RESUMO
Topical application of aluminum-chloride phthalocyanine (AlClPc) is a challenge because of the drug's extremely low solubility, which prevents its absorption into deeper skin layers and causes molecule aggregation, reducing the photophysical effect. The goal of this study was to obtain a formulation applied in a certain condition that would allow homogeneous accumulation of AlClPc in cutaneous tissues, meaning a safer and non-invasive topical treatment for skin tumors based on photodynamic therapy. We first prepared and characterized AlClPc complexes with cyclodextrin to increase the photosensitizing agent solubility. The inclusion complex of AlClPc with hydroxypropyl-ß-cyclodextrin (HP-ßCD) amplified its loading dose in aqueous medium and maintained its photosensitizing properties in terms of reactive oxygen species production. Assays to determine the complex's in vitro cytotoxicity against murine melanoma skin cancer cells showed that when irradiated, the complex significantly reduced cell viability, whereas the absence of irradiation did not affect cell viability. Three physical techniques for permeation enhancement (i.e., tape-stripping abrasion, microneedle pretreatment and iontophoresis) were then evaluated. When applied in impaired skin, the complex could not increase drug penetration. The skin penetration of AlClPc, however, increased 2.3-fold following iontophoresis application in a shorter period compared to passive permeation. Therefore, these results suggest the administration of complexed AlClPc mediated by iontophoresis, followed by application of photodynamic therapy, might be an effective and non-invasive alternative for topical treatment of cutaneous tumors.
Assuntos
2-Hidroxipropil-beta-Ciclodextrina/administração & dosagem , Cloreto de Alumínio/administração & dosagem , Indóis/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Compostos Organometálicos/administração & dosagem , Fármacos Fotossensibilizantes/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , 2-Hidroxipropil-beta-Ciclodextrina/química , Administração Cutânea , Cloreto de Alumínio/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Indóis/química , Iontoforese , Camundongos , Compostos Organometálicos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/química , Pele/metabolismo , Absorção Cutânea , SuínosRESUMO
BACKGROUND: Magnetic fluids containing superparamagnetic iron oxide nanoparticles represent an attractive platform as nanocarriers in chemotherapy. Recently, we developed a formulation of maghemite nanoparticles coated with rhodium (II) citrate, which resulted in in vitro cytotoxicity enhanced up to 4.6 times when compared to free rhodium (II) citrate formulation on breast carcinoma cells. In this work, we evaluate the antitumor activity and toxicity induced by these formulations in Balb/c mice bearing orthotopic 4T1 breast carcinoma. METHODS: Mice were evaluated with regard to the treatments' toxicity through analyses of hemogram, serum levels of alanine aminotransferase, iron, and creatinine; DNA fragmentation and cell cycle of bone marrow cells; and liver, kidney and lung histology. In addition, the antitumor activity of rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate was verified by tumor volume reduction, histology and immunohistochemistry. RESULTS: Regarding the treatments' toxicity, no experimental groups had alterations in levels of serum ALT or creatinine, and this suggestion was corroborated by the histopathologic examination of liver and kidney of mice. Moreover, DNA fragmentation frequency of bone marrow cells was lower than 15% in all experimental groups. On the other hand, the complexes rhodium (II) citrate-functionalized maghemite and free rhodium (II) citrate led to a marked growth inhibition of tumor and decrease in CD31 and Ki-67 staining. CONCLUSIONS: In summary, we demonstrated that both rhodium (II) citrate and maghemite nanoparticles coated with rhodium (II) citrate formulations exhibited antitumor effects against 4T1 metastatic breast cancer cell line following intratumoral administration. This antitumor effect was followed by inhibition of both cell proliferation and microvascularization and by tumor tissue injury characterized as necrosis and fibrosis. Remarkably, this is the first published report demonstrating the therapeutic efficacy of maghemite nanoparticles coated with rhodium (II) citrate. This treatment prolonged the survival period of treated mice without inducing apparent systemic toxicity, which strengthens its use for future breast cancer therapeutic applications.