Publications by authors named "Márcia Carvalho de Abreu Fantini"

9 Publications

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Liquid crystalline nanodispersion functionalized with cell-penetrating peptides improves skin penetration and anti-inflammatory effect of lipoic acid after in vivo skin exposure to UVB radiation.

Drug Deliv Transl Res 2020 12;10(6):1810-1828

School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n, Ribeirão Preto, SP, 14040-903, Brazil.

In this study, the development and the performance of a new targeted liquid crystalline nanodispersion (LCN) by the attachment of cell-penetrating peptides (CPP) onto their surfaces to improve skin delivery of lipoic acid (LA) were evaluated. For that, the synthesis and characterization of this new platform as well as its spatiotemporal analysis from in vitro and in vivo topical application were explored and extensively discussed in this paper. The TAT or D4 peptides were chosen as CPP due to specific target strategies by the charge grouping on the skin surface or target the overexpressed epidermal growth factor receptor (EGFR) of cell membrane of keratinocytes, respectively. Thus, the nanoparticle characterization results when taken together suggested that designed LCNs maintained their hexagonal phase structure, nanoscale particle size, and low polydispersity index even after drug, lipopolymers, and peptide additions, which are proved to be favorable for topical skin delivery. There were no statistical differences among the LCNs investigated, except for superficial charge of LCN conjugated with TAT which may have altered the LCN zeta potential due to cationic charge of TAT amino acid sequence compared with D4. The cumulative amounts of LA retained into the skin were determined to be even higher coming from the targeted LCNs. Moreover, the exogenous antioxidant application of the LA from the LCNs can prevent ROS damage, which was demonstrated by this study with the less myeloperoxidase (MPO) activity and decrease in cytokine levels (TNF-alpha and IL-1β) generated by the oxidative stress modulation. Together, the data presented highlights the potential of these targeted LCNs, and overall, opens new frontiers for preclinical trials.
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http://dx.doi.org/10.1007/s13346-020-00840-2DOI Listing
December 2020

Improvement of cutaneous delivery of methylene blue by liquid crystals.

Int J Pharm 2018 Sep 2;548(1):454-465. Epub 2018 Jul 2.

Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes 1524, São Paulo, SP, Brazil.

The purpose of this study was to evaluate the effect of composition and characteristics of liquid crystalline phases (LCPs) on cutaneous delivery of methylene blue (MB). LCPs were obtained by mixing Brij97® with water at various ratios; Brij97®:water at 8:2 (F8:2), 7:3 (F7:3), and 6:4 (F6:4) were selected, and MB was incorporated at 0.1%. F8:2 and F7:3 exhibited textures and small angle X-ray scattering (SAXS) patterns corresponding to lamellar phase, whereas F6:4 displayed characteristics of hexagonal phase. All three LCPs were stable for 9 months, and exhibited thixotropic pseudoplastic behaviour. Increasing water content increased viscosity. All three LCPs released less (3.2- to 6.6-fold) MB than control gel (3.0% hydroxyethylcellulose (HEC) + 0.1% MB), demonstrating their ability to sustain release. Despite the lower release, all LCPs improved skin retention of MB at 6 h post-application (1.3- to 2.1-fold) compared to the control gel. Among the LCPs, F8:2-mediated skin retention of MB was more pronounced, followed by F7:3. Consistent with the increased penetration, transepidermal water loss (TEWL) also increased after treatment with the LCPs (2.0-2.8 fold), which suggests their influence on skin barrier. Irritation studies by Hen's Egg Test - Chorioallantoic Membrane (HET-CAM) suggest that F7:3 and F6:4 may be better tolerated by the skin than F8:2.
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http://dx.doi.org/10.1016/j.ijpharm.2018.07.003DOI Listing
September 2018

In Vitro TyRP-1 Knockdown Based on siRNA Carried by Liquid Crystalline Nanodispersions: an Alternative Approach for Topical Treatment of Vitiligo.

Pharm Res 2018 Mar 20;35(5):104. Epub 2018 Mar 20.

School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Avenida do Café, s/n, Ribeirão Preto, SP, 14040-903, Brazil.

