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Irinotecan (IRN) is a semisynthetic derivative of camptothecin that acts as a topoisomerase I inhibitor. IRN is used worldwide for the treatment of several types of cancer, including colorectal cancer, however its use can lead to serious adverse effects, as diarrhea and myelosuppression. Liposomes are widely used as drug delivery systems that can improve chemotherapeutic activity and decrease side effects. Liposomes can also be pH-sensitive to release its content preferentially in acidic environments, like tumors, and be surface-functionalized for targeting purposes. Herein, we developed a folate-coated pH-sensitive liposome as a drug delivery system for IRN to reach improved tumor therapy without potential adverse events. Liposomes were prepared containing IRN and characterized for particle size, polydispersity index, zeta potential, concentration, encapsulation, cellular uptake, and release profile. Antitumor activity was investigated in a murine model of colorectal cancer, and its toxicity was evaluated by hematological/biochemical tests and histological analysis of main organs. The results showed vesicles smaller than 200 nm with little dispersion, a surface charge close to neutral, and high encapsulation rate of over 90%. The system demonstrated prolonged and sustained release in pH-dependent manner with high intracellular drug delivery capacity. Importantly, the folate-coated pH-sensitive formulation had significantly better antitumor activity than the pH-dependent system only or the free drug. Tumor tissue of IRN-containing groups presented large areas of necrosis. Furthermore, no evidence of systemic toxicity was found for the groups investigated. Thus, our developed nanodrug IRN delivery system can potentially be an alternative to conventional colorectal cancer treatment.

Resumen Objetivo El cancer de mama es un problema de salud en todo el mundo, con altas tasas de incidencia y mortalidad. Es bien sabido que el desarrollo de metodos de diagnostico mas sensibles y especificos es de gran importancia, ya que un diagnostico precoz es esencial para tratar con exito los tumores. Lapachol es un compuesto natural, perteneciente al grupo de la naftoquinona, que se ha utilizado ampliamente en la medicina tradicional para tratar diversas enfermedades, incluido el cancer. El objetivo de este estudio fue evaluar el lapachol marcado con tecnecio 99m (99mTc) como una sonda de imagenes para la identificacion del cancer de mama. Metodos Para lograr este proposito, el lapachol se marco con 99mTc, se determino la pureza radioquimica y la estabilidad in vitro. Tambien se evaluo el aclaramiento en sangre en ratones sanos y la biodistribucion en ratones con tumor 4T1. Resultados Lapachol fue exitosamente marcado con 99mTc, con altos valores de rendimiento radioquimico (95,9 ± 3,4%). La estabilidad in vitro mostro que el complejo radiomarcado permanecio estable hasta 24 h, con valores superiores al 90% tanto para solucion salina como para plasma (95,6 ± 3,6% y 96,4 ± 1,7%, respectivamente). El complejo radiomarcado decae de forma bifasica, con una vida media de distribucion y eliminacion igual a 3,3 y 50,0 min, respectivamente. La biodistribucion y las imagenes gammagraficas mostraron una alta captacion en los organos de excrecion (rinones, higado e intestino). Tambien se puede observar que la captacion tumoral fue mayor que en el musculo en todos los puntos temporales. La relacion de tumor/musculo alcanza ∼4,5 a las 24 h despues de la administracion. Conclusion Estos hallazgos indican que 99mTc-lapachol puede ser un potencial agente de diagnostico para los tumores de mama.

Aim Breast cancer is a health problem worldwide with high incidence and mortality rates. It is well known that the development of more sensitive and specific diagnostic methods is of great importance since an early diagnosis is essential to successfully treat tumors. Lapachol is a natural compound, belonging to the naphthoquinone group that has been widely used in traditional medicine to treat various illnesses, including cancer. The aim of this study was to evaluate technetium-99m-labeled lapachol as an imaging probe for breast cancer identification. Methods To achieve this purpose, lapachol was labeled with technetium-99m, radiochemical purity and in vitro stability were determined. Blood clearance, in healthy mice, and biodistribution, in 4T1 tumor-bearing mice, were also evaluated. Results Lapachol was successfully labeled with technetium-99m, with high values of radiochemical yield (95.9 ± 3.4%). In vitro stability showed that the radiolabeled complex remained stable for up to 24 h, with values above 90% for both saline and plasma (95.6 ± 3.6% and 96.4 ± 1.7%, respectively). The radiolabeled complex decays in a biphasic manner, with a half-life of distribution and elimination equal to 3.3 and 50.0 min, respectively. Biodistribution and scintigraphic images showed high uptake in organs of excretion (kidneys, liver, and intestine). It could be also noted that tumor uptake was higher than the muscle at all time points. Tumor-to-muscle ratio reaches ∼4.5 at 24 h after administration. Conclusion These findings suggest that 99mTc-Lapachol can be a potential diagnostic agent for breast tumors.

