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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 antitumor efficacy in 4T1-tumor bearing mice.(a) Tumor growth curves. (b) Tumor weight. (c) Images of representative tumors excised from mice. (d) Intratumoral delivery of miRNA-34a detected by PCR. (e) Bcl-2 expression in the tumors investigated by western blot. (f) Body weight changes. (g) Tumor burdens in the excised lungs. White arrow heads indicate tumor burdens. (h) H&E, Ki67 and TUNEL immunohistochemical analysis of harvested tumors. Yellow arrow heads indicate examples of positive tumor suppression with H&E staining. Brown staining indicates positive cells for Ki67 and TUNEL. Scale bar: 40 μm. *P < 0.05, **P < 0.01, ***P < 0.001.
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f9: In vivo antitumor efficacy in 4T1-tumor bearing mice.(a) Tumor growth curves. (b) Tumor weight. (c) Images of representative tumors excised from mice. (d) Intratumoral delivery of miRNA-34a detected by PCR. (e) Bcl-2 expression in the tumors investigated by western blot. (f) Body weight changes. (g) Tumor burdens in the excised lungs. White arrow heads indicate tumor burdens. (h) H&E, Ki67 and TUNEL immunohistochemical analysis of harvested tumors. Yellow arrow heads indicate examples of positive tumor suppression with H&E staining. Brown staining indicates positive cells for Ki67 and TUNEL. Scale bar: 40 μm. *P < 0.05, **P < 0.01, ***P < 0.001.

Mentions: The in vivo antitumor efficacy of different formulations was evaluated on 4T1 tumor-bearing mice models, in terms of tumor volumes, body weight changes, tumor weight, numbers of tumor burdens in the excised lungs and immunohistochemical analysis of the isolated tumors. Among these formulations, the CNCs suppressed the tumor growth most efficiently with regard to the tumor volume and weight (Fig. 9a,b and c). The inhibitory rates of DTX, DNCs, RNCs and CNCs calculated from the tumor weight were 44.3%, 55.2%, 40.3% and 77.1%, respectively, indicating the superior anticancer effect of the CNCs. Compared with DTX, the DNCs showed a better inhibition effect on tumor growth (P < 0.001), which might be ascribed to the efficient delivery of drugs to tumor cells by core-shell nanocarriers. Moreover, the PCR and western-blot results showed that RNCs and CNCs were able to efficiently deliver miRNA-34a to tumors (Fig. 9d) and suppress the anti-apoptotic Bcl-2 expression at the protein level (Fig. 9e).


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 antitumor efficacy in 4T1-tumor bearing mice.(a) Tumor growth curves. (b) Tumor weight. (c) Images of representative tumors excised from mice. (d) Intratumoral delivery of miRNA-34a detected by PCR. (e) Bcl-2 expression in the tumors investigated by western blot. (f) Body weight changes. (g) Tumor burdens in the excised lungs. White arrow heads indicate tumor burdens. (h) H&E, Ki67 and TUNEL immunohistochemical analysis of harvested tumors. Yellow arrow heads indicate examples of positive tumor suppression with H&E staining. Brown staining indicates positive cells for Ki67 and TUNEL. Scale bar: 40 μm. *P < 0.05, **P < 0.01, ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382875&req=5

f9: In vivo antitumor efficacy in 4T1-tumor bearing mice.(a) Tumor growth curves. (b) Tumor weight. (c) Images of representative tumors excised from mice. (d) Intratumoral delivery of miRNA-34a detected by PCR. (e) Bcl-2 expression in the tumors investigated by western blot. (f) Body weight changes. (g) Tumor burdens in the excised lungs. White arrow heads indicate tumor burdens. (h) H&E, Ki67 and TUNEL immunohistochemical analysis of harvested tumors. Yellow arrow heads indicate examples of positive tumor suppression with H&E staining. Brown staining indicates positive cells for Ki67 and TUNEL. Scale bar: 40 μm. *P < 0.05, **P < 0.01, ***P < 0.001.
Mentions: The in vivo antitumor efficacy of different formulations was evaluated on 4T1 tumor-bearing mice models, in terms of tumor volumes, body weight changes, tumor weight, numbers of tumor burdens in the excised lungs and immunohistochemical analysis of the isolated tumors. Among these formulations, the CNCs suppressed the tumor growth most efficiently with regard to the tumor volume and weight (Fig. 9a,b and c). The inhibitory rates of DTX, DNCs, RNCs and CNCs calculated from the tumor weight were 44.3%, 55.2%, 40.3% and 77.1%, respectively, indicating the superior anticancer effect of the CNCs. Compared with DTX, the DNCs showed a better inhibition effect on tumor growth (P < 0.001), which might be ascribed to the efficient delivery of drugs to tumor cells by core-shell nanocarriers. Moreover, the PCR and western-blot results showed that RNCs and CNCs were able to efficiently deliver miRNA-34a to tumors (Fig. 9d) and suppress the anti-apoptotic Bcl-2 expression at the protein level (Fig. 9e).

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&thinsp;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