Development and Antitumor Evaluation of Doxorubicin-Loaded Two-Layered Sheets for Local Chemotherapy via Direct Drug Application to the Tumor Surface

<b>Background/Objectives:</b> Non-specific distribution of anticancer drugs to non-lesional areas of the body and organs, followed by their rapid disappearance, limits the drug concentration in the tumor, impacting the chemotherapy efficacy. To address this issue, local drug administration is important for controlled drug distribution. Therefore, this study aimed to design two-layered sheets loaded with doxorubicin (DOX) and 10 or 20% (<i>w</i>/<i>w</i>) additives for direct tumor application. <b>Methods:</b> Polyethylene glycol, hydroxypropyl cellulose, and polyvinylpyrrolidone were used as additives to prepare poly(lactic-<i>co</i>-glycolic acid)-based DOX-loaded sheets. <i>In vitro</i> release, <i>in vivo</i> antitumor effects, and biodistribution of the drug were evaluated in mice. <b>Results:</b> Additive-containing sheets exhibited diverse <i>in vitro</i> release profiles and several sheets exerted significantly more potent antitumor effects than additive-free DOX sheets in Hepa1-6 tumor-bearing mice. Fourteen days after application, DOX was majorly distributed within the tumor, and its concentrations in most normal organs were below the detection limit. The overall antitumor effects of the additive-containing sheets, as measured by the area under the curve, were statistically indistinguishable; however, mean concentration in the 20% polyethylene glycol-DOX sheet group was approximately 7-fold higher than that in the 20% hydroxypropyl cellulose-DOX sheet group. These findings suggest that antitumor mechanisms do not rely solely on the absolute drug concentration at the tumor site. <b>Conclusions:</b> Overall, our findings provide important insights for the development of DOX-loaded two-layered sheets for direct tumor application.