Single-walled carbon nanotubes (SWCNT) are raising interest in biomedical field, as a drug delivery system, due to their large payload capacity and rich surface chemistry that allows attaching molecules. Generally, carbon nanotubes, without any surface modifications are cytotoxic to certain mammalian cells. However, after their functionalization, they become biocompatible and non-immunogenic. Thus, the aim of this work was to evaluate the effect of functionalization groups on the biocompatibility of SWCNT in vitro, as well as on its biodistribution in tumor-bearing mice. In this approach, carboxylate and bisphosphonate functionalized SWCNT were successfully synthesized and characterized by Raman, FTIR, and TGA techniques. The in vitro cytotoxicity against HEK-293 cells, and hemolysis assay were carried out and the results revealed important biocompatibility profile for both functionalized nanotubes. Furthermore, both types of SWCNT were successful radiolabeled with technetium-99 m, and biodistribution studies were conducted in Ehrlich tumor-bearing Swiss mice, showing higher tumor uptake by bisphosphonated SWCNT compared to carboxylated nanotubes. Moreover, acute toxicity study was performed in healthy Swiss mice revealing that none of the nanotubes displayed hematological, hepatic or renal toxicity. From all obtained results, the bisphosphonate functionalized SWCNT can be considered a plausible and alternative drug delivery platform for theranostic and therapeutics purposes.

Lapachol (LAP) is a natural compound with various biological properties, including anticancer activity. However, its clinical application is limited due to the low aqueous solubility and potential adverse side effects. Nanoemulsions are drug delivery systems that can assist in the administration of hydrophobic drugs, increasing their bioavailability and protecting from degradation. Thus, this study aimed to prepare a LAP-loaded nanoemulsion (NE-LAP), and evaluate its antitumor activity. For this purpose, the nanoemulsion was prepared using a hot homogenization method and characterized morphologically by cryogenic transmission electron microscopy (cryo-TEM). Mean diameter, polydispersity index, and zeta potential was evaluated by DLS, encapsulation efficiency was measured by HPLC. Moreover, the short-term storage stability, the drug release and hemolysis in vitro was determined. Additionally, pharmacokinetic, toxicology and toxicity properties of99mTc-NE-LAP were evaluated in a breast cancer (4T1) tumor model. The cryo-TEM showed spherical globules, and the physicochemical characterization of NE-LAP showed a homogeneous stable nanoemulsion with a mean diameter of ∼170 nm, zeta potential of around −20 mV, and encapsulation greater than 85 %. In vitro studies validated that encapsulation did not impair the cytotoxicity activity of LAP. The nanoemulsion was successfully radiolabeled and 99mTc-NE-LAP showed prolonged blood circulation and tumor affinity was confirmed by tumor-to-muscle ratio. Moreover, NE-LAP showed higher antitumor activity than the free drug and the treatment did not result in any signs of toxicity. Therefore, these findings suggest that NE-LAP can be considered an effective strategy for cancer treatment.

Gadodiamide (Gd-DTPA-BMA) is a gadolinium-based complex, used as a contrast agent in magnetic resonance imaging procedures. Recent studies revealed the capacity of this complex of inducing apoptosis in neoplastic cells. However, a great challenge for its use as an anticancer drug is low cellular internalization and drug delivery systems such as thermosensitive liposomes can be a strategy to overcome these limitations and increase anti-tumor efficacy. In this context, this study aimed to develop, characterize, and assess the cytotoxic activity and selectivity index of thermosensitive liposomes containing Gd-DTPA-BMA. Formulations were prepared by the lipid film hydration method and their physicochemical, morphological, and thermal properties were evaluated. Cell viability was performed 4T1/MDA-MB-231 tumor cells and WI-26 VA4 normal cells. Transmission electron microscopy analyses showed high electron density in the inner core of Gd-DTPA-BMA-loaded liposomes that can be attributed to the Gd-DTPA-BMA, since Gd-loaded nanosystems present low light transmittance and high electron density by this technique. The dynamic light scattering, differential scanning calorimetry, small-angle X-ray scattering, and in vitro release results confirm that the lipid composition was suitable since Tc (temperature of the transition Lβ → Lα) values are in accordance with those reported for thermosensitive liposomes used in the treatment of cancer. The cytotoxic studies against breast cancer cell lines demonstrated that the Gd-DTPA-BMA-loaded liposomes have higher cytotoxicity than free Gd-DTPA-BMA. Moreover, these liposomes presented minimal toxicity in a normal cell line when compared to the free Gd-DTPA-BMA. Therefore, the results of this study suggest that thermosensitive liposomes containing Gd-DTPA-BMA might be a new promising nanocarrier system for breast cancer treatment.

Despite the wide use of paclitaxel (PTX) as antitumor drug, its intravenous administration is still limited by the low aqueous solubility (