Abstract
The poor pharmacokinetics and selectivity of low-molecular-weight anticancer drugs contribute to the relatively low effectiveness of chemotherapy treatments. To improve the pharmacokinetics and selectivity of these treatments, the combination of a doxorubicin-glucuronide prodrug (DOX-propGA3) nanogel formulation and the liberation of endogenous β-glucuronidase from cells exposed to high-intensity focused ultrasound (HIFU) were investigated in vitro. First, a DOX-propGA3-polymer was synthesized. Subsequently, DOX-propGA3-nanogels were formed from this polymer dissolved in water using inverse mini-emulsion photopolymerization. In the presence of bovine β-glucuronidase, the DOX-propGA3 in the nanogels was quantitatively converted into the chemotherapeutic drug doxorubicin. Exposure of cells to HIFU efficiently induced liberation of endogenous β-glucuronidase, which in turn converted the prodrug released from the DOX-propGA3-nanogels into doxorubicin. β-glucuronidase liberated from cells exposed to HIFU increased the cytotoxicity of DOX-propGA3-nanogels to a similar extend as bovine β-glucuronidase, whereas in the absence of either bovine β-glucuronidase or β-glucuronidase liberated from cells exposed to HIFU, the DOX-propGA3-nanogels hardly showed cytotoxicity. Overall, DOX-propGA3-nanogels systems might help to further improve the outcome of HIFU-related anticancer therapy.
Highlights
Chemotherapy is one of the most commonly used treatment modalities in cancer, either as a monotherapy or in combination with another treatment modalities, such as radiotherapy and surgery [1]
Doxorubicin-glucuronide prodrug (DOX-propGA3) was coupled to the polymer hydroxyethyl methacrylamide-oligoglycolates-derivatized poly(hydroxyethyl methacrylamide-co-N-(2-azidoethyl)methacrylamide (p(HEMAm-co-AzEMAm)-Gly-HEMAm) via click chemistry (DOX-propGA3-polymer)
The synthesized DOX-propGA3-polymer conjugate was analyzed by gel permeation chromatography (GPC) using a Waters System (Waters Associates Inc., Milford, MA, USA) with refractive index (RI) and UV detection using two PLgel 5 μm MIXED-D columns (Agilent, Pal Alto, CA, USA) and DMF containing 10 mM LiCl as eluent, with an injection volume of 100 μL, and flow rate of 1 mL/min at a temperature of 60 ◦C
Summary
Chemotherapy is one of the most commonly used treatment modalities in cancer, either as a monotherapy or in combination with another treatment modalities, such as radiotherapy and surgery [1]. Since HIFU is a local and noninvasive technique [37], this enables the possibility of increasing the β-gus concentration available for prodrug conversion locally in the tumor by a noninvasive treatment, without damaging the normal tissue As mentioned, both the pharmacokinetics and tumor side selective activation of the prodrug are important factors for effective prodrug therapy treatment [28,29]. We investigated the combination of prodrug-nanogel formulation and UDEPT to address the shortcomings of small molecular prodrugs and increase the enzyme concentration available for prodrug conversion, in vitro To this end, doxorubicin-glucuronide prodrug (DOX-propGA3) (structure shown in Figure 1A) was coupled to the polymer hydroxyethyl methacrylamide-oligoglycolates-derivatized poly(hydroxyethyl methacrylamide-co-N-(2-azidoethyl)methacrylamide (p(HEMAm-co-AzEMAm)-Gly-HEMAm) via click chemistry (DOX-propGA3-polymer).
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