Purpose: Vitiligo is a skin disease characterized by depigmentation and the presence of white patches that are associated with the loss of melanocytes. The most common explanation for the cause of this condition is that it is an autoimmune condition. TyRP-1 is involved in melanin pigment synthesis but can also function as a melanocyte differentiation antigen. This protein plays a role in the autoimmune destruction of melanocytes, which results in the depigmentation, characteristic of this disease. In this study, we evaluated liquid crystalline nanodispersions as non-viral vectors to deliver siRNA-TyRP-1 as an alternative for topical treatment of vitiligo.

Methods: Liquid crystalline nanodispersions were obtained and characterized with respect to their physical-chemical parameters including size, PdI and zeta potential, as well as Small Angle X-ray Scattering and complexing to siRNA. The effects of the liquid crystalline nanodispersions on the cellular viability, cell uptake and levels of the knockdown target TyRP-1 were evaluated in melan-A cells after 24 h of treatment.

Results: The liquid crystalline nanodispersions demonstrated adequate physical-chemical parameters including nanometer size and a PdI below 0.38. These systems promoted a high rate of cell uptake and an impressive TyRP-1 target knockdown (> 80%) associated with suitable loading of TyRp-1 siRNA.

Conclusions: We demonstrated that the liquid crystalline nanodispersions showed promising alternative for the topical treatment of vitiligo due to their physical parameters and ability in knockdown the target protein involved with autoimmune destruction of melanocytes.
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http://dx.doi.org/10.1007/s11095-017-2330-0DOI Listing
March 2018

Liquid Crystalline Systems Based on Glyceryl Monooleate and Penetration Enhancers for Skin Delivery of Celecoxib: Characterization, In Vitro Drug Release, and In Vivo Studies.

J Pharm Sci 2018 03 4;107(3):870-878. Epub 2017 Nov 4.

School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café s/n, 14040-903 Ribeirão Preto, São Paulo, Brazil. Electronic address:

Celecoxib (CXB) is a widely used anti-inflammatory drug that also acts as a chemopreventive agent against several types of cancer, including skin cancer. As the long-term oral administration of CXB has been associated with severe side effects, the skin delivery of this drug represents a promising alternative for the treatment of skin inflammatory conditions and chemoprevention of skin cancer. We prepared and characterized liquid crystalline systems based on glyceryl monooleate and water containing penetration enhancers which were primarily designed to promote skin delivery of CXB. Analysis of their phase behavior revealed the formation of cubic and hexagonal phases depending on the systems' composition. The systems' structure and composition markedly affected the in vitro CXB release profile. Oleic acid reduced CXB release rate, but association oleic acid/propylene glycol increased the drug release rate. The developed systems significantly reduced inflammation in an aerosil-induced rat paw edema model. The systems' composition and liquid crystalline structure influenced their anti-inflammatory potency. Cubic phase systems containing oleic acid/propylene glycol association reduced edema in a sustained manner, indicating that they modulate CXB release and permeation. Our findings demonstrate that the developed liquid crystalline systems are potential carriers for the skin delivery of CXB.
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http://dx.doi.org/10.1016/j.xphs.2017.10.039DOI Listing
March 2018

An in situ gelling liquid crystalline system based on monoglycerides and polyethylenimine for local delivery of siRNAs.

Eur J Pharm Sci 2015 Jul 25;74:103-17. Epub 2015 Apr 25.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, 14040-903 Ribeirão Preto, SP, Brazil. Electronic address:

