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Cytosolic co-delivery of miRNA-34a and docetaxel with core-shell nanocarriers via caveolae-mediated pathway for the treatment of metastatic breast cancer

View Article: PubMed Central - PubMed

ABSTRACT

-: Codelivery of microRNAs and chemotherapeutic drugs into tumor cells is an attractive strategy for synergetic breast cancer therapy due to their complementary mechanisms. In this work, a core-shell nanocarrier coated by cationic albumin was developed to simultaneously deliver miRNA-34a and docetaxel (DTX) into breast cancer cells for improved therapeutic effect. The co-delivery nanocarriers showed a spherical morphology with an average particle size of 183.9 nm, and they efficiently protected miRNA-34a from degradation by RNase and serum. Importantly, the nanocarriers entered the cytosol via a caveolae-mediated pathway without entrapment in endosomes/lysosomes, thus improving the utilization of the cargo. In vitro, the co-delivery nanocarriers suppressed the expression of anti-apoptosis gene Bcl-2 at both transcription and protein levels, inhibited tumor cell migration and efficiently induced cell apoptosis and cytotoxicity. In vivo, the co-delivery nanocarriers prolonged the blood circulation of DTX, enhanced tumor accumulation of the cargo and significantly inhibited tumor growth and metastasis in 4T1-tumor bearing mice models. Taken together, the present nanocarrier co-loading with DTX and miRNA-34a is a new nanoplatform for the combination of insoluble drugs and gene/protein drugs and provides a promising strategy for the treatment of metastatic breast cancer.

No MeSH data available.


Related in: MedlinePlus

In vivo imaging and biodistribution of CNCs in 4T1 tumor-bearing mice.(a) Ex vivo fluorescence images of heart, lung, kidney, spleen, tumor and liver harvested from the mice at 1 h, 4 h, 8 h and 24 h after injection. (b) Biodistribution of dual fluorescence-labeled CNCs in tumors harvested from tumor-bearing mice at 4 h post-injection. Cell nuclei were stained with DAPI. C6: green; Cy5-RNA: red; Scale bar: 100 μm. (c) TEM images of sections from isolated tumor collected at 4 h post-injection. The control group was the tumor harvested from tumor-bearing mice without treatment. Red arrow heads indicate the distribution of the CNCs. Cyt, cytoplasm; N, nucleus; V, vesicle; L: lysosome. Scale bar: 2 μm.
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f8: In vivo imaging and biodistribution of CNCs in 4T1 tumor-bearing mice.(a) Ex vivo fluorescence images of heart, lung, kidney, spleen, tumor and liver harvested from the mice at 1 h, 4 h, 8 h and 24 h after injection. (b) Biodistribution of dual fluorescence-labeled CNCs in tumors harvested from tumor-bearing mice at 4 h post-injection. Cell nuclei were stained with DAPI. C6: green; Cy5-RNA: red; Scale bar: 100 μm. (c) TEM images of sections from isolated tumor collected at 4 h post-injection. The control group was the tumor harvested from tumor-bearing mice without treatment. Red arrow heads indicate the distribution of the CNCs. Cyt, cytoplasm; N, nucleus; V, vesicle; L: lysosome. Scale bar: 2 μm.

Mentions: The biodistribution of CNCs was investigated in 4T1 tumor-bearing mice using an in vivo imaging system. As shown in Fig. 8a and Supplementary Fig. S11, most of the free C6 and Cy5-RNA were distributed in the liver after injection and rapidly eliminated from the body. In contrast, significant fluorescent signals of C6 and Cy5 were detected at 1 h post-injection of the CNCs. Moreover, the fluorescence intensity at the tumor sites increased gradually with elapsed time, indicating the accumulation of CNCs in tumor sites. Ex vivo fluorescence images of isolated organs provided results that are consistent with those of in vivo imaging. The fluorescent intensity from free C6 and Cy5-RNA groups declined rapidly, and the tumor sites showed little accumulation after injection. In contrast, upon injection of CNCs, the fluorescent intensity of the tumor increased gradually and reached a peak at 8 h post-injection. The effective accumulation of CNCs in the tumors could be ascribed to the prolonged circulation time and the EPR effect.


