RESUMO
Combination therapy targeting both tumor growth and vascularization is considered to be a cornerstone for colorectal carcinomas (CRC) treatment. However, the major obstacles of most clinical anticancer drugs are their weak selective activity towards cancer cells and inherent inner organs toxicity, accompanied with fast drug resistance development. In our effort to discover novel selective and non-toxic agents effective against CRC, we designed, synthesized and characterized a series of rhenium(I) tricarbonyl-based complexes with increased lipophilicity. Two of these novel compounds were discovered to possess remarkable anticancer, anti-angiogenic and antimetastatic activity in vivo (zebrafish-human HCT-116 xenograft model), being effective at very low doses (1-3 µM). At doses as high as 250 µM the complexes did not provoke toxicity issues encountered in clinical anticancer drugs (cardio-, hepato-, and myelotoxicity). In vivo assays showed that the two compounds exceed the anti-tumor and anti-angiogenic activity of clinical drugs cisplatin and sunitinib malate, and display a large therapeutic window.
Assuntos
Neoplasias Colorretais/patologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Desenho de Fármacos , Rênio/química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Relação Dose-Resposta a Droga , Células HCT116 , Humanos , Metástase Neoplásica , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-ZebraRESUMO
A series of tricarbonyl manganese complexes bearing 4-ethynyl-2,2'-bipyridine and 5-ethynyl-1,10-phenanthroline α-diimine ligands were synthetized, characterized and conjugated to vitamin B12, previously used as a vector for drug delivery, to take advantage of its water solubility and specificity toward cancer cells. The compounds act as photoactivatable carbon monoxide-releasing molecules rapidly liberating on average ca. 2.3 equivalents of CO upon photo-irradiation. Complexes and conjugates were tested for their anticancer effects, both in the dark and following photo-activation, against breast cancer MCF-7, lung carcinoma A549 and colon adenocarcinoma HT29 cell lines as well as immortalized human bronchial epithelial cells 16HBE14o- as the non-carcinogenic control. Our results indicate that the light-induced cytotoxicity these molecules can be attributed to both their released CO and to their CO-depleted metal fragments including liberated ligands.
Assuntos
Monóxido de Carbono/química , Complexos de Coordenação/química , Luz , Manganês/química , Neoplasias/metabolismo , Células A549 , Monóxido de Carbono/metabolismo , Complexos de Coordenação/metabolismo , Cristalografia por Raios X/métodos , Células HT29 , Humanos , Ligantes , Células MCF-7 , Manganês/metabolismo , Neoplasias/patologia , Compostos Organometálicos/química , Compostos Organometálicos/metabolismo , Fenantrolinas/química , Fotólise , Solubilidade , Vitamina B 12/metabolismoRESUMO
Systemic toxicity and severe side effects are commonly associated with anticancer chemotherapies. New strategies based on enhanced drug selectivity and targeted delivery to cancer cells while leaving healthy tissue undamaged can reduce the global patient burden. Herein, we report the design, synthesis and characterization of a bio-inspired hybrid multifunctional drug delivery system based on diatom microalgae. The microalgae's surface was chemically functionalized with hybrid vitamin B12-photoactivatable molecules and the materials further loaded with highly active rhenium(I) tricarbonyl anticancer complexes. The constructs showed enhanced adherence to colorectal cancer (CRC) cells and slow release of the chemotherapeutic drugs. The overall toxicity of the hybrid multifunctional drug delivery system was further enhanced by photoactivation of the microalgae surface. Depending on the construct and anticancer drug, a 2-fold increase in the cytotoxic efficacy of the drug was observed upon light irradiation. The use of this targeted drug delivery strategy, together with selective spatial-temporal light activation, may lead to lower effective concentration of anticancer drugs, thereby reducing medication doses, possible side effects and overall burden for the patient.
RESUMO
Herein we report the synthesis of a new biomaterial designed for targeted delivery of poorly water-soluble inorganic anticancer drugs, with a focus on colorectal cancer. Diatomaceous earth microparticles derived from marine microalgae were coated with vitamin B12 (cyanocobalamin) as a tumor targeting agent and loaded with the well-known anticancer agents cisplatin, 5-fluorouracil (5-FU), and a tris-tetraethyl[2,2'-bipyridine]-4,4'-diamine-ruthenium(ii) complex. The successful functionalization of the biomaterial was demonstrated by different analytical techniques and by synthesizing an organometallic fluorescein analogue of cyanocobalamin detectable by confocal laser scanning microscopy. The drug releasing properties were evaluated for all three species. We found that while cisplatin and 5-FU are rapidly lost from the material, the ruthenium complex showed an unprecedented release profile, being retained in the material up to 5 days in aqueous media but readily released in lipophilic environments as in the cell membrane. The increased adherence of the B12 coated diatoms to colorectal cancer cell line HT-29 and breast cancer cell line MCF-7 was demonstrated in vitro. In both cases, the adherence of the B12 modified diatoms was at least 3 times higher than that of the unmodified ones and was correlated with the increased transcobalamin II (TC(II)) and transcobalamin II receptor (TC(II)-R) expression of the targeted tissue. Our results suggest that this type of B12 modified diatoms could be a promising tool to achieve targeted delivery of water insoluble inorganic complexes to tumor tissues by acting as a micro-shuttle interacting with the sites of interest before delivering the drug in the vicinity of the tumor tissue.