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Milk derived colloid as a novel drug delivery carrier for breast cancer.

ABSTRACT: Triple negative breast cancer has an extremely poor prognosis when chemotherapy is no longer effective. To overcome drug resistance, novel drug delivery systems based on nanoparticles have had remarkable success. We produced a novel nanoparticle component 'MDC' from milk-derived colloid. In order to evaluate the anti-cancer effect of MDC, we conducted in vitro and in vivo experiments on cancer cell lines and a primary tumor derived breast xenograft. Doxorubicin (Dox) conjugated to MDC (MDC-Dox) showed higher cancer cell growth inhibition than MDC alone especially in cell lines with high EGFR expression. In a mouse melanoma model, MDC-Dox significantly suppressed tumor growth when compared with free Dox. Moreover, in a primary tumor derived breast xenograft, one of the mice treated with MDC-Dox showed partial regression, while mice treated with free Dox failed to show any suppression of tumor growth. We have shown that a novel nanoparticle compound made of simple milk-derived colloid has the capability for drug conjugation, and serves as a tumor-specific carrier of anti-cancer drugs. Further research on its safety and ability to carry various anti-cancer drugs into multiple drug-resistant primary breast models is warranted.

SUBMITTER: Hayashi M

PROVIDER: S-EPMC4623025 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Milk derived colloid as a novel drug delivery carrier for breast cancer.

Hayashi Masamichi M Silanikove Nissim N Chang Xiaofei X Ravi Rajani R Pham Vui V Baia Gilson G Paz Keren K Brait Mariana M Koch Wayne M WM Sidransky David D

Cancer biology & therapy 20150101 8

Triple negative breast cancer has an extremely poor prognosis when chemotherapy is no longer effective. To overcome drug resistance, novel drug delivery systems based on nanoparticles have had remarkable success. We produced a novel nanoparticle component 'MDC' from milk-derived colloid. In order to evaluate the anti-cancer effect of MDC, we conducted in vitro and in vivo experiments on cancer cell lines and a primary tumor derived breast xenograft. Doxorubicin (Dox) conjugated to MDC (MDC-Dox) ...[more]

PMID: 26046946

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Project description:Background: The limitations of conventional treatment modalities in cancer, especially in breast cancer, facilitated the necessity for developing a safer drug delivery system (DDS). Inorganic nano-carriers based on calcium phosphates such as hydroxyapatite (HA) and carbonate apatite (CA) have gained attention due to their biocompatibility, reduced toxicity, and improved therapeutic efficacy. Methods: In this study, the potential of goose bone ash (GBA), a natural derivative of HA or CA, was exploited as a pH-responsive carrier to successfully deliver doxorubicin (DOX), an anthracycline drug into breast cancer cells (e.g., MCF-7 and MDA-MB-231 cells). GBA in either pristine form or in suspension was characterized in terms of size, morphology, functional groups, cellular internalization, cytotoxicity, pH-responsive drug (DOX) release, and protein corona analysis. Results: The pH-responsive drug release study demonstrated the prompt release of DOX from GBA through its disintegration in acidic pH (5.5-6.5), which mimics the pH of the endosomal and lysosomal compartments as well as the stability of GBA in physiological pH (pH 7.5). The result of DOX binding with GBA indicated an increment in binding affinity with increasing concentrations of DOX. Cell viability and cytotoxicity analysis showed no innate toxicity of GBA particles. Both qualitative and quantitative cellular uptake analysis in both cell lines displayed an enhanced cellular internalization of DOX-loaded GBA compared to free DOX molecules. The protein corona spontaneously formed on the surface of GBA particles exhibited its affinity toward transport proteins, structural proteins, and a few other selective proteins. The adsorption of transport proteins could extend the circulation half-life in biological environment and increase the accumulation of the drug-loaded NPs through the enhanced permeability and retention (EPR) effect at the tumor site. Conclusion: These findings highlight the potential of GBA as a DDS to successfully deliver therapeutics into breast cancer cells.

