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Pharm Res. 2013 Jul;30(7):1799-812. doi: 10.1007/s11095-013-1024-5. Epub 2013 Apr 9.

Riboflavin-targeted polymer conjugates for breast tumor delivery.

Author information

1
Department of Pharmaceutical Sciences Center for Nanomedicine and Cellular Drug Delivery, University of Maryland Baltimore, 20 Penn Street, Health Sciences Facility 2, Room 543, Baltimore, Maryland 21201, USA.

Abstract

PURPOSE:

In breast cancer, a significant decrease in riboflavin (RF) serum levels and increase in RF carrier protein occurs, indicating a potential role of RF in disease progression. To evaluate RF's ability to serve as a targeting agent, mitomycin C (MMC)-conjugated N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were synthesized and targeted to the RF internalization pathway in human breast cancer cells.

METHODS:

Competitive uptake studies were used to determine specificity of RF-targeted conjugates, and an MTT assay established the IC₅₀ for the conjugates. Endocytic mechanisms were investigated by confocal microscopy.

RESULTS:

Studies revealed a high-affinity endocytic mechanism for RF-specific internalization of fluorescently-labeled conjugates in both MCF-7 and SKBR-3 cells, whereas folic acid-mediated endocytosis showed high specificity only in SKBR-3 cells. MMC internalization was significantly higher following nontargeted and RF-targeted MMC-conjugate administration compared to that of free MMC. Cytotoxic analysis illustrated potent IC₅₀ values for RF-targeted MMC conjugates similar to free MMC. Maximum nuclear accumulation of MMC resulted from lysosomal release from RF-targeted and nontargeted MMC-conjugates following 6 h incubations, unlike that of free MMC seen within 10 min.

CONCLUSION:

Targeting polymer-MMC conjugates to the RF internalization pathway in breast cancer cells enabled an increase in MMC uptake and nuclear localization, resulting in potent cytotoxic activity.

PMID:
23568523
DOI:
10.1007/s11095-013-1024-5
[Indexed for MEDLINE]

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