Combination of selol nanocapsules and magnetic hyperthermia hinders breast tumor growth in aged mice after a short-time treatment.

Short time treatment with reduced dosages of selol-loaded PLGA nanocapsules (NcSel) combined with magnetic hyperthermia (MHT) is evaluated in aged Erhlich tumor-bearing mice. Clinical, hematological, biochemical, genotoxic and histopathological parameters are assessed during 7 d treatment with NcSel and MHT, separately or combined. The time evolution of the tumor volume is successfully modeled using the logistic mathematical model. The combined therapy comprising NcSel and MHT is able to hinder primary tumor growth and a case of complete tumor remission is recorded. Moreover, no metastasis was diagnosed and the adverse effects are negligible. NcSel plus MHT may represent an effective and safe alternative to cancer control in aged patients. Future clinical trials are encouraged.

Carcinoembryonic Antigen (CEA) and Hepatic Metastasis in Colorectal Cancer: Update on Biomarker for Clinical and Biotechnological Approaches.

BACKGROUND: Carcinoembryonic Antigen (CEA) is a recommended prognostic marker in Colorectal Cancer (CRC) for tumor diagnosis and monitoring response to therapy. High CEA levels are specifically associated with CRC progression and increased levels of the marker are expected to fall following surgical treatment. Due to its role in CRC, CEA has also been explored as a target for cancer therapy and diagnosis approaches. OBJECTIVE: The goal of this work is to highlight the role of CEA in CRC progression and liver metastasis as well as its potential as a biomarker for clinical and biotechnological approaches. METHOD: A literature search of electronic medical and patent databases Pubmed, Scopus, and Science Direct, Google patents, Esp@cenet and United States Patent and Trademark Office (USPTO), was performed. Information was collected in recent publications, including 81 articles besides 13 patents related to different CEA targeting biotechnological approaches for CRC therapy and diagnosis. RESULTS: CEA enhances CRC metastatic potential through many ways. CEA protects metastatic cells from death, changes the microenvironment of sinusoids, promoting the expression of adhesion molecule and malignant cell survival, besides being considered a proangiogenic molecule. Furthermore CEA has also been evaluated as a target in drug delivery systems, photodynamic therapy, radioimmunotherapy, cancer imaging and nanotechnological devices, leading to many patents concerning to development of anti-CEA antibodies or their fragments with potential to target colorectal cancer and liver metastasis cells. CONCLUSION: CEA is already clinically used to monitor CRC patients, and it is a very promising targeting biomarker for multiple biotechnological applications. As far as we know this is the first report on CEA that addresses patents database.

In vitro assessment of anti-tumorigenic mechanisms and efficacy of NanoALA, a nanoformulation of aminolevulic acid designed for photodynamic therapy of cancer.

BACKGROUND: The development of nanocarriers is an important approach to increase the bioavailability of hydrophilic drugs in target cells. In this work, we evaluated the anti-tumorigenic mechanisms and efficacy of NanoALA, a novel nanoformulation of aminolevulic acid (ALA) based on poly(lactide-co-glycolide) (PLGA) nanocapsules designed for anticancer photodynamic therapy (PDT). METHODS: For this purpose, physicochemical characterization, prodrug incorporation kinetics, biocompatibility and photocytotoxicity tests, analysis of the cell death type and mitochondrial function, measurement of the intracellular reactive oxygen species production and DNA fragmentation were performed in murine mammary carcinoma (4T1) cells. RESULTS: NanoALA formulation, stable over a period of 90days following synthesis, presented hydrodynamic diameter of 220±8.7nm, zeta potential of -30.6mV and low value of polydispersity index (0.28). The biological assays indicated that the nanostructured product promotes greater ALA uptake by 4T1 cells and consequently more cytotoxicity in the PDT process. For the first time in the scientific literature, there is a therapeutic efficacy report of approximately 80%, after only 1h of incubation with 100µgmL-1 prodrug (0.6mM ALA equivalent). The mitochondria are probably the initial target of treatment, culminating in energy metabolism disorders and cell death by apoptosis. CONCLUSIONS: NanoALA emerges as a promising strategy for anticancer PDT. Besides being effective against a highly aggressive tumor cell line, the treatment may be economically advantageous because it allows a reduction in the dose and frequency of application compared to free ALA.

Prevention of Distant Lung Metastasis After Photodynamic Therapy Application in a Breast Cancer Tumor Model.

The objective of this study was to investigate the activity of photodynamic therapy mediated by aluminum-chlorophthalocyanine contained in a polymeric nanostructured carrier composed by methyl vinyl ether-co-maleic anhydride (PVM/MA) against local subcutaneous breast cancer tumors and its effects against distant metastasis in a mouse tumor model. In our results, we observed a decrease in breast cancer tumor growth, prevention of distant lung metastases, and a significant increased survival in mice treated with photodynamic therapy. In addition to these results, we observed that tumor-bearing mice without treatment developed a significant extension of liver hematopoiesis that was significantly reduced in mice treated with photodynamic therapy. We hypothesized and showed that this reduction in (1) metastasis and (2) liver hematopoiesis may be related to the systemic activity of immature hematopoietic cells, specifically the myeloid-derived suppressor cells, which were suppressed in mice treated with photodynamic therapy. These cells produce a tolerogenic tumor environment that protects tumor tissues from immunological surveillance. Therefore, we suggest that photodynamic therapy could be employed in combination with other conventional therapies; such as surgery and radiotherapy, to improve the overall survival of patients diagnosed with breast cancer, as observed in our experimental resuIts.