The development of delivery systems able to complex and release siRNA into the cytosol is essential for therapeutic use of siRNA. Among the delivery systems, local delivery has advantages over systemic administration. In this study, we developed and characterized non-viral carriers to deliver siRNA locally, based on polyethylenimine (PEI) as gene carrier, and a self-assembling drug delivery system that forms a gel in situ. Liquid crystalline formulations composed of monoglycerides (MO), PEI, propylene glycol (PG) and 0.1M Tris buffer pH 6.5 were developed and characterized by polarized light microscopy, Small Angle X-ray Scattering (SAXS), for their ability to form inverted type liquid crystalline phases (LC2) in contact with excess water, water absorption capacity, ability to complex with siRNA and siRNA release. In addition, gel formation in vivo was determined by subcutaneous injection of the formulations in mice. In water excess, precursor fluid formulations rapidly transformed into a viscous liquid crystalline phase. The presence of PEI influences the liquid crystalline structure of the LC2 formed and was crucial for complexing siRNA. The siRNA was released from the crystalline phase complexed with PEI. The release rate was dependent on the rate of water uptake. The formulation containing MO/PEI/PG/Tris buffer at 7.85:0.65:76.5:15 (w/w/w/w) complexed with 10 μM of siRNA, characterized as a mixture of cubic phase (diamond-type) and inverted hexagonal phase (after contact with excess water), showed sustained release for 7 days in vitro. In mice, in situ gel formation occurred after subcutaneous injection of the formulations, and the gels were degraded in 30 days. Initially a mild inflammatory process occurred in the tissue surrounding the gel; but after 14 days the tissue appeared normal. Taken together, this work demonstrates the rational development of an in situ gelling formulation for local release of siRNA.
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http://dx.doi.org/10.1016/j.ejps.2015.04.017DOI Listing
July 2015

Mucoadhesive system formed by liquid crystals for buccal administration of poly(hexamethylene biguanide) hydrochloride.

J Pharm Sci 2014 Dec 21;103(12):3914-3923. Epub 2014 Oct 21.

School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo 14040-903, Brazil.

Antimicrobial approaches are valuable in controlling the development of buccal diseases, but some antibacterial agents have a short duration of activity. Therefore, the development of prolonged delivery systems would be advantageous. Liquid crystalline systems comprising monoolein (GMO)/water have been considered to be a potential vehicle to deliver drugs to the buccal mucosa because of the phase properties that allow for controlled drug release as well as its mucoadhesive properties. Therefore, the aim of this study was to develop a GMO/water system for the slow release of poly(hexamethylene biguanide) hydrochloride (PHMB) on the buccal mucosa and test the properties of this system with regard to swelling, release profile, antimicrobial activity, and strength of mucoadhesion, with the overall goal of treating buccal infections. The tested systems were capable of modulating drug release, which is controlled by diffusion of the drug throughout the system. Furthermore, PHMB appeared to improve the mucoadhesive properties of the system and may synergistically act with the drug to promote antimicrobial activity against S. mutas and C. albicans, indicating that liquid crystals may be suitable for the administration of PHMB on the buccal mucosa. Therefore, this system could be proposed as a novel system for mucoadhesive drug delivery.
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http://dx.doi.org/10.1002/jps.24198DOI Listing
December 2014

Self-assembling gelling formulation based on a crystalline-phase liquid as a non-viral vector for siRNA delivery.

Eur J Pharm Sci 2014 Jul 12;58:72-82. Epub 2014 Apr 12.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, 14040-903 Ribeirão Preto, SP, Brazil. Electronic address:

Liquid crystalline systems (LCSs) form interesting drug delivery systems. These include in situ gelling delivery systems, which present several advantages for use as self-assembling systems for local drug delivery. The aim of this study was to develop and characterize in situ gelling delivery systems for local siRNA delivery. The influence of the components that form the systems was investigated, and the systems were characterized by polarized light microscopy, Small Angle X-ray Scattering (SAXS), swelling studies, assays of their ability to form a complex with genes and of the stability of the genes in the system, as well as assays of in situ gelling formation and local toxicity using an animal model. The system containing a mixture of monoglycerides (MO), oleylamine (OAM), propylene glycol (PG) and tris buffer (8.16:0.34:76.5:15, w/w/w/w) was considered the most appropriate for local siRNA delivery purposes. The molecular structure was characterized as hexagonal phase; the swelling studies followed a second order kinetic model and the water absorption was a fast process reaching equilibrium at 2 h. The system formed a complex with siRNA and remained in a stable form. The gel was formed in vivo after subcutaneous administration of a precursor fluid formulation in mice and was biodegradable in 30 days. The inflammatory process that took place was considered normal. Therefore, the developed liquid crystalline delivery system shows the appropriate characteristics for use as a local siRNA delivery method for gene therapy.
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http://dx.doi.org/10.1016/j.ejps.2014.04.001DOI Listing
July 2014

Surface treatment of dental porcelain: CO2 laser as an alternative to oven glaze.

