5-Fluorouracil (5-FU) is used for the topical treatment of pre-cancerous skin lesions. However, p... more 5-Fluorouracil (5-FU) is used for the topical treatment of pre-cancerous skin lesions. However, previous reports focus on 5-FU quantification in plasma samples, failing to provide information about drug quantification in the skin. Therefore, the aim of this work was to develop a simple and reliable analytical method employing HPLC-UV for 5-FU quantification in skin samples. Chromatographic separation was obtained using the commonly available Lichrospher RP-C18 endcapped column. Porcine ear skin matrix-based analytical curves with thymine, as internal standard, were used. 5-FU was eluted at 5.2 min and thymine at 13.0 min. The method was selective, precise and accurate in the linear range from 0.3 to 6 μg/mL. The samples were stable after three cycles of freeze/thawing and extraction efficiency rates above 95% were obtained. In vitro skin penetration studies of an aqueous solution and a commercial cream of 5-FU were performed. The cream improved 5-FU retention into the skin and permeation through the skin compared to the solution. Therefore, the method developed herein can be applied to the study of formulations for topical delivery of 5-FU.
Prolonged skin exposure to ultraviolet radiation (UVR) induces premature aging in both the epider... more Prolonged skin exposure to ultraviolet radiation (UVR) induces premature aging in both the epidermis and the dermis. Chronic exposure to UVR induces the activation of mitogen‐activated protein kinase (MAPK) signaling pathway, activating c‐Jun, c‐Fos expression, and transcription factor of AP‐1 activating protein. AP‐1 activation results in the positive induction of matrix metalloproteinase (MMP) synthesis, which degrade skin collagen fibers. Polysaccharides from the fruit of Lycium barbarum (LBP fraction) have a range of activities and have been demonstrate to repair the photodamage. In different approaches, laser application aims to recover the aged skin without destroying the epidermis, promoting a modulation, called photobiomodulation (PBM), which leads to protein synthesis and cell proliferation, favoring tissue repair. Here we developed a topical hydrogel formulation from a polysaccharide‐rich fraction of Lycium barbarum fruits (LBP). This formulation was associated with PBM (r...
Abstract Ultraviolet B (UVB) irradiation causes free radical production, increase inflammation an... more Abstract Ultraviolet B (UVB) irradiation causes free radical production, increase inflammation and oxidative stress, thus, supporting the use of antioxidants by topical administration as therapeutic approaches. Quercetin (QC) is a flavonoid with antioxidant activity, however, high liposolubility makes it difficult to remain in the viable skin layer. Thus, this study evaluated whether microencapsulation of QC would enhance its activity in comparison with the same dose of free QC (non-active dose) and unloaded-microcapsules added in formulation for topical administration in a mouse model of UVB irradiation targeting the skin. Topical formulation containing Quercetin-loaded microcapsules (TFcQCMC) presents physico-chemical (colour, consistence, phase separation and pH) and functional antioxidant stability at 4 °C, room temperature and 40 °C for 6 months. TFcQCMC inhibited the UVB-triggered depletion of antioxidants observed by GSH (reduced glutathione), ability to reduce iron, ability to scavenge 2,2’-azinobis radical and catalase activity. TFcQCMC also inhibited markers of oxidation (lipid hydroperoxides and superoxide anion production). Concerning inflammation, TFcQCMC reduced the production of inflammatory cytokines, matrix metalloproteinase-9 activity, skin edoema, collagen fibre damage, myeloperoxidase activity/neutrophil recruitment, mast cell and sunburn cell counts. The pharmacological activity of TFcQCMC was not shared by the same pharmaceutical form containing the same dose of free QC or unloaded control microcapsules.
Abstract Topical application of drugs is the choice route of administration for treating skin dis... more Abstract Topical application of drugs is the choice route of administration for treating skin diseases. The stratum corneum, a natural skin barrier, protects the body against external agents but also limits penetration of topically applied drugs into deeper skin layers. Nanoparticles are nano-sized drug delivery systems with several advantages for topical administration, including protection against drug degradation and sustained drug delivery, leading to a more effective and less toxic treatment, compared to conventional topically applied formulations. Nanoparticle interactions and distribution within the skin, whether associated or not with physical methods like iontophoresis, modifies drugs penetration. It is, consequently, important to evaluate nanoparticle characteristics which bring about these interactions. Therefore, this chapter will address nanoparticle characteristics affecting skin drug penetration, their possible penetration pathways, in addition to in vitro and in vivo techniques commonly used in assessing penetration and distribution of drugs into the skin when nanoparticles are used as topical delivery systems.
