A hyaluronic acid-camptothecin nanoprodrug with cytosolic mode of activation for targeting cancer
2013 (English)In: POLYM CHEM-UK, ISSN 1759-9954, Vol. 4, no 17, 4621-4630 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2013. Vol. 4, no 17, 4621-4630 p.
IdentifiersURN: urn:nbn:se:uu:diva-207489DOI: 10.1039/c3py00402cISI: 000323361300013OAI: oai:DiVA.org:uu-207489DiVA: diva2:648946