, Kercia P. et al. Development and characterization of PLGA nanoparticles containing 17-DMAG, an Hsp90 inhibitor. Frontiers in Chemistry, v. 9, 2021.
In Vivo Efficacy and Toxicity of Curcumin Nanoparticles in Breast Cancer Treatment: A Systematic Review
Breast cancer is one of the most prevalent types of malignant tumors in the world, resulting in a high incidence of death. The development of new molecules and technologies aiming to apply more effective and safer therapy strategies has been intensively explored to overcome this situation. The association of nanoparticles with known antitumor compounds (including plant-derived molecules such as curcumin) has been considered an effective approach to enhance tumor growth suppression and reduce adverse effects. Therefore, the objective of this systematic review was to summarize published data regarding evaluations about efficacy and toxicity of curcumin nanoparticles (Cur-NPs) in in vivo models of breast cancer. The search was carried out in the databases: CINAHL, Cochrane, LILACS, Embase, FSTA, MEDLINE, ProQuest, BSV regional portal, PubMed, ScienceDirect, Scopus, and Web of Science. Studies that evaluated tumor growth in in vivo models of breast cancer and showed outcomes related to Cur-NP treatment (without association with other antitumor molecules) were included. Of the 528 initially gathered studies, 26 met the inclusion criteria. These studies showed that a wide variety of NP platforms have been used to deliver curcumin (e.g., micelles, polymeric, lipid-based, metallic). Attachment of poly(ethylene glycol) chains (PEG) and active targeting moieties were also evaluated. Cur-NPs significantly reduced tumor volume/weight, inhibited cancer cell proliferation, and increased tumor apoptosis and necrosis. Decreases in cancer stem cell population and angiogenesis were also reported. All the studies that evaluated toxicity considered Cur-NP treatment to be safe regarding hematological/biochemical markers, damage to major organs, and/or weight loss. These effects were observed in different in vivo models of breast cancer (e.g., estrogen receptor-positive, triple-negative, chemically induced) showing better outcomes when compared to treatments with free curcumin or negative controls. This systematic review supports the proposal that Cur-NP is an effective and safe therapeutic approach in in vivo models of breast cancer, reinforcing the currently available evidence that it should be further analyzed in clinical trials for breast cancer treatments.
OMBREDANE, Alicia S. et al. In vivo efficacy and toxicity of curcumin nanoparticles in breast cancer treatment: a systematic review. Frontiers in Oncology, v. 11, p. 247, 2021.
Improved anti-cutibacterium acnes activity of tea tree oil loaded chitosan-poly(e-caprolactone) core-shell nanocapsules
The purpose of this study was to develop tea tree oil (TTO)-loaded chitosan-poly(ε-caprolactone) core-shell nanocapsules (NC-TTO-Ch) aiming the topical acne treatment. TTO was analyzed by gas chromatography-mass spectrometry, and nanocapsules were characterized regarding mean particle size (Z-average), polydispersity index (PdI), zeta potential (ZP), pH, entrapment efficiency (EE), morphology by Atomic Force Microscopy (AFM), and anti-Cutibacterium acnes activity. The main constituents of TTO were terpinen-4-ol (37.11 %), γ-terpinene (16.32 %), α-terpinene (8.19 %), ρ-cimene (6.56 %), and α-terpineol (6.07 %). NC-TTO-Ch presented Z-average of 268.0 ± 3.8 nm and monodisperse size distribution (PdI < 0.3). After coating the nanocapsules with chitosan, we observed an inversion in ZP to a positive value (+31.0 ± 1.8 mV). This finding may indicate the presence of chitosan on the nanocapsules' surface, which was corroborated by the AFM images. In addition, NC-TTO-Ch showed a slightly acidic pH (∼5.0), compatible with topical application. The EE, based on Terpinen-4-ol concentration, was approximately 95 %. This data suggests the nanocapsules' ability to reduce the TTO volatilization. Furthermore, NC-TTO-Ch showed significant anti-C. acnes activity, with a 4× reduction in the minimum inhibitory concentration, compared to TTO and a decrease in C. acnes cell viability, with an increase in the percentage of dead cells (17 %) compared to growth control (6.6 %) and TTO (9.7 %). Therefore, chitosan-poly(ε-caprolactone) core-shell nanocapsules are a promising tool for TTO delivery, aiming at the activity against C. acnes for the topical acne treatment.