Targeted therapy has been recently highlighted due to the reduction of side effects and improveme... more Targeted therapy has been recently highlighted due to the reduction of side effects and improvement in overall efficacy and survival from different types of cancers. Considering the approval of many monoclonal antibodies in the last twenty years, cancer treatment can be accomplished by the combination of monoclonal antibodies and small molecule chemotherapeutics. Thus, strategies to combine both drugs in a single administration system are relevant in the clinic. In this context, two strategies are possible and will be further discussed in this review: antibody-drug conjugates (ADCs) and antibody-functionalized nanoparticles. First, it is important to better understand the possible molecular targets for cancer therapy, addressing different antigens that can selectively bind to antibodies. After selecting the best target, ADCs can be prepared by attaching a cytotoxic drug to an antibody able to target a cancer cell antigen. Briefly, an ADC will be formed by a monoclonal antibody (MAb), a cytotoxic molecule (cytotoxin) and a chemical linker. Usually, surface-exposed lysine or the thiol group of cysteine residues are used as anchor sites for linker-drug molecules. Another strategy that should be considered is antibody-functionalized nanoparticles. Basically, liposomes, polymeric and inorganic nanoparticles can be attached to specific antibodies for targeted therapy. Different conjugation strategies can be used, but nanoparticles coupling between maleimide and thiolated antibodies or activation with the addition of ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)/ N-hydroxysuccinimide (NHS) (1:5) and further addition of the antibody are some of the most used strategies. Herein, molecular targets and conjugation strategies will be presented and discussed to better understand the in vitro and in vivo applications presented. Also, the clinical development of ADCs and antibody-conjugated nanoparticles are addressed in the clinical development section. Finally, due to the innovation related to the targeted therapy, it is convenient to analyze the impact on patenting and technology. Information related to the temporal evolution of the number of patents, distribution of patent holders and also the number of patents related to cancer types are presented and discussed. Thus, our aim is to provide an overview of the recent developments in immunoconjugates for cancer targeting and highlight the most important aspects for clinical relevance and innovation.
Nanoparticles have been extensively employed to deliver many drugs, including siRNA, for the trea... more Nanoparticles have been extensively employed to deliver many drugs, including siRNA, for the treatment of a variety of diseases, particularly cancer. Lately, there has been a great deal of effort to design nanoparticles with materials that are able to respond to intrinsic or extrinsic stimuli for "on…
5-Fluorouracil (5-FU) is used for the topical treatment of pre-cancerous skin lesions. However, p... more 5-Fluorouracil (5-FU) is used for the topical treatment of pre-cancerous skin lesions. However, previous reports focus on 5-FU quantification in plasma samples, failing to provide information about drug quantification in the skin. Therefore, the aim of this work was to develop a simple and reliable analytical method employing HPLC-UV for 5-FU quantification in skin samples. Chromatographic separation was obtained using the commonly available Lichrospher RP-C18 endcapped column. Porcine ear skin matrix-based analytical curves with thymine, as internal standard, were used. 5-FU was eluted at 5.2 min and thymine at 13.0 min. The method was selective, precise and accurate in the linear range from 0.3 to 6 μg/mL. The samples were stable after three cycles of freeze/thawing and extraction efficiency rates above 95% were obtained. In vitro skin penetration studies of an aqueous solution and a commercial cream of 5-FU were performed. The cream improved 5-FU retention into the skin and permeation through the skin compared to the solution. Therefore, the method developed herein can be applied to the study of formulations for topical delivery of 5-FU.
Prolonged skin exposure to ultraviolet radiation (UVR) induces premature aging in both the epider... more Prolonged skin exposure to ultraviolet radiation (UVR) induces premature aging in both the epidermis and the dermis. Chronic exposure to UVR induces the activation of mitogen‐activated protein kinase (MAPK) signaling pathway, activating c‐Jun, c‐Fos expression, and transcription factor of AP‐1 activating protein. AP‐1 activation results in the positive induction of matrix metalloproteinase (MMP) synthesis, which degrade skin collagen fibers. Polysaccharides from the fruit of Lycium barbarum (LBP fraction) have a range of activities and have been demonstrate to repair the photodamage. In different approaches, laser application aims to recover the aged skin without destroying the epidermis, promoting a modulation, called photobiomodulation (PBM), which leads to protein synthesis and cell proliferation, favoring tissue repair. Here we developed a topical hydrogel formulation from a polysaccharide‐rich fraction of Lycium barbarum fruits (LBP). This formulation was associated with PBM (r...