Cytosolic co-delivery of miRNA-34a and docetaxel with core-shell nanocarriers via caveolae-mediated pathway for the treatment of metastatic breast cancer
In vivo imaging and biodistribution of CNCs in 4T1 tumor-bearing mice.(a) Ex vivo fluorescence images of heart, lung, kidney, spleen, tumor and liver harvested from the mice at 1 h, 4 h, 8 h and 24 h after injection. (b) Biodistribution of dual fluorescence-labeled CNCs in tumors harvested from tumor-bearing mice at 4 h post-injection. Cell nuclei were stained with DAPI. C6: green; Cy5-RNA: red; Scale bar: 100 μm. (c) TEM images of sections from isolated tumor collected at 4 h post-injection. The control group was the tumor harvested from tumor-bearing mice without treatment. Red arrow heads indicate the distribution of the CNCs. Cyt, cytoplasm; N, nucleus; V, vesicle; L: lysosome. Scale bar: 2 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5382875&req=5

f8: In vivo imaging and biodistribution of CNCs in 4T1 tumor-bearing mice.(a) Ex vivo fluorescence images of heart, lung, kidney, spleen, tumor and liver harvested from the mice at 1 h, 4 h, 8 h and 24 h after injection. (b) Biodistribution of dual fluorescence-labeled CNCs in tumors harvested from tumor-bearing mice at 4 h post-injection. Cell nuclei were stained with DAPI. C6: green; Cy5-RNA: red; Scale bar: 100 μm. (c) TEM images of sections from isolated tumor collected at 4 h post-injection. The control group was the tumor harvested from tumor-bearing mice without treatment. Red arrow heads indicate the distribution of the CNCs. Cyt, cytoplasm; N, nucleus; V, vesicle; L: lysosome. Scale bar: 2 μm.
Mentions: The biodistribution of CNCs was investigated in 4T1 tumor-bearing mice using an in vivo imaging system. As shown in Fig. 8a and Supplementary Fig. S11, most of the free C6 and Cy5-RNA were distributed in the liver after injection and rapidly eliminated from the body. In contrast, significant fluorescent signals of C6 and Cy5 were detected at 1 h post-injection of the CNCs. Moreover, the fluorescence intensity at the tumor sites increased gradually with elapsed time, indicating the accumulation of CNCs in tumor sites. Ex vivo fluorescence images of isolated organs provided results that are consistent with those of in vivo imaging. The fluorescent intensity from free C6 and Cy5-RNA groups declined rapidly, and the tumor sites showed little accumulation after injection. In contrast, upon injection of CNCs, the fluorescent intensity of the tumor increased gradually and reached a peak at 8 h post-injection. The effective accumulation of CNCs in the tumors could be ascribed to the prolonged circulation time and the EPR effect.

View Article: PubMed Central - PubMed

ABSTRACT

-: Codelivery of microRNAs and chemotherapeutic drugs into tumor cells is an attractive strategy for synergetic breast cancer therapy due to their complementary mechanisms. In this work, a core-shell nanocarrier coated by cationic albumin was developed to simultaneously deliver miRNA-34a and docetaxel (DTX) into breast cancer cells for improved therapeutic effect. The co-delivery nanocarriers showed a spherical morphology with an average particle size of 183.9 nm, and they efficiently protected miRNA-34a from degradation by RNase and serum. Importantly, the nanocarriers entered the cytosol via a caveolae-mediated pathway without entrapment in endosomes/lysosomes, thus improving the utilization of the cargo. In vitro, the co-delivery nanocarriers suppressed the expression of anti-apoptosis gene Bcl-2 at both transcription and protein levels, inhibited tumor cell migration and efficiently induced cell apoptosis and cytotoxicity. In vivo, the co-delivery nanocarriers prolonged the blood circulation of DTX, enhanced tumor accumulation of the cargo and significantly inhibited tumor growth and metastasis in 4T1-tumor bearing mice models. Taken together, the present nanocarrier co-loading with DTX and miRNA-34a is a new nanoplatform for the combination of insoluble drugs and gene/protein drugs and provides a promising strategy for the treatment of metastatic breast cancer.

No MeSH data available.


Related in: MedlinePlus