Project description:MicroRNAs (miRNAs) are small non-coding RNAs with a known role as mediators of gene expression in crucial biological processes, which converts them into high potential contenders in the ongoing search for effective therapeutic strategies. However, extracellular RNAs are unstable and rapidly degraded, reducing the possibility of successfully exerting a biological function in distant target cells. Strategies aimed at enhancing the therapeutic potential of miRNAs include the development of efficient, tissue-specific and nonimmunogenic delivery methods. Since miRNAs were discovered to be naturally transported within exosomes, a type of extracellular vesicle that confers protection against RNase degradation and increases miRNA stability have been proposed as ideal delivery vehicles for miRNA-based therapy. Although research in this field has grown rapidly in the last few years, a standard, reproducible and cost-effective protocol for exosome isolation and extracellular RNA delivery is lacking. We aimed to evaluate the use of milk-derived extracellular vesicles as vehicles for extracellular RNA drug delivery. With this purpose, exosomes were isolated from raw bovine milk, combining ultracentrifugation and size exclusion chromatography (SEC) methodology. Isolated exosomes were then loaded with exogenous hsa-miR148a-3p, a highly expressed miRNA in milk exosomes. The suitability of exosomes as delivery vehicles for extracellular RNAs was tested by evaluating the absorption of miR-148a-3p in hepatic (HepG2) and intestinal (Caco-2) cell lines. The potential exertion of a biological effect by miR-148a-3p was assessed by gene expression analysis, using microarrays. Results support that bovine milk is a cost-effective source of exosomes which can be used as nanocarriers of functional miRNAs with a potential use in RNA-based therapy. In addition, we show here that a combination of ultracentrifugation and SEC technics improve exosome enrichment, purity, and integrity for subsequent use.

Project description:1. A non-diffusible mucoid, showing a single peak in the ultracentrifuge, was isolated from human colloid breast carcinoma by treatment with trypsin and pepsin. The material contained threonine, leucine (isoleucine), valine, proline, glycine and glutamic acid in the approximate molar proportions 5:1:1:2:1:1. Smaller amounts of aspartic acid and serine were also found. For each 5 threonine residues, 6 N-acetylgalactosamine and 3-4 galactose residues were present. 2. The mucoid possessed reducing properties by the Park & Johnson (1949) procedure; these were attributable to the action of mild alkali, as employed in this procedure. Mild alkaline treatment by the Aminoff, Morgan & Watkins (1952) procedure gave rise to a diffusible N-acetylgalactosamine chromophore that gave an enhanced colour with Ehrlich's reagent. That galactosyl-(1-->3)-N-acetylgalactosamine residues were liberated was supported by periodate studies. 3. Alkaline liberation of hexosamine residues was accompanied by a specific destruction of threonine. After 40 min. at 100 degrees in 0.18 n-lithium hydroxide, both moieties had almost completely disappeared from the ninhydrin-positive components formed on subsequent acid hydrolysis. Glycine and alpha-oxobutyric acid were present in the acid hydrolysate, showing that both possible pathways of a beta-elimination reaction were involved. Formation of diffusible peptide on very mild alkaline treatment was attributable to the rupture of the original peptide core, necessitated by the second of these two pathways. 4. Hydroxamate formation on treatment with hydroxylamine showed the presence of carbohydrate linkage to glutamic acid or aspartic acid residues or both. This could account for the single N-acetylgalactosamine residue not linked to threonine. 5. The native mucin contained sialic acid, which was cleaved by the acid environment used in the treatment with pepsin. A statistical model of the mucin would require each prosthetic group to be linked, via N-acetylgalactosamine, to threonine, which would occupy every alternate position among the amino acids in the peptide core.

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Milk derived colloid as a novel drug delivery carrier for breast cancer.

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Milk derived colloid as a novel drug delivery carrier for breast cancer.

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