Dextran-functionalized magnetic fluid mediating magnetohyperthermia for treatment of Ehrlich-solid-tumor-bearing mice: toxicological and histopathological evaluations.

Dextran-functionalized maghemite fluid (DexMF) has been tested to treat Ehrlich-solid-tumor-bearing mice, evidencing its potential use in mediating magnetohyperthermia in breast cancer treatment. However, although magnetic nanoparticles tend to accumulate in tumor tissues, part of the nanomaterial can reach the blood stream, and then the organism. The aim of this study was to investigate the acute systemic effects of the intratumoral injection of DexMF mediating magnetohyperthermia in the treatment of an advanced clinical Ehrlich-solid-tumor, assessed through histopathological analyses of liver, kidneys, heart and spleen, comet assay, micronucleus test, hemogram, and serum levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, creatinine, and urea. The tumor's histopathology and morphometry were used to assess its aggressiveness and regression. DexMF mediating hyperthermia was effective in containing tumor aggressiveness and in inducing tumor regression, besides showing no toxic effects. Its physical characteristics also suggest that it is safe to use in other biomedical applications.

Antitumor activity of photodynamic therapy performed with nanospheres containing zinc-phthalocyanine.

BACKGROUND: The increasing incidence of cancer and the search for more effective therapies with minimal collateral effects have prompted studies to find alternative new treatments. Among these, photodynamic therapy (PDT) has been proposed as a very promising new modality in cancer treatment with the lowest rates of side effects, revealing itself to be particularly successful when the photosensitizer is associated with nanoscaled carriers. This study aimed to design and develop a new formulation based on albumin nanospheres containing zinc-phthalocyanine tetrasulfonate (ZnPcS4-AN) for use in the PDT protocol and to investigate its antitumor activity in Swiss albino mice using the Ehrlich solid tumor as an experimental model for breast cancer. METHODS: Ehrlich tumor's volume, histopathology and morphometry were used to assess the efficacy of intratumoral injection of ZnPcS4-AN in containing tumor aggressiveness and promoting its regression, while the toxicity of possible treatments was assessed by animal weight, morphological analysis of the liver and kidneys, hemogram, and serum levels of total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase, creatinine and urea. In order to evaluate the efficacy of PDT, groups of animals treated with intratumoral injection of doxorubicin (Dox) were also investigated. RESULTS: Intratumoral injection of ZnPcS4-AN was found to be efficient in mediating PDT to refrain tumor aggressiveness and to induce its regression. Although tumor volume reduction was not significant, PDT induced a remarkable increase in the necrosis area seen in the tumor's central region, as in other experimental groups, including tumor and Dox treated groups, but also in the tumor's peripheral region. Further, PDT showed minimal adverse effects. Indeed, the use of ZnPcS4-AN in mediating PDT revealed anti-neoplastic activity similar to that obtained while using intratumoral Dox therapy. CONCLUSIONS: PDT mediated by the new formulation ZnPcS4-AN enhanced the inhibition of tumor growth while producing practically no adverse effects and thus emerges as a very promising nanotechnology-based strategy for solid cancer treatment.

Dextran-functionalized magnetic fluid mediating magnetohyperthermia combined with preventive antioxidant pequi-oil supplementation: potential use against cancer.

This work aimed to test a dextran-functionalized magnetic fluid (DexMF) sample in mediating magnetohyperthermia to treat an advanced clinical Ehrlich-solid-tumor, to verify the effects of oral antioxidant administration of pequi-oil on this treatment and to investigate the potential of these treatments for future use as an adjuvant in cancer therapy. Animals received the treatments: (a) filtered water (control); (b) tumor implantation and no treatment (tumor group); (c) tumor implantation followed by intratumoral injection of DexMF and alternating current magnetic field exposure (MHT group) for three consecutive days; (d) oral pequi-oil supplementation followed by tumor implantation and the same treatment as group MHT (PMHT group). Analyses took place 1 and 2 weeks after tumor implantation. Both treatments were effective in increasing the tumor necrosis process and controlling tumor growth, besides keeping lymphocyte-dependent immunity. Although the MHT treatment was more efficient after the first week in reducing DNA damage to blood peripheral leucocytes, PMHT therapy appeared to be more effective with the advance of the carcinogenesis process after the second week. Our findings evidence the potential use of DexMF mediating magnetohyperthermia in cancer treatment and also suggest that the preventive pequi oil administration could increase the efficiency of this process.

