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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

Conceptual schema and design of photoacoustic “nanobomb”.(a) A schema showing typical chemoresistance pathway mediated by vesicular compartmentalization of anticancer drugs (Left panel), and a proposed chemosensitizing pathway that selectively disrupts undesirable vesicular sequestration using a photoacoustic “nanobomb” (Right panel). (b) TEM images of the SWCNTs. (c) Conjugation strategy of FA-SWCNTs and FA-SWCNTs-6G. (d) UV-VIS-NIR absorption spectrum of the SWCNTs in water; inset shows a photograph of the solution. (e) Illustration of the mechanism of photoacoustic shockwave generated by SWCNTs upon laser irradiation. (f) Generation of a photoacoustic signal after irradiation with a single laser pulse at a width of 5 ns and a power of 0.25 mJ per pulse.
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f1: Conceptual schema and design of photoacoustic “nanobomb”.(a) A schema showing typical chemoresistance pathway mediated by vesicular compartmentalization of anticancer drugs (Left panel), and a proposed chemosensitizing pathway that selectively disrupts undesirable vesicular sequestration using a photoacoustic “nanobomb” (Right panel). (b) TEM images of the SWCNTs. (c) Conjugation strategy of FA-SWCNTs and FA-SWCNTs-6G. (d) UV-VIS-NIR absorption spectrum of the SWCNTs in water; inset shows a photograph of the solution. (e) Illustration of the mechanism of photoacoustic shockwave generated by SWCNTs upon laser irradiation. (f) Generation of a photoacoustic signal after irradiation with a single laser pulse at a width of 5 ns and a power of 0.25 mJ per pulse.

Mentions: The concept of this novel strategy is depicted in Fig. 1a. The left panel shows typical chemoresistance pathways by which nucleus-targeting drugs are sequestered by vesicular compartmentalization; the right panel shows a designed pathway to induce chemosensitivity by breakdown of undesirable vesicular sequestration using photoacoustic “nanobombs”. The “nanobombs” are initiated from purified single-walled carbon nanotubes (SWCNTs) produced using a chemical vapor deposition method, having an average length of 100–200 nm and a diameter of 2 nm (Fig. 1b). To improve their biological capabilities and to further modify their performance characteristics, the SWCNTs were conjugated with chitosan oligomer (CS) using a non-covalent approach2327. Folic acid (FA) was then covalently coupled to the chitosan coated SWCNTs. The folate enables the nanobomb to specifically interact with folate receptors commonly overexpressed on most cancer cells232425, thereby, aiding the cellular internalization of the nanotubes (Fig. 1c). To dynamically track the biodistribution of SWCNTs in cells, the FA-SWCNT were further labeled with a fluorescent rhodamine-6G (FA-SWCNT-6G) (Fig. 1c). The functionalized carbon nanotubes exhibited monodispersity in aqueous solution, and had strong absorbance around 1050 and 1300 nm (Fig. 1d). These two absorption bands originated from the electronic transition between the first or second Van Hove singularities of nanotubes (Fig. 1e). The Van Hove-like singularities enhance the effective density of states near the Fermi energy and increase the electron–phonon interaction, thereby increasing the temperature of the nanotube. Upon irradiation by pulsed laser at a wavelength of 1064 nm using a pulse width of 5 nanoseconds and pulse energy of 0.25 mJ, an acoustic shockwave was generated from the carbon nanotube (Fig. 1f).


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)

Conceptual schema and design of photoacoustic “nanobomb”.(a) A schema showing typical chemoresistance pathway mediated by vesicular compartmentalization of anticancer drugs (Left panel), and a proposed chemosensitizing pathway that selectively disrupts undesirable vesicular sequestration using a photoacoustic “nanobomb” (Right panel). (b) TEM images of the SWCNTs. (c) Conjugation strategy of FA-SWCNTs and FA-SWCNTs-6G. (d) UV-VIS-NIR absorption spectrum of the SWCNTs in water; inset shows a photograph of the solution. (e) Illustration of the mechanism of photoacoustic shockwave generated by SWCNTs upon laser irradiation. (f) Generation of a photoacoustic signal after irradiation with a single laser pulse at a width of 5 ns and a power of 0.25 mJ per pulse.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Conceptual schema and design of photoacoustic “nanobomb”.(a) A schema showing typical chemoresistance pathway mediated by vesicular compartmentalization of anticancer drugs (Left panel), and a proposed chemosensitizing pathway that selectively disrupts undesirable vesicular sequestration using a photoacoustic “nanobomb” (Right panel). (b) TEM images of the SWCNTs. (c) Conjugation strategy of FA-SWCNTs and FA-SWCNTs-6G. (d) UV-VIS-NIR absorption spectrum of the SWCNTs in water; inset shows a photograph of the solution. (e) Illustration of the mechanism of photoacoustic shockwave generated by SWCNTs upon laser irradiation. (f) Generation of a photoacoustic signal after irradiation with a single laser pulse at a width of 5 ns and a power of 0.25 mJ per pulse.
Mentions: The concept of this novel strategy is depicted in Fig. 1a. The left panel shows typical chemoresistance pathways by which nucleus-targeting drugs are sequestered by vesicular compartmentalization; the right panel shows a designed pathway to induce chemosensitivity by breakdown of undesirable vesicular sequestration using photoacoustic “nanobombs”. The “nanobombs” are initiated from purified single-walled carbon nanotubes (SWCNTs) produced using a chemical vapor deposition method, having an average length of 100–200 nm and a diameter of 2 nm (Fig. 1b). To improve their biological capabilities and to further modify their performance characteristics, the SWCNTs were conjugated with chitosan oligomer (CS) using a non-covalent approach2327. Folic acid (FA) was then covalently coupled to the chitosan coated SWCNTs. The folate enables the nanobomb to specifically interact with folate receptors commonly overexpressed on most cancer cells232425, thereby, aiding the cellular internalization of the nanotubes (Fig. 1c). To dynamically track the biodistribution of SWCNTs in cells, the FA-SWCNT were further labeled with a fluorescent rhodamine-6G (FA-SWCNT-6G) (Fig. 1c). The functionalized carbon nanotubes exhibited monodispersity in aqueous solution, and had strong absorbance around 1050 and 1300 nm (Fig. 1d). These two absorption bands originated from the electronic transition between the first or second Van Hove singularities of nanotubes (Fig. 1e). The Van Hove-like singularities enhance the effective density of states near the Fermi energy and increase the electron–phonon interaction, thereby increasing the temperature of the nanotube. Upon irradiation by pulsed laser at a wavelength of 1064 nm using a pulse width of 5 nanoseconds and pulse energy of 0.25 mJ, an acoustic shockwave was generated from the carbon nanotube (Fig. 1f).

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