Toxicological Issues Faced after Liposomes Administration

Nanoparticles are defined as structures in nanometric range-often smaller than 100 nm [1-4]. These particles can be made of sundry materials, the most common being metals, metal oxides, silicates,&nbsp; polymers, carbon, lipids and biomolecules. In addition, they can assume different shapes such as spheres, cylinders, platelets, tubes, etc. The study of these structures in living organisms, for diagnosis, monitoring physical and pathologic processes, therapy and control of biological systems is known as nanomedicine [1]. The study and development of these nanoparticles, mainly lipid carriers, has gained great notoriety for many uses, especially due to their potential as cytotoxic drugs carriers. Over the years, many lipid nanosystems have been developed and applied for different purposes. Liposomes are one of the most studied nanocarrier since Bangham and colleagues [5] reported their preparation in 1965. Afterwards, several kinds of enclosed phospholipid bilayer structures, formed by single bilayers, were described. In this scenario, Gregory Gregoriadis established a new concept that liposomes could entrap drugs, being promising drug delivery systems [6]. Moreover, other researchers showed that liposomes could change the in vivo distribution of entrapped drugs leading to better pharmacokinetics compared to free drugs [7-9]. As a result, these systems may have some advantages, such as the improvement of physicochemical characteristics of the drugs, the delivery to a specific site and controlled release of these molecules. These factors lead to a positive impact on the safety profile. Currently, there are over ten liposomal formulations approved for human use, apart from many preparations in advanced stage of clinical study [8].</p

Radiolabeling of cidofovir with technetium-99m and biodistribution studies

Radiolabeling cidofovir with technetium-99m (99mTc-CDV) is an innovative procedure that enables real-time monitoring of the drug. Essays were performed in vitro, showing high radiolabel stability within 24 h. Blood clearance, biodistribution studies, and scintigraphic images were performed in healthy mice in order to evaluate the profile of the drug in vivo. 99mTc-CDV showed biphasic blood circulation time and significant kidney uptake, indicating that 99mTc-CDV is preferentially eliminated by the renal route. Bones also showed important uptake throughout the experiment. In summary, cidofovir was successfully labeled with technetium-99m and might be used in further studies to track the drug

Cisplatin-Loaded Thermosensitive Liposomes Functionalized with Hyaluronic Acid: Cytotoxicity and In Vivo Acute Toxicity Evaluation

Cisplatin (CDDP) is a potent antitumor drug used in first-line chemotherapy against several solid tumors, including breast cancer. However, toxicities and drug resistance limit its clinical application. Thermosensitive liposome (TSL) functionalized with hyaluronic acid (HA) containing cisplatin (TSL-CDDP-HA) was developed by our research group aiming to promote the release of CDDP in the tumor region under hyperthermia conditions, as well as to decrease toxicity. Thus, this study aimed to evaluate this new formulation (HA-coated TSL-CDDP) concerning in vitro behavior and in vivo toxicity compared to non-coated TSL-CDDP and free CDDP. Cytotoxicity assays and nuclear morphology were carried out against triple-negative breast cancer cells (MDA-MB-231), while an in vivo toxicity study was performed using healthy Swiss mice. The results showed an increase (around 3-fold) in cytotoxicity of the cationic formulation (non-coated TSL-CDDP) compared to free CDDP. On the other hand, TSL-CDDP treatment induced the appearance of 2.5-fold more senescent cells with alteration of nuclear morphology than the free drug after hyperthermia condition. Furthermore, the association of liposomal formulations treatment with hyperthermia increased the percentage of apoptotic cells compared to those without heating. The percentage of apoptotic cells was 1.7-fold higher for TSL-CDDP-HA than for TSL-CDDP. For the in vivo toxicity data, the TSL-CDDP treatment was also toxic to healthy cells, inducing nephrotoxicity with a significant increase in urea levels compared to the saline control group (73.1 &plusmn; 2.4 vs. 49.2 &plusmn; 2.8 mg/mL). On the other hand, the HA-coated TSL-CDDP eliminated the damages related to the use of CDDP since the animals did not show changes in hematological and biochemical examinations and histological analyses. Thus, data suggest that this new formulation is a potential candidate for the intravenous therapy of solid tumors

Cisplatin-Loaded Thermosensitive Liposomes Functionalized with Hyaluronic Acid: Cytotoxicity and In Vivo Acute Toxicity Evaluation

Cisplatin (CDDP) is a potent antitumor drug used in first-line chemotherapy against several solid tumors, including breast cancer. However, toxicities and drug resistance limit its clinical application. Thermosensitive liposome (TSL) functionalized with hyaluronic acid (HA) containing cisplatin (TSL-CDDP-HA) was developed by our research group aiming to promote the release of CDDP in the tumor region under hyperthermia conditions, as well as to decrease toxicity. Thus, this study aimed to evaluate this new formulation (HA-coated TSL-CDDP) concerning in vitro behavior and in vivo toxicity compared to non-coated TSL-CDDP and free CDDP. Cytotoxicity assays and nuclear morphology were carried out against triple-negative breast cancer cells (MDA-MB-231), while an in vivo toxicity study was performed using healthy Swiss mice. The results showed an increase (around 3-fold) in cytotoxicity of the cationic formulation (non-coated TSL-CDDP) compared to free CDDP. On the other hand, TSL-CDDP treatment induced the appearance of 2.5-fold more senescent cells with alteration of nuclear morphology than the free drug after hyperthermia condition. Furthermore, the association of liposomal formulations treatment with hyperthermia increased the percentage of apoptotic cells compared to those without heating. The percentage of apoptotic cells was 1.7-fold higher for TSL-CDDP-HA than for TSL-CDDP. For the in vivo toxicity data, the TSL-CDDP treatment was also toxic to healthy cells, inducing nephrotoxicity with a significant increase in urea levels compared to the saline control group (73.1 ± 2.4 vs. 49.2 ± 2.8 mg/mL). On the other hand, the HA-coated TSL-CDDP eliminated the damages related to the use of CDDP since the animals did not show changes in hematological and biochemical examinations and histological analyses. Thus, data suggest that this new formulation is a potential candidate for the intravenous therapy of solid tumors

