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Dual Functional Mesoporous Silicon Nanoparticles Enhance the Radiosensitivity of VPA in Glioblastoma 1

View Article: PubMed Central - PubMed

ABSTRACT

Radiotherapy is a critical strategy and standard adjuvant approach to glioblastoma treatment. One of the major challenges facing radiotherapy is to minimize radiation damage to normal tissue without compromising therapeutic effects on cancer cells. Various agents and numerous approaches have been developed to improve the therapeutic index of radiotherapy. Among them, radiosensitizers have attracted much attention because they selectively increase susceptibility of cancer cells to radiation and thus enhance biological effectiveness of radiotherapy. However, clinical translation of radiosensitizers has been severely limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this hindrance. In this study, a dual functional mesoporous silica nanoparticle (MSN) formulation of the valproic acid (VPA) radiosensitizer was developed, which specifically recognized folic acid–overexpressing cancer cells and released VPA conditionally in acidic turmeric microenvironment. The efficacy of this targeted and pH-responsive VPA nanocarrier was evaluated as compared to VPA treatment approach in two cell lines: rat glioma cells C6 and human glioma U87. Compared to VPA treatment, targeted VPA-MSNs not only potentiated the toxic effects of radiation and led to a higher rate of cell death but also enhanced inhibition on clonogenic assay. More interestingly, these effects were further accentuated by VPA-MSNs at low pH values. Western blot analysis showed that the effects were mediated via enhanced apoptosis-inducing effects. Our results suggest that the adjunctive use of VPA-MSNs may enhance the effectiveness of radiotherapy in glioma treatment by lowering the radiation doses required to kill cancer cells and thereby minimize collateral damage to healthy adjacent tissue.

No MeSH data available.


Related in: MedlinePlus

Clonogenic survival after VPA, nanoparticles, and IR exposure. (A) Clonogenic assay of C6 cells treated with VPA/or MSNs combined with 8-Gy IR; photographs of Petri dishes in a representative experiment are shown. (B) Percentage inhibition of colony formation as shown in A. Values represent the mean from three independent experiments. Error bars indicate 1 SD.
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f0035: Clonogenic survival after VPA, nanoparticles, and IR exposure. (A) Clonogenic assay of C6 cells treated with VPA/or MSNs combined with 8-Gy IR; photographs of Petri dishes in a representative experiment are shown. (B) Percentage inhibition of colony formation as shown in A. Values represent the mean from three independent experiments. Error bars indicate 1 SD.

Mentions: Furthermore, the augmented apoptotic responses in C6 and U87 cell (Figure 6) were used to account for the radiosensitization measured by clonogenic assay. To examine effects of VPA-MSNs on VPA-induced cell irradiation (IR) sensitivity, the clonogenic assay was performed. Log-phase cells were trypsinized and plated as single cells. After 6 hours of incubation to allow for cell attachment, cells were pretreated with 100 μg/ml of VPA, MSNs, VPA-MSNs, pH 6 VPA-MSNs for 16 hours and then exposed to 0-, 2.0-, 4.0-, 6.0-, and 8.0-Gy doses of IR. Colony survival was determined 14 to 20 days later. As shown in Figure 7, A and B, VPA-MSNs treatment remarkably potentiated the decreasing effects of 8-Gy IR on C6 cell numbers as compared to cells treated with VPA- or MSNs-only groups. A significant reduction in clonogenic survival with the addition of VPA-MSNs at pH 6 could be observed (Figure 7B). The SER for combined X-ray and VPA-MSNs at pH 6 compared to X-ray only was 1.7137. To further characterize the effects of the MSNs, the cell survival fraction was simulated by a multitarget click mathematical model. The SER in VPA-MSNs group was 1.506662, higher than the VPA group in C6 cells. In pH 6.0 conditions, the SER was 1.7137 higher than that in normal conditions (Table 2), respectively.


Dual Functional Mesoporous Silicon Nanoparticles Enhance the Radiosensitivity of VPA in Glioblastoma 1
Clonogenic survival after VPA, nanoparticles, and IR exposure. (A) Clonogenic assay of C6 cells treated with VPA/or MSNs combined with 8-Gy IR; photographs of Petri dishes in a representative experiment are shown. (B) Percentage inhibition of colony formation as shown in A. Values represent the mean from three independent experiments. Error bars indicate 1 SD.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5304234&req=5

f0035: Clonogenic survival after VPA, nanoparticles, and IR exposure. (A) Clonogenic assay of C6 cells treated with VPA/or MSNs combined with 8-Gy IR; photographs of Petri dishes in a representative experiment are shown. (B) Percentage inhibition of colony formation as shown in A. Values represent the mean from three independent experiments. Error bars indicate 1 SD.
Mentions: Furthermore, the augmented apoptotic responses in C6 and U87 cell (Figure 6) were used to account for the radiosensitization measured by clonogenic assay. To examine effects of VPA-MSNs on VPA-induced cell irradiation (IR) sensitivity, the clonogenic assay was performed. Log-phase cells were trypsinized and plated as single cells. After 6 hours of incubation to allow for cell attachment, cells were pretreated with 100 μg/ml of VPA, MSNs, VPA-MSNs, pH 6 VPA-MSNs for 16 hours and then exposed to 0-, 2.0-, 4.0-, 6.0-, and 8.0-Gy doses of IR. Colony survival was determined 14 to 20 days later. As shown in Figure 7, A and B, VPA-MSNs treatment remarkably potentiated the decreasing effects of 8-Gy IR on C6 cell numbers as compared to cells treated with VPA- or MSNs-only groups. A significant reduction in clonogenic survival with the addition of VPA-MSNs at pH 6 could be observed (Figure 7B). The SER for combined X-ray and VPA-MSNs at pH 6 compared to X-ray only was 1.7137. To further characterize the effects of the MSNs, the cell survival fraction was simulated by a multitarget click mathematical model. The SER in VPA-MSNs group was 1.506662, higher than the VPA group in C6 cells. In pH 6.0 conditions, the SER was 1.7137 higher than that in normal conditions (Table 2), respectively.

View Article: PubMed Central - PubMed

ABSTRACT

Radiotherapy is a critical strategy and standard adjuvant approach to glioblastoma treatment. One of the major challenges facing radiotherapy is to minimize radiation damage to normal tissue without compromising therapeutic effects on cancer cells. Various agents and numerous approaches have been developed to improve the therapeutic index of radiotherapy. Among them, radiosensitizers have attracted much attention because they selectively increase susceptibility of cancer cells to radiation and thus enhance biological effectiveness of radiotherapy. However, clinical translation of radiosensitizers has been severely limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this hindrance. In this study, a dual functional mesoporous silica nanoparticle (MSN) formulation of the valproic acid (VPA) radiosensitizer was developed, which specifically recognized folic acid–overexpressing cancer cells and released VPA conditionally in acidic turmeric microenvironment. The efficacy of this targeted and pH-responsive VPA nanocarrier was evaluated as compared to VPA treatment approach in two cell lines: rat glioma cells C6 and human glioma U87. Compared to VPA treatment, targeted VPA-MSNs not only potentiated the toxic effects of radiation and led to a higher rate of cell death but also enhanced inhibition on clonogenic assay. More interestingly, these effects were further accentuated by VPA-MSNs at low pH values. Western blot analysis showed that the effects were mediated via enhanced apoptosis-inducing effects. Our results suggest that the adjunctive use of VPA-MSNs may enhance the effectiveness of radiotherapy in glioma treatment by lowering the radiation doses required to kill cancer cells and thereby minimize collateral damage to healthy adjacent tissue.

No MeSH data available.


Related in: MedlinePlus