RESUMO
Glucocorticoid and Mineralocorticoid receptors are principally ligand-dependent intracellular transcription factors that are known to influence the development and growth of many human cancers. Our study investigates the potential of these receptors to act as a target for oral cancer treatment since findings in this regard are sparse till date. Leveraging the aberrant behavior of steroid hormone receptors (SHRs) in cancer, we have targeted oral cancer cells in 2D-culture using liposomes containing both synthetic as well as crude, natural SHR ligands isolated from an aqueous Indian medicinal plant. Lipoplexes thus formulated demonstrated targeted transfectability as indicated by expression of green fluorescent protein. Transfection of oral squamous cell carcinoma cells with exogenous, anticancer gene p53 lipoplexed with crude saponin-based liposome induced apoptosis of cancer cells via regulation of BAX and B-cell leukemia/lymphoma-2 (BCL2) protein levels at levels comparable with pre-established delivery systems based on synthetic SHR ligands. Our findings strongly indicate a possibility of developing plant saponin-based inexpensive delivery systems which would target cancer cells selectively with reduced risks of off target delivery and its side effects.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Saponinas , Humanos , Neoplasias Bucais/terapia , Transfecção , Lipossomos , Hormônios , EsteroidesRESUMO
Microbial infections due to biofilms on medical implants can be prevented by antimicrobial coatings on biomaterial surfaces. Mesoporous silica nanoparticles (MSNPs) were synthesized via base-catalyzed sol-gel process at room temperature, functionalized with phenazine-1-carboxamide (PCN) and characterized by UV-visible, FT-IR, DLS, XRD spectroscopic techniques, SEM, TEM, TGA and BET analysis. Native MSNPs, PCN and PCN-MSNPs were evaluated for anti-Candida minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), Candida albicans (C. albicans) biofilms and C. albicans-Staphylococcus aureus (S. aureus) polymicrobial biofilm inhibition. PCN-MSNPs were four-fold effective (MIC 3.9 µg mL-1; 17.47 µM) and MFC (7.8 µg mL-1; 34.94 µM) as compared to pure PCN (MIC 15.6 µg mL-1; 69.88 µM) and MFC (31.2 µg mL-1; 139.76 µM). PCN-MSNPs inhibited in vitro C. albicans MTCC 227-S. aureus MTCC 96 biofilms at very low concentration (10 µg mL-1; 44.79 µM) as compared to pure PCN (40 µg mL-1; 179.18 µM). Mechanistic studies revealed that PCN induced intracellular ROS accumulation in C. albicans MTCC 227, S. aureus MTCC 96 and S. aureus MLS-16 MTCC 2940, reduction in total ergosterol content, membrane permeability, disruption of ionic homeostasis followed by Na+, K+ and Ca2+ leakage leading to cell death in C. albicans MTCC 227 as confirmed by confocal laser scanning micrographs. The silicone urethral catheters coated with PCN-MSNPs (500 µg mL-1; 2.23 mM) exhibited no formation of C. albicans MTCC 227 - S. aureus MTCC 96 and C. albicans MTCC 227 - S. aureus MLS -16 MTCC 2940 biofilms. This is the first report on PCN-MSNPs for use as antimicrobial coatings against microbial adhesion and biofilm formation on silicone urethral catheters.
Assuntos
Anti-Infecciosos/uso terapêutico , Materiais Revestidos Biocompatíveis/química , Controle de Infecções/métodos , Nanopartículas/química , Cateteres Urinários , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/uso terapêutico , Testes de Sensibilidade Microbiana , Nanopartículas/uso terapêutico , Fenazinas/química , Dióxido de Silício/química , Silicones , Staphylococcus aureus/efeitos dos fármacos , Cateteres Urinários/microbiologiaRESUMO
In the present article, we report the in vitro and in vivo delivery of doxorubicin using biosynthesized gold nanoparticles (b-Au-PP). Gold nanoparticles were synthesized by a simple, fast, efficient, environmentally friendly and economical green chemistry approach using an extract of Peltophorum pterocarpum (PP) leaves. Because the biosynthesized b-Au-PP was highly stable in various physiological buffers for several weeks and biocompatible in both in vitro and in vivo systems, we designed and developed a biosynthesized gold nanoparticle (b-Au-PP)-based drug-delivery system (DDS) using doxorubicin (Dox) (b-Au-PP-Dox). Both b-Au-PP and b-Au-PP-Dox were thoroughly characterized using several analytical tools. Administration of doxorubicin-loaded DDS (b-Au-PP-Dox) resulted in a significant inhibition of the proliferation of cancer cells (A549, B16F10) in vitro and of tumor growth in an in vivo model compared to doxorubicin alone. Furthermore, we found that the cellular uptake and release of Dox in the nanoconjugated form (b-Au-PP-Dox) were faster than the uptake and release of unconjugated Dox. The in vivo toxicity study did not show any significant changes in the hematology, serum clinical biochemistry or histopathology in the C57BL6/J female mice after consecutive intraperitoneal (IP) injections over a period of seven days. To the best of our knowledge, our study is the first to report the application of a biosynthesized gold nanoparticle-based DDS for cancer therapy in an animal model, in addition to a detailed in vivo toxicity study. Together, the results demonstrate that a biosynthesized gold nanoparticle-based drug-delivery system (b-Au-PP-Dox) could be used in the near future as an alternative cost-effective treatment strategy for cancer therapy.
Assuntos
Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Fabaceae/química , Nanocápsulas/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Animais , Antibióticos Antineoplásicos/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Feminino , Ouro/química , Química Verde/métodos , Taxa de Depuração Metabólica , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Nanocápsulas/ultraestrutura , Neoplasias Experimentais/patologia , Especificidade de Órgãos , Extratos Vegetais/química , Distribuição Tecidual , Resultado do TratamentoRESUMO
Aggressive melanoma is commonly associated with rapid angiogenic growth in tumor mass, tumor cells acquiring apoptosis resistance, inhibition of cellular differentiation etc. Designing a single anticancer molecule which will target all these factors simultaneously is challenging. In the pretext of inciting anticancer effect through inhibiting nitric oxide synthase (NOS) via estrogen receptors (ER) in ER-expressing skin cancer cells, we developed an estrogen-linked L-nitro-arginine molecule (ESAr) for inciting anticancer effect in melanoma cells. ESAr showed specific anticancer effect through diminishing aggressiveness and metastatic behavior in melanoma cells and tumor. In comparison, ESAr showed significantly higher antiproliferative effect than parent molecule L-nitroarginine methyl ester (L-NAME, a NOS inhibitor) through induction of prominent apoptosis in melanoma cells. ESAr-pretreated aggressive melanoma cells could not form tumor possibly because of transformation/differentiation into epithelial-type cells. Furthermore, its antiangiogenic effect was demonstrated through ESAr-induced antiproliferation in HUVEC cells and apoptosis-induction in tumor-associated vascular endothelial cells, thereby significantly restricting severe growth in melanoma tumor. The targeting moiety, estrogen, at the therapeutic concentration of ESAr has apparently no effect in tumor-growth reduction. Albeit, no specific NOS-inhibition was observed, but ESAr could simultaneously induce these three cancer-specific antiaggressiveness factors, which the parent molecule could not induce. Our data rationalize and establish a new use of estrogen as a ligand for potentially targeting multiple cellular factors for treating aggressive cancers.