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Direct evaluation of intracellular accumulation of free and polymer-bound anthracyclines
T Bogush1, G Smirnova, I Shubina
1Department of Pharmacology and Toxicology, Russian Academy of Medical Sciences, Moscow.
Abstract:
Nanoparticulate carriers of anthracyclines are being developed with the aim of improving the pharmacokinetic or pharmacodynamic behavior of these drugs. To understand how the drug reaches its nuclear targets, we have developed two methods that allow the quantification of the interaction between an anthracycline and cellular DNA: (1) by direct evaluation of the quenching of anthracycline fluorescence due to the intercalation of the drug into DNA and (2) by the measurement of Hoechst 33258 fluorescence associated with its displacement from DNA-binding sites for which it competes with the anthracycline. We show that the intracellular accumulation and DNA binding of doxorubicin encapsulated in polyisohexylcyanoacrylate nanospheres (dox-NS) and of daunorubicin bound to polyglutamic acid are reduced by 30%-40% in comparison with those obtained for free doxorubicin (dox) and daunorubicin, respectively. The results obtained with dox or NS-dox are not modified by prior incubation with either of these compounds. The two methods yielded similar results, and we conclude that either technique is applicable to the evaluation of the interaction of carrier-bound anthracyclines with cellular DNA.
Insights
Nanoparticle drug carriers reduce anthracycline accumulation and DNA binding by 30-40%. Two novel methods accurately quantify drug-DNA interactions for carrier-bound anthracyclines.
Area of Science:
- Pharmacology
- Nanotechnology
- Molecular Biology
Background:
- Anthracyclines are crucial chemotherapy agents.
- Nanoparticulate carriers aim to improve drug delivery and efficacy.
- Understanding drug-DNA interaction is key to optimizing nanocarrier design.
Purpose of the Study:
- To develop and validate methods for quantifying anthracycline-DNA interactions.
- To assess the impact of nanoparticulate carriers on intracellular drug accumulation and DNA binding.
- To compare the behavior of carrier-bound anthracyclines with their free forms.
Main Methods:
- Quantification of anthracycline-DNA interaction via fluorescence quenching.
- Measurement of Hoechst 33258 fluorescence displacement assay.
- Comparison of doxorubicin-nanospheres (dox-NS) and daunorubicin-polyglutamic acid with free drugs.
Main Results:
- Intracellular accumulation and DNA binding of dox-NS and daunorubicin-polyglutamic acid were reduced by 30-40% compared to free drugs.
- Pre-incubation with compounds did not alter results for doxorubicin or NS-dox.
- Both developed methods provided consistent and comparable results.
Conclusions:
- Nanoparticulate carriers significantly reduce intracellular accumulation and DNA binding of anthracyclines.
- The fluorescence quenching and displacement assays are reliable for evaluating carrier-bound anthracycline-DNA interactions.
- These findings aid in the development of improved nanocarrier-based drug delivery systems.
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