DA SILVA, Natália Prado et al. Improved anti-Cutibacterium acnes activity of tea tree oil-loaded chitosan-poly (ε-caprolactone) core-shell nanocapsules. Colloids and Surfaces B: Biointerfaces, v. 196, p. 111371, 2020.
Bicontinuous microemulsions containing Melaleuca alternifolia essential oil as a therapeutic agent for cutaneous wound healing
The Melaleuca alternifolia essential oil (MEO) has been widely used due to its healing and antimicrobial action. Its incorporation into drug delivery systems is a reality, and numerous studies have already been developed for this purpose. In this regard, the aim of this work was to develop, characterize, and evaluate the in vivo pharmacological activity of bicontinuous microemulsions (BME) containing MEO. Through diagram construction, a formulation consisting of Kolliphor® HS 15 (31.05%), Span® 80 (3.45%), isopropyl myristate (34.5%), and distilled water (31%) was selected and MEO was incorporated in the proportion of 3.45% (v/v). Morphological analysis characterization confirms that the system studied herein is a BME. The evaluated formulation showed physicochemical characteristics that allow its topical use. Rheologically, samples were characterized as pseudo-plastic non-Newtonian thixotropic fluids. The chromatographic method developed is in accordance with the current recommendations. The extraction method used assured a 100% recovery of the pharmacological marker (terpinen-4-ol). In vivo studies suggest that BME loaded with MEO may contribute to the healing process of skin wounds. In addition, it demonstrated antibacterial activity for Gram-positive and Gram-negative bacteria. Therefore, the BME system loaded with MEO is promising as a healing and antimicrobial agent for skin wounds.
DE ASSIS, Karoll Moangella Andrade et al. Bicontinuous microemulsions containing Melaleuca alternifolia essential oil as a therapeutic agent for cutaneous wound healing. Drug Delivery and Translational Research, v. 10, n. 6, p. 1748-1763, 2020.
Towards the advance of a novel iontophoretic patch for needle-free buccal anesthesia
The aim of this work was to develop a mucoadhesive iontophoretic patch for anesthetic delivery in the buccal epithelium. The patch was comprised of three different layers, namely i) drug release (0.64 cm2); ii) mucoadhesive (1.13 cm2); and iii) backing (1.13 cm2). Prilocaine and lidocaine hydrochlorides were used as model drugs (1:1 ratio, 12.5 mg per unit). An anode electrode (0.5 cm2 spiral silver wire) was placed in between the drug release and mucoadhesive/backing layers to enable iontophoresis. Surface microscopy; mechanical and in vitro mucoadhesive properties; drug release kinetics and mechanism; and drug permeation through the porcine esophageal epithelium were assessed. Topographic analysis evidenced differences in the physical structures for the several layers. All layers presented suitable handling properties i.e., flexibility, elasticity and resistance. Both the release and mucoadhesive layers presented features of a soft and tough material, while the backing layer matched the characteristics of a hard and brittle material. A synergy between the drug release and mucoadhesive layers on the mucoadhesive force and work of adhesion of the tri-layered patch was observed. Passive drug release of both drugs fitted to First-order, Hixson-Crowell and Weibull kinetic models; and the release mechanism was attributed to anomalous transport. Iontophoresis remarkably enhanced the permeation of both drugs, but mainly prilocaine through the mucosa as evidenced by the permeability coefficient parameter (3.0-fold). The amount of these amino amide salts retained in the mucosa were also equally enhanced (4.7-fold), while the application of a tiny constant electric current (1 mA·cm−2·h−1) significantly decreased the lag time for lidocaine permeation by about 45%. In view of possible in vitro / in vivo correlations, the buccal iontophoretic patch displays a promising strategy for needle-free and patient-friendly local anesthesia in dentistry.
DO COUTO, Renê Oliveira et al. Towards the advance of a novel iontophoretic patch for needle-free buccal anesthesia. Materials Science and Engineering: C, p. 111778, 2021.