Leishmanicidal activity of amphotericin B encapsulated in PLGA-DMSA nanoparticles to treat cutaneous leishmaniasis in C57BL/6 mice.

The major goal of this work was to design a new nanoparticle drug delivery system for desoxycholate amphotericin B (D-AMB), based on controlled particle size, looking for the most successful release of the active agents in order to achieve the best site-specific action of the drug at the therapeutically optimal rate and dose regimen. For this, AMB nanoencapsulated in poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) nanoparticles (Nano-D-AMB) has been developed, and its efficacy was evaluated in the treatment of experimental cutaneous leishmaniasis in C57BL/6 mice, to test if our nano-drug delivery system could favor the reduction of the dose frequency required to achieve the same therapeutic level of free D-AMB, and so, an extended dosing interval. Magnetic citrate-coated maghemite nanoparticles were added to this nanosystem (Nano-D-AMB-MG) aiming to increase controlled release of AMB by magnetohyperthermia. Female mice (N=6/group) were infected intradermally in the right footpad with promastigotes of Leishmania amazonensis in the metacyclic phase, receiving the following intraperitoneal treatments: 1% PBS for 10 consecutive days; D-AMB at 2 mg/kg/day for 10 days (totalizing 20 mg/kg/animal); Nano-D-AMB and Nano-D-AMB-MG at 6 mg/kg on the 1st, 4th and 7th days and at 2 mg/kg on the 10th day, also totalizing 20 mg/kg/animal by treatment end. The Nano-D-AMB-MG group was submitted to an AC magnetic field, allowing the induction of magnetohyperthermia. The evaluations were through paw diameter measurements; parasite number and cell viability were investigated by limiting dilution assay. D-AMB-coated PLGA-DMSA nanoparticles showed the same efficacy as free D-AMB to reduce paw diameter; however, the Nano-D-AMB treatment also promoted a significantly greater reduction in parasite number and cell viability compared with free D-AMB. The nano-drug AMB delivery system appeared more effective than free D-AMB therapy to reduce the dose frequency required to achieve the same therapeutic level. It thus favors a longer interval between doses, as expected with development of a new nano drug delivery system, and may be useful in the treatment of many different pathologies, from cancer to neurodegenerative diseases.

WITHDRAWN: Effects of oral administration of Bacillus thuringiensis as spore-crystal strains Cry1Aa, Cry1Ab, Cry1Ac or Cry2Aa on hematologic and genotoxic endpoints of Swiss albino mice.

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Successful strategy for targeting the central nervous system using magnetic albumin nanospheres.

This study reports on the successful use of magnetic albumin nanosphere (MAN), consisting of maghemite nanoparticles hosted by albumin-based nanosphere, to target different sites within the central nervous system (CNS). Ultrastructural analysis by transmission electron microscopy (TEM) of the material collected from the mice was performed in the time window of 30 minutes up to 30 days after administration. Evidence found that the administered MAN was initially internalized and transported by erythrocytes across the blood-brain-barrier and transferred to glial cells and neuropils before internalization by neurons, mainly in the cerebellum. We hypothesize that the efficiency of MAN in crossing the BBB with no pathological alterations is due to the synergistic effect of its two main components, the iron-based nanosized particles and the hosting albumin-based nanospheres. We found that the MAN in targeting the CNS represents an important step towards the design of nanosized materials for clinical and diagnostic applications.

Evaluation of the use of low level laser and photosensitizer drugs in healing.

BACKGROUND AND OBJECTIVES: In the last decade, many different kinds of therapies have emerged as a consequence of advances in the field of applied technology. It is known that low level laser therapy contributes to tissue healing; however, the use of photodynamic therapy (PDT) in healing and the scar formation processes has not been fully explored. The present study analyses the effect of low level laser InGaAIP (685 nm), radiation, either alone or combined with a phthalocyanine-derived photosensitizer (PS) in a gel base delivery (GB) system, on the healing process of cutaneous wounds in rats. STUDY DESIGN/MATERIALS AND METHODS: The rats were divided into six groups: control (untreated) (CG), gel base (GB), photosensitizer (PS), laser (LG), laser+photosensitizer (LPS), and laser+photosensitizer in a GB (LPSG). Standardized circular wounds were made on the dorsum of each rat with a skin punch biopsy instrument. After wounding, treatment was performed once daily and the animals were killed at day 8. Tissue specimens containing the whole wound area were removed and processed for histological analysis using conventional techniques. Serial cross-sections were analyzed to evaluate the organization of the dermis and epidermis as well as collagen deposition. RESULTS: The animals of groups LG, PS, LPS, and LPSG presented higher collagen content and enhanced re-epithelialization as compared to CG (control) and GB rats. Connective tissue remodeling was more evident in groups LPS and LPSG. CONCLUSIONS: The results clearly indicated a synergetic effect of light+photosensitizer+delivery drug on tissue healing. PDT did not cause any healing inhibition or tissue damage during the healing process.