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Issue 17, 2013
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A hyaluronic acidcamptothecin nanoprodrug with cytosolic mode of activation for targeting cancer

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Abstract

We have developed a nanoprodrug that enables the uptake by cancer cells and the subsequent intracellular activation. The nanoprodrug is composed of a cancer cell-targeting biopolymer, hyaluronic acid (HA), and an anti-cancer drug, camptothecin (CPT). The chemical linkage between the polymer and the drug is stable outside the cells, thus maintaining the drug in an “off” state. The specific uptake of the nanoprodrug by cancer cells should then lead to an environmental change that results in the cleavage of the linkage, liberating the drug and thus entering the “on” state. The natural cancer-targeting biopolymer HA was modified with aldehyde “click” groups. This “clickable” HA was then conjugated to CPT modified with a hydrazide linker using a mild hydrazone-coupling reaction. The linker consists of a thiol-activated self-immolative dithioethoxycarbonyl spacer, which is stable in PBS buffer but should be rapidly cleaved in the reductive cytosolic environment of cancer cells. The resulting HA–CPT nanoprodrug released CPT only at low levels in PBS buffer. However, the drug was efficiently cleaved after the addition of dithiothreitol (DTT). Consistent with these data, the HA–CPT nanoprodrug showed a 3-fold greater cytotoxicity to cancer cells compared to free CPT. Fluorescence microscopy confirmed the rapid and efficient uptake of the HA–CPT nanoprodrug by the cancer cells.

Graphical abstract: A hyaluronic acid–camptothecin nanoprodrug with cytosolic mode of activation for targeting cancer

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Publication details

The article was received on 27 Mar 2013, accepted on 06 Jun 2013 and first published on 07 Jun 2013


Article type: Paper
DOI: 10.1039/C3PY00402C
Citation: Polym. Chem., 2013,4, 4621-4630
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    A hyaluronic acidcamptothecin nanoprodrug with cytosolic mode of activation for targeting cancer

    X. Yang, I. Dogan, V. R. Pannala, S. Kootala, J. Hilborn and D. Ossipov, Polym. Chem., 2013, 4, 4621
    DOI: 10.1039/C3PY00402C

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