Arginine-conjugated chitosan nanoparticles for topical arginine release in wounds
Arginine is a conditionally essential amino acid in the healing process. Catabolized by nitric oxide synthases and arginases, arginine is rapidly depleted during the healing process of chronic wounds, hampering collagen synthesis, and other proteins that contribute to tissue regeneration. The administration of arginine at a wound site can compensate for its deficiency. To avoid its rapid metabolism, its sustained release in the wound bed is desired. In this work, arginine was encapsulated in arginine-modified chitosan nanoparticles (NP-CHITARG) to have arginine-conjugated chitosan polymer (CHITARG) as a late source of arginine after the sustained release of the drug encapsulated from the nanoparticle. The conjugate CHITARG was characterized by proton nuclear magnetic resonance, thermal and elemental analysis, and scanning electron microscopy. NP-CHITARG, obtained by a modified nanoprecipitation method, was characterized in terms of size, polydispersity, zeta potential, morphology, and encapsulation efficiency of arginine. In vitro cytotoxicity assay was also performed on fibroblast cells (NIH-3T3). NP-CHITARG dispersions showed 177 ± 35 nm, positive zeta potential, and pH 6. Encapsulation of arginine in NP-CHITARG increased 1.5-fold the size of the nanoparticles and decreased the pH of the dispersions to 5.5. NP-CHITARG was able to encapsulate about 10% of arginine. The release of arginine remained constant and slow after a burst release of approximately 20%. Nanoparticles were not cytotoxic to fibroblasts. The amount of arginine slowly released over time combined with CHITARG's antimicrobial and anticoagulant properties suggest a promising effect of nanoparticles in the treatment of wounds.
SHIKIDA, Danielle Nishida Ramos et al. Arginine-conjugated chitosan nanoparticles for topical arginine release in wounds. Journal of Drug Delivery Science and Technology, p. 102115, 2020.
Evaluation of in vitro and in vivo Efficacy of a Novel Amphotericin B-Loaded Nanostructured Lipid Carrier in the Treatment of Leishmania braziliensis Infection
Background: Leishmaniasis is a neglected disease, and the current therapeutic arsenal for its treatment is seriously limited by high cost and toxicity. Nanostructured lipid carriers (NLCs) represent a promising approach due to high drug loading capacity, controlled drug release profiles and superior stability. Here, we explore the efficacy of a unique pH-sensitive amphotericin B-loaded NLC (AmB-NLC) in Leishmania braziliensis infection in vitro and in vivo.
Methods and Results: AmB-NLC was assessed by dynamic light scattering and atomic force microscopy assays. The carrier showed a spherical shape with a nanometric size of 242.0 ± 18.3 nm. Zeta potential was suggestive of high carrier stability (− 42.5 ± 1.5 mV), and the NLC showed ∼ 99% drug encapsulation efficiency (EE%). In biological assays, AmB-NLC presented a similar IC50 as free AmB and conventional AmB deoxycholate (AmB-D) (11.7 ± 1.73; 5.3 ± 0.55 and 13 ± 0.57 ng/mL, respectively), while also presenting higher selectivity index and lower toxicity to host cells, with no observed production of nitric oxide or TNF-α by in vitro assay. Confocal microscopy revealed the rapid uptake of AmB-NLC by infected macrophages after 1h, which, in association with more rapid disruption of AmB-NLC at acidic pH levels, may directly affect intracellular parasites. Leishmanicidal effects were evaluated in vivo in BALB/c mice infected in the ear dermis with L. braziliensis and treated with a pentavalent antimonial (Sb5+), liposomal AmB (AmB-L) or AmB-NLC. After 6 weeks of infection, AmB-NLC treatment resulted in smaller ear lesion size in all treated mice, indicating the efficacy of the novel formulation.
Conclusion: Here, we preliminarily demonstrate the effectiveness of an innovative and cost-effective AmB-NLC formulation in promoting the killing of intracellular L. braziliensis. This novel carrier system could be a promising alternative for the future treatment of cutaneous leishmaniasis.
REBOUÇAS-SILVA, Jéssica et al. Evaluation of in vitro and in vivo Efficacy of a Novel Amphotericin B-Loaded Nanostructured Lipid Carrier in the Treatment of Leishmania braziliensis Infection. International Journal of Nanomedicine, v. 15, p. 8659, 2020.
