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Photoacoustic "nanobombs" fight against undesirable vesicular compartmentalization of anticancer drugs.

Chen A, Xu C, Li M, Zhang H, Wang D, Xia M, Meng G, Kang B, Chen H, Wei J - Sci Rep (2015)

Bottom Line: Strategies aimed at circumventing this problem may improve chemotherapeutic efficacy.Side effects were not observed.These findings provide insights of using nanotechnology to improve cancer chemotherapy, i.e. not only for drug delivery, but also for overcoming intracellular drug-transport hurdles.

View Article: PubMed Central - PubMed

Affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 210093, China.

ABSTRACT
Undesirable intracellular vesicular compartmentalization of anticancer drugs in cancer cells is a common cause of chemoresistance. Strategies aimed at circumventing this problem may improve chemotherapeutic efficacy. We report a novel photophysical strategy for controlled-disruption of vesicular sequestration of the anticancer drug doxorubicin (DOX). Single-walled carbon nanotubes (SWCNTs), modified with folate, were trapped in acidic vesicles after entering lung cancer cells. Upon irradiation by near-infrared pulsed laser, these vesicles were massively broken by the resulting photoacoustic shockwave, and the vesicle-sequestered contents were released, leading to redistribution of DOX from cytoplasm to the target-containing nucleus. Redistribution resulted in 12-fold decrease of the EC50 of DOX in lung cancer cells, and enhanced antitumor efficacy of low-dose DOX in tumor-bearing mice. Side effects were not observed. These findings provide insights of using nanotechnology to improve cancer chemotherapy, i.e. not only for drug delivery, but also for overcoming intracellular drug-transport hurdles.

No MeSH data available.


Related in: MedlinePlus

Photoacoustic “nanobombs” amplify therapeutic efficacy of DOX in vitro and in vivo.(a) In vitro cytotoxicity of DOX with and without SWCNTs/laser. Means ± SD are shown (n = 6). The laser irradiation was 15 min at 100 mW cm−2, and the SWCNT concentration was 10 μg ml−1. (b) The growth curves of A549 tumors on mice receiving different therapeutic formulations. Means + SD are shown (n = 5 per group). The laser irradiation was 1 min at 600 mW cm−2, and the SWCNT concentration was 1.5 mg kg−1. (c) Representative images of A549 tumor-bearing mice (left panel) and the separated tumor tissues after treatment (right panel). (d) The weight of tumor tissues after different treatments. Means + SD are shown (n = 5 per group). (e) Body weight variation of the mice during the treatment. Means + SD are shown (n = 5 per group). (f) Tumor sections were processed with hematoxylin (for nuclear staining, dark purple dots) and eosin (for cytoplasm counterstaining, deep pink). Black arrows head depict necrotic areas containing less or no cells. Scale bars = 100 μm.
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f4: Photoacoustic “nanobombs” amplify therapeutic efficacy of DOX in vitro and in vivo.(a) In vitro cytotoxicity of DOX with and without SWCNTs/laser. Means ± SD are shown (n = 6). The laser irradiation was 15 min at 100 mW cm−2, and the SWCNT concentration was 10 μg ml−1. (b) The growth curves of A549 tumors on mice receiving different therapeutic formulations. Means + SD are shown (n = 5 per group). The laser irradiation was 1 min at 600 mW cm−2, and the SWCNT concentration was 1.5 mg kg−1. (c) Representative images of A549 tumor-bearing mice (left panel) and the separated tumor tissues after treatment (right panel). (d) The weight of tumor tissues after different treatments. Means + SD are shown (n = 5 per group). (e) Body weight variation of the mice during the treatment. Means + SD are shown (n = 5 per group). (f) Tumor sections were processed with hematoxylin (for nuclear staining, dark purple dots) and eosin (for cytoplasm counterstaining, deep pink). Black arrows head depict necrotic areas containing less or no cells. Scale bars = 100 μm.

Mentions: We wanted to determine whether reduced vesicular sequestration and enhanced nuclear accumulation of free DOX mediated by SWCNT/Laser could amplify therapeutic efficacy. We found that the half maximal effective concentration (EC50) of DOX was reduced about 12 fold in A549 cells treated with SWCNT/Laser (0.04 μg ml−1) compared to cells treated with DOX alone (0.48 μg ml−1) (Fig. 4a). Of note, there was no significant cytotoxicity of SWCNT/Laser treatment, as shown by the data points of DOX = 0 μg ml−1 in Fig. 4a. We further investigated the feasibility of recruiting photoacoustic “nanobombs” to enhance therapeutic outcomes of low-dose DOX (to minimize toxicity) in tumor-bearing mice. While DOX single therapy exerted a mild antitumor effect, tumor growth was remarkably inhibited in mice treated with DOX/SWCNT/Laser (Fig. 4b–d). No obvious side effects were observed during the treatment as evidenced by comparable body weight among the four treatment groups (Fig. 4e). Consistently, as determined by histological examination in tumor tissues dissected from mice, we found that cell density was reduced; bleeding and necrotic areas were increased in tumors treated with DOX/SWCNT/Laser compared to other groups (Fig. 4f). These results indicate that photoacoustic “nanobombs” enhanced the therapeutic efficacy of free DOX both in vitro and in vivo.