Lasers Med Sci 2015 Feb 24;30(2):661-7. Epub 2013 Jul 24.

Departamento de Materiais Dentários, Faculdade de Odontologia, Universidade de São Paulo, Av. Prof. Lineu Prestes, 2227, Cidade Universitária "Armando Salles de Oliveira", São Paulo, SP, CEP 05508-900, Brazil.

This work tested continuous CO2 laser as a surface treatment to dental porcelain and compared it to oven glaze (auto-glaze) by means of roughness and color parameters. Three commercial veneering porcelains with different crystalline content were tested: VM7, VM9, and VM13. Porcelain discs (3.5 × 2.0 mm, diameter × height) were sintered and had one side ground by a diamond bur (45 μm) simulating a chairside adjustment in a clinical office. Specimens (n = 7) were divided into the following groups: C--control (no treatment), G--auto-glaze (oven), and L--surface continuous irradiation with CO2 laser (Gem Laser, Coherent; λ = 10.6 μm). Laser was tested in three exposure times (3, 4, or 5 min) and two irradiances (45 and 50 W/cm(2)). Roughness parameters (Ra, Rz, and Rpm/Rz) were measured using a rugosimeter (Surftest 301, Mitutoyo). Color differences (ΔE) between the G and L groups were calculated (VITA Easyshade); ΔE values up to 3.3 were considered as not perceivable. A surface analysis was conducted by stereomicroscopy (Olympus SZ61) and SEM (Stereoscan 440, LEO). Crystalline content of specimens from groups C and L (50 W/cm(2), 5 min) was assessed by X-ray diffraction and then compared. Surface roughness (Ra and Rz) observed for laser-irradiated groups was similar to G for all studied porcelains. Rpm/Rz ratios were near 1.0 for all groups that indicated a sharp ridge profile for all specimens. Only one laser condition studied (50 W/cm(2), 3 min) from VM7 porcelain resulted in color difference (ΔE = 3.5) to G. Specimens irradiated with 50 W/cm(2) for 5 min presented the smoother surface observed by SEM, comparable to G. X-ray diffraction data revealed an increase in leucite crystallite size for VM9 and VM13 porcelains after laser treatment. Regarding roughness, continuous CO2 laser applied on porcelain surface was as effective as conventional oven auto-glaze.
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http://dx.doi.org/10.1007/s10103-013-1392-4DOI Listing
February 2015

Nanostructured SBA-15 silica as an adjuvant in immunizations with hepatitis B vaccine.

Einstein (Sao Paulo) 2011 Dec;9(4):436-41

Immunochemistry Laboratory, Instituto Butantan, São Paulo, SP, BR.

Objective: To evaluate the applicability of SBA-15 silica as an adjuvant in immunizations with purified particles of the viral protein HBsAg, the main component of hepatitis B vaccine, Butang®, produced by Instituto Butantan.

Methods: BALB/c mice orally or subcutaneously received 0.5 μg of HBsAg adsorbed/encapsulated to SBA-15 or adsorbed to Al(OH)3. To assess the secondary immune response, a subcutaneous booster was administered 30 days after the first immunization. Individual serum and fecal samples of each group were periodically collected for specific antibody titration by ELISA.

Results: Analysis of secretory IgA showed that mice orally primed with HBsAg on SBA-15 had increased levels of specific antibodies in primary and secondary immune responses. Specific serum IgA and IgG titers in HBsAg:SBA-15-orally immunized mice reached higher levels after the booster, demonstrating the effectiveness of oral vaccination with the use of silica. All immunized groups showed higher IgG1 levels.

Conclusion: Our results clearly indicate the promising use of SBA-15 as an adjuvant, especially in oral immunizations.
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http://dx.doi.org/10.1590/S1679-45082011AO2162DOI Listing
December 2011