Preparation and characterization od spiro-acridine derivative and 2-hydroxypropyl-b-cyclodextrin inclusion complex
The spiro-acridine derivative (E)-1′-(benzylideneamino)-5′-oxo-1′,5′-dihydro-10H-spiro[acridine-9,2′-pyrrole]-4-carbonitrile (AMTAC-01) is a synthetic compound with limited water solubility, which restricts its physiological activities and therapeutic applications. Hence, we investigated the complexation of AMTAC-01 with 2-hydroxypropyl‑β‑cyclodextrin (HPβCD) using the freeze-drying method. Complex formation was characterized by scanning electron microscopy, X-ray diffractometry(XRD), nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, Raman spectroscopy, and fluorescence spectrophotometry. Additionally, molecular modeling and phase solubility studies were performed. Molecular modeling demonstrated the most stable inclusion model, and phase solubility studies indicated that AMTAC-01 and HPβCD formed a 1:1 inclusion complex with an apparent stability constant of 1145.3 M − 1. XRD and spectroscopy results suggest intermolecular interactions between AMTAC-01 and HPβCD, with the formation of a 1:1 inclusion complex demonstrating an amorphous pattern and alterations in band distribution intensities compared with free drug.
DE OLIVEIRA MELO, Camila et al. Preparation and characterization of spiro-acridine derivative and 2-hydroxypropyl-β-cyclodextrin inclusion complex. Journal of Molecular Structure, v. 1222, p. 128945, 2020.
Effect of Oleic Acid, Cholesterol, and Octadecylamine on Membrane Stability of Freeze-Dried Liposomes Encapsulating Natural Antimicrobials
Liposomes have been broadly studied as delivery systems for bioactive compounds, although its relatively low stability remains a limitation for commercial application. In this study, phosphatidylcholine (PC) liposomes were prepared entrapping a mixture of garlic extract (GE) and nisin (Nis) using cholesterol (CHO), oleic acid (OA), or octadecylamine (ODA) as membrane stabilizers to evaluate their physical, chemical, bioactive, and stability properties, in fully hydrated state and after freeze-drying. GE/Nisloaded liposomes presented hydrodynamic diameter below 200 nm and polydispersity index below 0.30, typical for small unilamellar vesicles produced by thin film method. Under induced oxidation, the PC-OA-GE/Nis liposomes presented 91% less lipid peroxidation compared with the unloaded PC liposomes. The Fourier transform infrared spectroscopy (FTIR) analysis revealed a high level of hydrogen bonds in the polar head group of PC after addition of GE/Nis in all liposome formulations, in agreement to the high values of water activity and hygroscopicity found in the samples after freeze-drying. During 5 months storage at 4 °C, fully hydrated and lyophilized liposomes showed an increment in their average size and polydispersity index, but these values were reduced by the trehalose addition as lyoprotector. All liposome preparations maintained 100% activity against Listeria monocytogenes; nevertheless, a gradual reduction of activity against Salmonella enterica serovar Enteritidis was observed, suggesting a partial loss of GE active compounds. Despite some physical modifications, freeze-dried liposomes containing OA as stabilizer showed best antimicrobial properties and high lipid oxidation resistance, constituting a promising approach to stabilize GE/Nis for long-term storage.
PINILLA, Cristian Mauricio Barreto; REQUE, Priscilla Magro; BRANDELLI, Adriano. Effect of Oleic Acid, Cholesterol, and Octadecylamine on Membrane Stability of Freeze-Dried Liposomes Encapsulating Natural Antimicrobials. Food and Bioprocess Technology, p. 1-12, 2020.
Ivermectin: an award-winning drug with expected antiviral activity against COVID-19
Ivermectin is an FDA-approved broad-spectrum antiparasitic agent with demonstrated antiviral activity against a number of DNA and RNA viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite this promise, the antiviral activity of ivermectin has not been consistently proven in vivo. While ivermectin's activity against SARS-CoV-2 is currently under investigation in patients, insufficient emphasis has been placed on formulation challenges. Here, we discuss challenges surrounding the use of ivermectin in the context of coronavirus disease-19 (COVID-19) and how novel formulations employing micro- and nanotechnologies may address these concerns.
FORMIGA, Fabio Rocha et al. Ivermectin: an award-winning drug with expected antiviral activity against COVID-19. Journal of Controlled Release, 2020.
