Riboflavin-targeted polymer conjugates for breast tumor delivery.

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.

• Authors: Lisa M Bareford, Brittany R Avaritt, Hamidreza Ghandehari, Anjan Nan, Peter W Swaan
• Journal: Pharmaceutical research (Pharm Res) Vol. 30 Issue 7 Pg. 1799-812 (Jul 2013) ISSN: 1573-904X [Electronic] United States
• PMID: 23568523 (Publication Type: Journal Article)

Chemical References

• Acrylamides
• Antibiotics, Antineoplastic
• Mitomycin
• N-(2-hydroxypropyl)methacrylamide
• Riboflavin

Topics

• Acrylamides (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Antibiotics, Antineoplastic (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Breast (drug effects)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Drug Delivery Systems
• Endocytosis
• Female
• Humans
• Mitomycin (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Riboflavin (metabolism)