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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.

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Related in: MedlinePlus

Schematic illustration of core-shell nanocarriers for the co-delivery of DTX and miRNA-34a.(a) Preparation of the CNCs. (b) Proposed mechanism for the cancer cell killing. The CNCs enter the blood vessel via systemic administration. Then, they accumulate in tumor tissue through the EPR effect, are taken up by cancer cells, obtain cytosolic delivery, and finally induce cell apoptosis via the synergistic anticancer effect of DTX and miRNA-34a.
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f1: Schematic illustration of core-shell nanocarriers for the co-delivery of DTX and miRNA-34a.(a) Preparation of the CNCs. (b) Proposed mechanism for the cancer cell killing. The CNCs enter the blood vessel via systemic administration. Then, they accumulate in tumor tissue through the EPR effect, are taken up by cancer cells, obtain cytosolic delivery, and finally induce cell apoptosis via the synergistic anticancer effect of DTX and miRNA-34a.

Mentions: We previously reported that a globular protein-coated nanoparticle obtained cellular entry without entrapment in endosomes/lysosomes via a caveolae-mediated pathway2425. Encouraged by these findings, a core-shell nanocarrier coated by cationic bovine serum albumin (CBSA) was developed in the present study for the co-delivery of miRNA-34a and DTX (Fig. 1a). It was expected that the designed nanocarriers would achieve enhanced drug delivery performance via the caveolae-mediated pathway, highly accumulate at the tumor site via the enhanced permeation and retention (EPR) effect and prolonged circulation time, and finally achieve synergistic treatment of metastatic breast cancer through the combination of miRNA-34a and DTX (Fig. 1b). To obtain a proof of this concept, various experiments were performed, including characterization of the nanocarriers, cellular internalization, pharmacokinetics, biodistribution, antitumor efficacy, etc.


Cytosolic co-delivery of miRNA-34a and docetaxel with core-shell nanocarriers via caveolae-mediated pathway for the treatment of metastatic breast cancer
Schematic illustration of core-shell nanocarriers for the co-delivery of DTX and miRNA-34a.(a) Preparation of the CNCs. (b) Proposed mechanism for the cancer cell killing. The CNCs enter the blood vessel via systemic administration. Then, they accumulate in tumor tissue through the EPR effect, are taken up by cancer cells, obtain cytosolic delivery, and finally induce cell apoptosis via the synergistic anticancer effect of DTX and miRNA-34a.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Schematic illustration of core-shell nanocarriers for the co-delivery of DTX and miRNA-34a.(a) Preparation of the CNCs. (b) Proposed mechanism for the cancer cell killing. The CNCs enter the blood vessel via systemic administration. Then, they accumulate in tumor tissue through the EPR effect, are taken up by cancer cells, obtain cytosolic delivery, and finally induce cell apoptosis via the synergistic anticancer effect of DTX and miRNA-34a.
Mentions: We previously reported that a globular protein-coated nanoparticle obtained cellular entry without entrapment in endosomes/lysosomes via a caveolae-mediated pathway2425. Encouraged by these findings, a core-shell nanocarrier coated by cationic bovine serum albumin (CBSA) was developed in the present study for the co-delivery of miRNA-34a and DTX (Fig. 1a). It was expected that the designed nanocarriers would achieve enhanced drug delivery performance via the caveolae-mediated pathway, highly accumulate at the tumor site via the enhanced permeation and retention (EPR) effect and prolonged circulation time, and finally achieve synergistic treatment of metastatic breast cancer through the combination of miRNA-34a and DTX (Fig. 1b). To obtain a proof of this concept, various experiments were performed, including characterization of the nanocarriers, cellular internalization, pharmacokinetics, biodistribution, antitumor efficacy, etc.

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