Novel Eudragit® -based polymeric nanoparticles for sustained release of simvastatin
This paper reports on the development of nanoparticles aiming at the in vitro controlled release of simvastatin (SVT). The nanoparticles were prepared by the nanoprecipitation method with polymers Eudragit® FS30D (EDGFS) or Eudragit® NE30D (EDGNE). EDGFS+SVT nanoparticles showed mean size of 148.8 nm and entrapment efficiency of 76.4%, whereas EDGNE+SVT nanoparticles showed mean size of 105.0 nm and entrapment efficiency of 103.2%. Infrared absorption spectra demonstrated that SVT incorporated into the polymer matrix, especially EDGNE. Similarly, the differential scanning calorimeter (DSC) curve presented no endothermic peak of fusion, indicating that the system is amorphous and the drug is not in the crystalline state. The maintenance of SVT in the amorphous state may favors its solubilization in the target release sites. In the in vitro dissolution assay, the SVT incorporated into the EDGFS+SVT nanoparticles showed a rapid initial release, which may be related to the pH of the dissolution medium used. Regarding the EDGNE+SVT nanoparticles, the in vitro release occurred in a bimodal behavior, i.e., an initial “burst” followed by a sustained delivery, with the kinetics of drug release following Baker-Lonsdale’s mathematical model. All these features suggest the nanoparticulate system’s potential to modulate SVT delivery and enhance its bioavailability.
RODRIGUES, Deborah Fernandes et al. Novel Eudragit®-based polymeric nanoparticles for sustained release of simvastatin. Brazilian Journal of Pharmaceutical Sciences, v. 56, 2020.
Oral Treatment of spontaneously hypertensive rats with captopril-surface funcionalized furosemid-loaded multi-well lipid-core nanocapsules
Multi-wall lipid-core nanocapsule (MLNC) functionalized with captopril and nanoencapsulating furosemide within the core was developed as a liquid formulation for oral administration. The nanocapsules had mean particle size below 200 nm, showing unimodal and narrow size distributions with moderate dispersity (laser diffraction and dynamic light scattering). Zeta potential was inverted from -14.3 mV [LNC-Fur(0,5)] to +18.3 mV after chitosan coating. Transmission electron microscopy and atomic force microscopy showed spherical structures corroborating the nanometric diameter of the nanocapsules. Regarding the systolic pressure, on the first day, the formulations showed antihypertensive effect and a longer effect than the respective drug solutions. When both drugs were associated, the anti-hypertensive effect was prolonged. On the fifth day, a time effect reduction was observed for all treatments, except for the nanocapsule formulation containing both drugs [Capt(0.5)-Zn(25)-MLNC-Fur(0.45)]. For diastolic pressure, only Capt(0.5)-Zn(25)-MLNC-Fur(0.45) presented a significant difference (p < 0.05) on the first day. On the fifth day, both Capt(0.5)-MLNC-Fur(0.45) and Capt(0.5)-Zn(25)-MLNC-Fur(0.45) had an effect lasting up to 24 h. The analysis of early kidney damage marker showed a potential protection in renal function by Capt(0.5)-Zn(25)-MLNC-Fur(0.45). In conclusion, the formulation Capt(0.5)-Zn(25)-MLNC-Fur(0.45) proved to be suitable for hypertension treatment envisaging an important innovation.
MICHALOWSKI, Cecilia B. et al. Oral Treatment of Spontaneously Hypertensive Rats with Captopril-Surface Functionalized Furosemide-Loaded Multi-Wall Lipid-Core Nanocapsules. Pharmaceutics, v. 12, n. 1, p. 80, 2020.
Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche
Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vessels that regulates blood-cell traffic as well as the maintenance and function of haematopoietic stem and progenitor cells. Here, we report the design and in vivo performance of systemically injected lipid–polymer nanoparticles encapsulating small interfering RNA (siRNA), for the silencing of genes in bone-marrow endothelial cells. In mice, nanoparticles encapsulating siRNA sequences targeting the proteins stromal-derived factor 1 (Sdf1) or monocyte chemotactic protein 1 (Mcp1) enhanced (when silencing Sdf1) or inhibited (when silencing Mcp1) the release of stem and progenitor cells and of leukocytes from the bone marrow. In a mouse model of myocardial infarction, nanoparticle-mediated inhibition of cell release from the haematopoietic niche via Mcp1 silencing reduced leukocytes in the diseased heart, improved healing after infarction and attenuated heart failure. Nanoparticle-mediated RNA interference in the haematopoietic niche could be used to investigate haematopoietic processes for therapeutic applications in cancer, infection and cardiovascular disease.
KROHN-GRIMBERGHE, Marvin et al. Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche. Nature Biomedical Engineering, p. 1-14, 2020.
Design of chitosan-based particle system: A review 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.
