Novel Hyaluronic Acid Conjugates for Dual Nuclear Imaging and Therapy in CD44-Expressing Tumors in Mice In Vivo

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Hyaluronic acid, a natural CD44 receptor ligand, has attracted attention in the past years as a macromolecular delivery of anticancer agents to cancer. At the same time, the clinical applications of Gemcitabine (Gem) have been hindered by its short biological half-life, high dose and development of drug resistance. This work reports the synthesis of a hyaluronic acid (HA) conjugate for nuclear imaging, and in vivo Gem delivery to CD44-expressing solid tumors in mice. HA was individually conjugated, via amide coupling, to Gem (HA-Gem), 4'-(aminomethyl)fluorescein hydrochloride (HA-4’-AMF) or
tris(hydroxypyridinone) amine (HA-THP) for cancer therapy, in vitro tracking or single photon emission computed tomography/computed tomography (SPECT/CT) imaging, respectively. Gem conjugation to
HA was directly confirmed by nuclear magnetic resonance (1H NMR), gel permeation chromatography (GPC) and UV–visible spectrometry, or indirectly by a nucleoside transporter inhibition study. Gem
conjugation to HA improved its plasma stability, reduced blood hemolysis and resulted in delayed cytotoxicity in vitro. Uptake inhibition studies in colon CT26 and pancreatic PANC-1 cells, by flow
cytometry, revealed that uptake of fluorescent HA conjugate is CD44 receptor and macropinocytosis-dependent. Gamma scintigraphy and SPECT/CT imaging confirmed the relatively
prolonged blood circulation profile and uptake in CT26 (1.5 % ID/gm) and PANC-1 (1 % ID/gm) subcutaneous tumors at 24 h after intravenous injection in mice. Four injections of HA-Gem at ~15
mg/kg, over a 28-day period, resulted in significant delay in CT26 tumor growth and prolonged mice survival compared to the free drug. This study reports for the first time dual nuclear imaging and drug
delivery (Gem) of HA conjugates to solid tumors in mice. The conjugates show great potential in targeting, imaging and killing of CD44-over expressing cells in vivo. This work is likely to open new
avenues for the application of HA-based macromolecules in the field of image-guided delivery in oncology.
Original languageEnglish
Issue number1
Publication statusPublished - 1 Jan 2017


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