Combining Nanocarrier-Assisted Delivery of Molecules and Radiotherapy.

Cancer is responsible for a significant proportion of death all over the world. Therefore, strategies to improve its treatment are highly desired. The use of nanocarriers to deliver anticancer treatments has been extensively investigated and improved since the approval of the first liposomal formulation for cancer treatment in 1995. Radiotherapy (RT) is present in the disease management strategy of around 50% of cancer patients. In the present review, we bring the state-of-the-art information on the combination of nanocarrier-assisted delivery of molecules and RT. We start with formulations designed to encapsulate single or multiple molecules that, once delivered to the tumor site, act directly on the cells to improve the effects of RT. Then, we describe formulations designed to modulate the tumor microenvironment by delivering oxygen or to boost the abscopal effect. Finally, we present how RT can be employed to trigger molecule delivery from nanocarriers or to modulate the EPR effect.

Radiolytic synthesis and characterization of selenium nanoparticles: comparative biosafety evaluation with selenite and ionizing radiation.

The goal of this work is use a green chemistry route to synthesize selenium nanoparticles (SeNPs) that do not trigger oxidative stress, typical of metallic, oxide metallic and carbonaceous nanostructures, and supply the same beneficial effects as selenium nanostructures. SeNPs were synthesized using a radiolytic method involving irradiating a solution containing sodium selenite (Se4+) as the precursor in 1% Yeast extract, 2% Peptone, 2% Glucose (YPG) liquid medium with gamma-rays (60Cobalt). The method did not employ any hazardous reducing agents. Saccharomyces cerevisiae cells were incubated with 1 mM SeNPs for 24 h and/or then challenged with 400 Gy of ionizing radiation were assessed for viability and biomarkers of oxidative stress: lipid peroxidation, protein carbonylation, free radical generation, and total sulfhydryl content. Spherical SeNPs with variable diameters (from 100 to 200 nm) were formed after reactions of sodium selenite with hydrated electrons (eaq-) and hydrogen radicals (H·). Subsequent structural characterizations indicated an amorphous structure composed of elemental selenium (Se0). Compared to 1 mM selenite, SeNPs were considered safe and less toxic to Saccharomyces cerevisiae cells as did not elicit significant modifications in cell viability or oxidative stress parameters except for increased protein carbonylation. Furthermore, SeNPs treatment afforded some protection against ionizing radiation exposure. SeNPs produced using green chemistry attenuated the reactive oxygen species generation after in vitro ionizing radiation exposure opens up tremendous possibilities for radiosensitizer development.

Experimental studies of boron neutron capture therapy (BNCT) using histone deacetylase inhibitor (HDACI) sodium butyrate, as a complementary drug for the treatment of poorly differentiated thyroid cancer (PDTC).

PURPOSE: The present study analyzed different protocols of administration of boronophenylalanine (BPA) and sodium butyrate (NaB) to increase the BNCT efficacy for poorly differentiated thyroid cancer (PDTC). MATERIALS AND METHODS: Nude mice implanted with human PDTC cells (WRO) were distributed into four protocols: 1) BPA; 2) BPA + ip NaB; 3) BPA + oral NaB; 4) Control. Biodistribution and histologic studies were performed. LAT (BPA transporter) isoforms gene expression was assessed by RT-PCR. RESULTS: Tumor growth delay was observed in animals of the Protocol #3 (p < 0.05). NaB (Protocol #2) increased tumor boron uptake 2-h post BPA injection (p < 0.05). On the other hand, NaB upregulated the expression of all the isoforms of the LAT transporter in vitro. Histologic studies showed a significant decrease of mitotic activity and an increase of vacuoles in tumors of Protocol #3. Neutrons alone or combined with NaB caused some tumor growth delay (p < 0.05), while in the BNCT and BNCT + NaB groups, there was a halt in tumor growth in 70 and 80% of the animals, respectively. CONCLUSIONS: Intraperitoneally administration of NaB increased boron uptake while oral administration for a longer period of time induced tumor growth delay previous to BPA administration. The use of NaB via ip would optimize the irradiation results.

Flavonoid silybin improves the response to radiotherapy in invasive bladder cancer.

Conservative treatment for invasive bladder cancer (BC) involves a complete transurethral tumor resection combined with chemotherapy (CT) and radiotherapy (RT). The major obstacles of chemo-radiotherapy are the addition of the toxicities of RT and CT, and the recurrence due to RT and CT resistances. The flavonoid Silybin (Sb) inhibits pathways involved in cell survival and resistance mechanisms, therefore the purpose of this paper was to study in vitro and in vivo, the ability of Sb to improve the response to RT, in two murine BC cell lines, with different levels of invasiveness, placing emphasis on radio-sensitivity, and pathways involved in radio-resistance and survival. In vitro, Sb radio-sensitized murine invasive cells through the inhibition of RT-induced NF-κB and PI3K pathways, and the increase of oxidative stress, while non-invasive cells did not show to be sensitized. In vivo, Sb improved RT-response and overall survival in invasive murine tumors. As Sb is already being tested in clinical trials for other urological cancers and it improves RT-response in invasive BC, these results could have translational relevance, supporting further research.

The potential roles of bacteria to improve radiation treatment outcome.

Many combined therapies have been proposed to enhance radiotherapy outcome, but they have several limitations. As a new feasible strategy, combination of radiotherapy with bacteria showed a significant positive impact on the tumor treatment and metastasis inhibition. Although probiotic bacteria and radiotherapy alone can be effective in the treatment of different cancers, the combination of these two therapies seems to enhance therapeutic outcome and is cost-effective. Bacterial cells can act as therapeutic/gene/drug delivery vehicles as well as theranostic agents. In this communication, we reviewed current evidences, studies, suggestions, and future-based directions on combination of radiotherapy and bacteria. In another sections, an overview on tumor hypoxia, bacteria in cancer therapy, and combination of radiotherapy and bacteria is presented. A brief overview on trials and animal studies which used bacteria to protect normal tissues against radiotherapy-induced complications is also included.

Bacillus Calmette-Guerin improves local and systemic response to radiotherapy in invasive bladder cancer.

BACKGROUND: A key factor contributing to radio-resistance in conservative invasive bladder cancer (BCa) treatment is tumor hypoxia and a strategy to overcome it is to trigger the production of nitric oxide (NO). On the other hand, ionizing radiation (IR) applied to a primary tumor can induce immunogenic cell death which may set off a cytotoxic immune response against the primary tumor and its metastasis. PURPOSE: To study in vitro and in vivo, the role of BCG as a local sensitizer to overcome hypoxia-associated radio-resistance through the production of NO, and as an immune-stimulator to be used in combination with IR to generate a systemic response for invasive BCa treatment. MATERIALS AND METHODS: We selected the invasive murine BCa cell line MB49-I which expresses inducible NO synthase and produces NO, cultured in vitro in 2D and 3D models, and inoculated in vivo in the subcutaneous of syngeneic mice. RESULTS: in vitro, multicellular murine invasive spheroids mimicked in vivo central tumor necrosis. BCG pre-treatment radio-sensitized spheroids through the induction of NO production, while no effect was shown in monolayers. In vivo, not only did BCG improve the local response to IR but it also decreased the metastatic spread and promoted the development of abscopal effect/rejection of a second tumor. CONCLUSION: Since BCG has already and successfully been used for the treatment of non-invasive BCa and it improves the response to ionizing radiation in invasive BCa, these results are translational relevant to be analyzed in patients with this pathology.