FERREIRA, Leonardo MB et al. Design of chitosan-based particle systems: a review of the physicochemical foundations for tailored properties. Carbohydrate Polymers, p. 116968, 2020.
Targeted uptake of folic acid-functionalized polymeric nanoparticles loading glycoalkaloidic extract in vitro and in vivo assays
Solanum lycocarpum fruits contain two major glycoalkaloids (GAs), solamargine (SM) and solasonine (SS). These compounds are reported as cytotoxic. However, they have poor water solubility and low bioavailability. To overcome these disadvantages and getting an efficient formulation the current study aimed to develop, characterize, and test the effectiveness of a nanotechnology-based strategy using poly(D,L-lactide) (PLA) nanoparticles functionalized with folate as delivery system of glycoalkaloidic extract (AE) for bladder cancer therapy. The strategic of adding folic acid into nanoformulations can increase the selectivity of the compounds to the cancer cells reducing the side effects. Our results revealed the successful preparation of AE-loaded folate-targeted nanoparticles (NP-F-AE) with particle size around 177 nm, negative zeta potential, polydispersity index <0.20, and higher efficiency of encapsulation for both GAs present in the extract (>85 %). To investigate the cellular uptake, the ﬂuorescent dye coumarin-6 was encapsulated into the nanoparticle (NP-F-C6). The cell studies showed high uptake of nanoparticles by breast (MDA-MB-231) and bladder (RT4) cancer cells, but not for normal keratinocytes cells (HaCaT) indicating the target uptake to cancer cells. The cytotoxicity of nanoparticles was evaluated on RT4 2D culture model showing 2.16-fold lower IC50 than the free AE. Furthermore, the IC50 increased on the RT4 spheroids compared to 2D model. The nanoparticles penetrated homogeneously into the urotheliumof porcine bladder. These results showed that folate-conjugated polymeric nanoparticles are potential carriers for targeted glycoalkaloidic extract delivery to bladder cancer cells.
MIRANDA, M. A. et al. Targeted uptake of folic acid-functionalized polymeric nanoparticles loading glycoalkaloidic extract in vitro and in vivo assays. Colloids and Surfaces B: Biointerfaces, p. 111106, 2020.
Nanoestructured lipid carrier co-delivering tacrolimus and TNF-alfa siRNA as na innovate approach to psioriasis
Since psoriasis is an immuno-mediated skin disease, long-term therapies are necessary for its treatment. In clinical investigations, tacrolimus (TAC), a macrolide immunosuppressive inhibitor of calcineurin, arises as an alternative for the treatment of psoriasis, acting in some cytokines involved in the pathogenesis of the disease. Here, we aim to study the psoriasis treatment with TAC and siRNA for one of most cytokines expressed in psoriasis, the TNF-α. A multifunctional nanostructure lipid carrier (NLC) was developed to co-delivery TAC and siRNA. Results showed that the particle size and zeta potential were around 230 nm and + 10 mV, respectively. The release study demonstrated a controlled release of TAC, and the permeation and retention profile in the skin tissue show to be promising for topical application. The cell viability and uptake in murine fibroblast presented low toxicity associated to uptake of NLC in 4 h, and finally, the in vivo animal model demonstrates the efficiency of the NLC multifunctional, exhibiting a reduction of the cytokine TNF-α expression about 7-fold and presenting a synergic effect between the TAC and TNF-α siRNA. The developed system was successfully to treat in vivo psoriatic animal model induced by imiquimod and the synergic combination was reported here for the first time.
VIEGAS, Juliana Santos Rosa et al. Nanostructured lipid carrier co-delivering tacrolimus and TNF-α siRNA as an innovate approach to psoriasis. Drug Delivery and Translational Research, p. 1-15, 2020.