Photoacoustic "nanobombs" fight against undesirable vesicular compartmentalization of anticancer drugs.

Chen A, Xu C, Li M, Zhang H, Wang D, Xia M, Meng G, Kang B, Chen H, Wei J - Sci Rep (2015)

Photoacoustic “nanobombs” amplify therapeutic efficacy of DOX in vitro and in vivo.(a) In vitro cytotoxicity of DOX with and without SWCNTs/laser. Means ± SD are shown (n = 6). The laser irradiation was 15 min at 100 mW cm−2, and the SWCNT concentration was 10 μg ml−1. (b) The growth curves of A549 tumors on mice receiving different therapeutic formulations. Means + SD are shown (n = 5 per group). The laser irradiation was 1 min at 600 mW cm−2, and the SWCNT concentration was 1.5 mg kg−1. (c) Representative images of A549 tumor-bearing mice (left panel) and the separated tumor tissues after treatment (right panel). (d) The weight of tumor tissues after different treatments. Means + SD are shown (n = 5 per group). (e) Body weight variation of the mice during the treatment. Means + SD are shown (n = 5 per group). (f) Tumor sections were processed with hematoxylin (for nuclear staining, dark purple dots) and eosin (for cytoplasm counterstaining, deep pink). Black arrows head depict necrotic areas containing less or no cells. Scale bars = 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4612315&req=5

f4: Photoacoustic “nanobombs” amplify therapeutic efficacy of DOX in vitro and in vivo.(a) In vitro cytotoxicity of DOX with and without SWCNTs/laser. Means ± SD are shown (n = 6). The laser irradiation was 15 min at 100 mW cm−2, and the SWCNT concentration was 10 μg ml−1. (b) The growth curves of A549 tumors on mice receiving different therapeutic formulations. Means + SD are shown (n = 5 per group). The laser irradiation was 1 min at 600 mW cm−2, and the SWCNT concentration was 1.5 mg kg−1. (c) Representative images of A549 tumor-bearing mice (left panel) and the separated tumor tissues after treatment (right panel). (d) The weight of tumor tissues after different treatments. Means + SD are shown (n = 5 per group). (e) Body weight variation of the mice during the treatment. Means + SD are shown (n = 5 per group). (f) Tumor sections were processed with hematoxylin (for nuclear staining, dark purple dots) and eosin (for cytoplasm counterstaining, deep pink). Black arrows head depict necrotic areas containing less or no cells. Scale bars = 100 μm.
Mentions: We wanted to determine whether reduced vesicular sequestration and enhanced nuclear accumulation of free DOX mediated by SWCNT/Laser could amplify therapeutic efficacy. We found that the half maximal effective concentration (EC50) of DOX was reduced about 12 fold in A549 cells treated with SWCNT/Laser (0.04 μg ml−1) compared to cells treated with DOX alone (0.48 μg ml−1) (Fig. 4a). Of note, there was no significant cytotoxicity of SWCNT/Laser treatment, as shown by the data points of DOX = 0 μg ml−1 in Fig. 4a. We further investigated the feasibility of recruiting photoacoustic “nanobombs” to enhance therapeutic outcomes of low-dose DOX (to minimize toxicity) in tumor-bearing mice. While DOX single therapy exerted a mild antitumor effect, tumor growth was remarkably inhibited in mice treated with DOX/SWCNT/Laser (Fig. 4b–d). No obvious side effects were observed during the treatment as evidenced by comparable body weight among the four treatment groups (Fig. 4e). Consistently, as determined by histological examination in tumor tissues dissected from mice, we found that cell density was reduced; bleeding and necrotic areas were increased in tumors treated with DOX/SWCNT/Laser compared to other groups (Fig. 4f). These results indicate that photoacoustic “nanobombs” enhanced the therapeutic efficacy of free DOX both in vitro and in vivo.

Bottom Line: Strategies aimed at circumventing this problem may improve chemotherapeutic efficacy.Side effects were not observed.These findings provide insights of using nanotechnology to improve cancer chemotherapy, i.e. not only for drug delivery, but also for overcoming intracellular drug-transport hurdles.

View Article: PubMed Central - PubMed

Affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 210093, China.

ABSTRACT
Undesirable intracellular vesicular compartmentalization of anticancer drugs in cancer cells is a common cause of chemoresistance. Strategies aimed at circumventing this problem may improve chemotherapeutic efficacy. We report a novel photophysical strategy for controlled-disruption of vesicular sequestration of the anticancer drug doxorubicin (DOX). Single-walled carbon nanotubes (SWCNTs), modified with folate, were trapped in acidic vesicles after entering lung cancer cells. Upon irradiation by near-infrared pulsed laser, these vesicles were massively broken by the resulting photoacoustic shockwave, and the vesicle-sequestered contents were released, leading to redistribution of DOX from cytoplasm to the target-containing nucleus. Redistribution resulted in 12-fold decrease of the EC50 of DOX in lung cancer cells, and enhanced antitumor efficacy of low-dose DOX in tumor-bearing mice. Side effects were not observed. These findings provide insights of using nanotechnology to improve cancer chemotherapy, i.e. not only for drug delivery, but also for overcoming intracellular drug-transport hurdles.

No MeSH data available.


Related in: MedlinePlus