Nuclear factor kappa B expression in non-small cell lung cancer

In this mini-review, we discuss the role of NF-κB, a proinflammatory transcription factor, in the expression of genes involved in inflammation, proliferation, and apoptosis pathways, and link it with prognosis of various human cancers, particularly non-small cell lung cancer (NSCLC). We and others have shown that NF-κB activity can be impacted by post-translational S-glutathionylation through reversible formation of a mixed disulfide bond between its cysteine residues and glutathione (GSH). Clinical data analysis showed that high expression of NF-κB correlated with shorter overall survival (OS) in NSCLC patients, suggesting a tumor promotion function for NF-κB. Moreover, NF-κB expression was associated with tumor stage, lymph node metastasis, and 5-year OS in these patients. NF-κB was over-expressed in the cytoplasm of tumor tissue compared to adjacent normal tissues. S-glutathionylation of NF-κB caused negative regulation by interfering with DNA binding activities of NF-κB subunits. In response to oxidants, S-glutathionylation of NF-κB also correlated with enhanced lung inflammation. Thus, S-glutathionylation is an important contributor to NF-κB regulation and clinical results highlight the importance of NF-κB in NSCLC, where NF-κB levels are associated with unfavorable prognosis

Thermosensitive Nanosystems Associated with Hyperthermia for Cancer Treatment

Conventional chemotherapy regimens have limitations due to serious adverse effects. Targeted drug delivery systems to reduce systemic toxicity are a powerful drug development platform. Encapsulation of antitumor drug(s) in thermosensitive nanocarriers is an emerging approach with a promise to improve uptake and increase therapeutic efficacy, as they can be activated by hyperthermia selectively at the tumor site. In this review, we focus on thermosensitive nanosystems associated with hyperthermia for the treatment of cancer, in preclinical and clinical use

Recent advances and limitations in the application of kahalalides for the control of cancer

Since the discovery of the kahalalide family of marine depsipeptides in 1993, considerable work has been done to develop these compounds as new and biologically distinct anti-cancer agents. Clinical trials and laboratory research have yielded a wealth of data that indicates tolerance of kahalalides in healthy cells and selective activity against diseased cells. Currently, two molecules have attracted the greates level of attention, kahalalide F (KF) and isokahalalide F (isoKF, Irvalec, PM 02734, elisidepsin). Both compounds were originally isolated from the sarcoglossan mollusk Elysia rufescens but due to distinct structural characteristics it has been hypothesized and recently shown that the ultimate origin of the molecules is microbial. The search for their true source has been a subject of considerable research in the anticipation of finding new analogs and a culturable expression system that can produce sufficient material through fermentation to be industrially relevant

Protective effect of Lactobacillus delbrueckii subsp. Lactis CIDCA 133 in a model of 5 Fluorouracil-Induced intestinal mucositis

Mucositis is a cytotoxic side effect caused by chemotherapy drugs, such as 5-Fluorouracil (5-FU), being a serious clinical issue. Lactobacillus spp. could be a helpful strategy to alleviate 5-FU chemotherapy-caused intestinal damage, due to their ability to contribute to intestinal homeostasis through improvement of microbiota balance and immunomodulation. In this work we evaluated the effect of Lactobacillus delbrueckii subsp. lactis CIDCA 133 fermented milk in 5-FU-induced experimental mucositis. Intestinal histology, permeability and biochemical parameters showed that animals administrated with 5-FU and treated with CIDCA 133 fermented milk presented reduced intestinal IgA secretion and lower permeability in the small bowel. We showed that this strain preserves villus/crypt ratio, reduces the loss of goblet cells and inflammatory infiltration in ileum sections of 5-FU-treated animals. In conclusion, CIDCA 133 is able to prevent the intestinal mucosa damage caused by 5-FU revealing to be a promising strategy for intestinal mucositis treatment.Fil: De Jesus, Luís Cláudio Lima. Universidade Federal de Minas Gerais; BrasilFil: Martins Drumond, Mariana. Universidade Federal de Minas Gerais; BrasilFil: de Carvalho, André. Universidade Federal de Minas Gerais; BrasilFil: Santos, Spencer S.. Universidade Federal de Minas Gerais; BrasilFil: Martins, Flaviano S.. Universidade Federal de Minas Gerais; BrasilFil: Ferreira, Ênio. Universidade Federal de Minas Gerais; BrasilFil: Salgado Fernandes, Renata. Universidade Federal de Minas Gerais; BrasilFil: Branco de Barros, André Luís. Universidade Federal de Minas Gerais; BrasilFil: do Carmo, Fillipe Luis R. Universidade Federal de Minas Gerais; BrasilFil: Perez, Pablo Fernando. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Criotecnología de Alimentos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Criotecnología de Alimentos; ArgentinaFil: Carvalho Azevedo, Vasco Ariston. Universidade Federal de Minas Gerais; BrasilFil: Mancha Agresti, Pamela. Universidade Federal de Minas Gerais; Brasi