N,N,N-trimethylchitosan-poly (n-butylcyanoacrylate) core-shell nanoparticles as a potential oral delivery system for acyclovir
This study investigated the feasibility of polysaccharide-coated poly(n-butyl cyanoacrylate) (PBCA) nanoparticles for oral delivery of acyclovir (ACV). PBCA nanoparticles were obtained by the emulsion polymerization method. Chitosan was chemically modified to obtain N,N,N-trimethylchitosan (TMC), which was used to coat the nanoparticles (PBCA-TMC). Nanoparticles were characterized by dynamic light scattering, zeta potential, differential scanning calorimetry (DSC), atomic force microscopy (AFM), cytotoxicity, and the effect on the transepithelial electrical resistance (TEER) of the Caco-2 cells. The size of the coated nanoparticles (296.2 nm) was significantly larger than uncoated (175.0 nm). Furthermore, PBCA nanoparticles had a negative charge (-11.7 mV), which was inverted to highly positive values (+36.5 mV) after coating. DSC analysis suggested the occurrence of the coating, which was confirmed by AFM images. The MTT assay revealed concentration-dependent cytotoxicity for the core-shell nanoparticles. Additionally, PBCA-TMC caused a significant but reversible decrease in the Caco-2 cell monolayer TEER. Entrapped ACV (PBCA-ACV-TMC), a Biopharmaceutical Classification System class III drug substance, increased approximately 3.25 times the Papp of ACV in the Caco-2 permeability assay. The nanoparticles were also able to provide in vitro ACV controlled release using media with different pH values (1.2; 6.8; 7.4). Accordingly, this new core-shell nanoparticle showed the potential to improve the oral delivery of ACV.
TAVARES, Guilherme Diniz et al. N, N, N-trimethylchitosan-poly (n-butylcyanoacrylate) core-shell nanoparticles as a potential oral delivery system for acyclovir. Colloids and Surfaces B: Biointerfaces, v. 196, p. 111336, 2020.
Role of the complement cascade in the biological fate of liposomes in rodents
Nanomedicines, including liposomes, have been used to improve the clinical efficacy and safety of drugs. In some liposomal formulations, a hydrophilic polymer coating of poly(ethylene glycol) (PEG) is used to increase the circulation time. Understanding the biological mechanisms responsible for the clearance of PEGylated and non-PEGylated nanomedicines is necessary to develop better-performing materials. The purpose of this work is to explore the role of complement in the elimination of intravenously administered liposomes (PEGylated and non-PEGylated) in mice and rats. Here, the complement cascade was depleted by intraperitoneal injections of cobra venom factor (CVF) 12 and 24 hours before the intravenous injection of radiolabeled liposomes. In both mice and rats, non-PEGylated liposomes showed faster elimination than PEGylated liposomes. At a lipid dose of 20 mg kg−1, the abrogation of the complement cascade (in CVF group) did not alter the circulation time of either PEGylated or non-PEGylated liposomes. In contrast, at lower doses (2 mg kg−1), animals treated with CVF had slightly higher levels of circulating liposomes, especially during the 24 hours pharmacokinetic studies. The complement cascade seems to govern the uptake of non-PEGylated liposomes by splenic B cells. Altogether, these results suggest that although PEGylated and non-PEGylated liposomes can activate complement, the impact of this cascade on their circulation time is minor and mostly perceivable at later phases of distribution. This work enlightens biological pathways responsible for in vivo clearance of liposomes and will help in orienting future research in elucidating the nano-bio interface.
DE OLIVEIRA VIANA, Iara Maíra et al. Role of the complement cascade in the biological fate of liposomes in rodents. Nanoscale, v. 12, n. 36, p. 18875-18884, 2020.
Xylan microparticles for controlled release of mesalamine: Production and physicochemical characterization
D Xylan extracted from corn cobs was used to produce mesalamine-loaded xylan microparticles (XMP5-ASA) by cross-linking polymerization using a non-hazardous cross-linking agent. The microparticles were characterized by thermal analysis (DSC/TG), X-ray diffraction (XRD), Infrared spectroscopy (FTIR-ATR) and scanning electron microscopy (SEM). A comparative study of the in vitro drug release from XMP5-ASA and from gastro-resistant capsules filled with XMP5-ASA (XMPCAP5-ASA) or 5-ASA was also performed. NMR, FTIR-ATR, XRD and DSC/TG studies indicated molecularly dispersed drug in the microparticles with increment on drug stability. The release studies showed that XMPCAP5-ASA allowed more efficient drug retention in the simulated gastric fluid and a prolonged drug release lasting up to 24 h. XMPCAP5-ASA retained approximately 48 % of its drug content after 6 h on the drug release assay. Thus, the encapsulation of 5-ASA into xylan microparticles together with gastro-resistant capsules allowed a better release control of the drug during different simulated gastrointestinal medium.
DA COSTA URTIGA, Silvana Cartaxo et al. Xylan microparticles for controlled release of mesalamine: Production and physicochemical characterization. Carbohydrate Polymers, v. 250, p. 116929, 2020.