Abstract Ultraviolet B (UVB) irradiation causes free radical production, increase inflammation an... more Abstract Ultraviolet B (UVB) irradiation causes free radical production, increase inflammation and oxidative stress, thus, supporting the use of antioxidants by topical administration as therapeutic approaches. Quercetin (QC) is a flavonoid with antioxidant activity, however, high liposolubility makes it difficult to remain in the viable skin layer. Thus, this study evaluated whether microencapsulation of QC would enhance its activity in comparison with the same dose of free QC (non-active dose) and unloaded-microcapsules added in formulation for topical administration in a mouse model of UVB irradiation targeting the skin. Topical formulation containing Quercetin-loaded microcapsules (TFcQCMC) presents physico-chemical (colour, consistence, phase separation and pH) and functional antioxidant stability at 4 °C, room temperature and 40 °C for 6 months. TFcQCMC inhibited the UVB-triggered depletion of antioxidants observed by GSH (reduced glutathione), ability to reduce iron, ability to scavenge 2,2’-azinobis radical and catalase activity. TFcQCMC also inhibited markers of oxidation (lipid hydroperoxides and superoxide anion production). Concerning inflammation, TFcQCMC reduced the production of inflammatory cytokines, matrix metalloproteinase-9 activity, skin edoema, collagen fibre damage, myeloperoxidase activity/neutrophil recruitment, mast cell and sunburn cell counts. The pharmacological activity of TFcQCMC was not shared by the same pharmaceutical form containing the same dose of free QC or unloaded control microcapsules.
Abstract Topical application of drugs is the choice route of administration for treating skin dis... more Abstract Topical application of drugs is the choice route of administration for treating skin diseases. The stratum corneum, a natural skin barrier, protects the body against external agents but also limits penetration of topically applied drugs into deeper skin layers. Nanoparticles are nano-sized drug delivery systems with several advantages for topical administration, including protection against drug degradation and sustained drug delivery, leading to a more effective and less toxic treatment, compared to conventional topically applied formulations. Nanoparticle interactions and distribution within the skin, whether associated or not with physical methods like iontophoresis, modifies drugs penetration. It is, consequently, important to evaluate nanoparticle characteristics which bring about these interactions. Therefore, this chapter will address nanoparticle characteristics affecting skin drug penetration, their possible penetration pathways, in addition to in vitro and in vivo techniques commonly used in assessing penetration and distribution of drugs into the skin when nanoparticles are used as topical delivery systems.
Targeted therapy has been recently highlighted due to the reduction of side effects and improveme... more Targeted therapy has been recently highlighted due to the reduction of side effects and improvement in overall efficacy and survival from different types of cancers. Considering the approval of many monoclonal antibodies in the last twenty years, cancer treatment can be accomplished by the combination of monoclonal antibodies and small molecule chemotherapeutics. Thus, strategies to combine both drugs in a single administration system are relevant in the clinic. In this context, two strategies are possible and will be further discussed in this review: antibody-drug conjugates (ADCs) and antibody-functionalized nanoparticles. First, it is important to better understand the possible molecular targets for cancer therapy, addressing different antigens that can selectively bind to antibodies. After selecting the best target, ADCs can be prepared by attaching a cytotoxic drug to an antibody able to target a cancer cell antigen. Briefly, an ADC will be formed by a monoclonal antibody (MAb), a cytotoxic molecule (cytotoxin) and a chemical linker. Usually, surface-exposed lysine or the thiol group of cysteine residues are used as anchor sites for linker-drug molecules. Another strategy that should be considered is antibody-functionalized nanoparticles. Basically, liposomes, polymeric and inorganic nanoparticles can be attached to specific antibodies for targeted therapy. Different conjugation strategies can be used, but nanoparticles coupling between maleimide and thiolated antibodies or activation with the addition of ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC)/ N-hydroxysuccinimide (NHS) (1:5) and further addition of the antibody are some of the most used strategies. Herein, molecular targets and conjugation strategies will be presented and discussed to better understand the in vitro and in vivo applications presented. Also, the clinical development of ADCs and antibody-conjugated nanoparticles are addressed in the clinical development section. Finally, due to the innovation related to the targeted therapy, it is convenient to analyze the impact on patenting and technology. Information related to the temporal evolution of the number of patents, distribution of patent holders and also the number of patents related to cancer types are presented and discussed. Thus, our aim is to provide an overview of the recent developments in immunoconjugates for cancer targeting and highlight the most important aspects for clinical relevance and innovation.
Nanoparticles have been extensively employed to deliver many drugs, including siRNA, for the trea... more Nanoparticles have been extensively employed to deliver many drugs, including siRNA, for the treatment of a variety of diseases, particularly cancer. Lately, there has been a great deal of effort to design nanoparticles with materials that are able to respond to intrinsic or extrinsic stimuli for "on…
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Papers by Renata Fonseca Vianna Lopez