Overcomes limitations of temperature-, light-, and pH-based systems… enables precise control in deep tissues using a low 3V electrical stimulus

Maintains therapeutic drug levels for over 14 days and demonstrates immune activation and inhibition of tumor angiogenesis

Research published in Biomaterials (IF=12.9), a leading journal in the field of biomaterials 

Image: Schematic illustration of an electrically responsive hyaluronic acid–based hydrogel enabling metronomic chemotherapy through electrically controlled release of the anticancer drug doxorubicin (Doxorubicin)

 The Catholic University of Korea (President Choi Jun-gyu) announced that a research team led by Professor Na Geon of the Department of Biomedical Chemical Engineering and Professor Kim Kyung-seop of the School of Biotechnology has developed a next-generation precision drug delivery system, “HTZ@D hydrogel,” which enables precise control over the timing and dosage of anticancer drug release through external electrical stimulation. The study is being recognized for significantly enhancing the clinical feasibility of “metronomic chemotherapy,” which aims to minimize side effects associated with high-dose anticancer treatments.

Conventional chemotherapy typically relies on administering high doses of anticancer drugs over a short period to achieve strong therapeutic effects. However, this approach often leads to severe toxic side effects, weakened immunity, and drug resistance. As an alternative, metronomic therapy—characterized by the long-term administration of low-dose drugs—has gained attention. Nevertheless, existing oral and intravenous delivery methods face challenges in maintaining stable drug concentrations in the body and place a significant burden on patients due to repeated dosing.

In particular, traditional drug delivery systems have utilized external stimuli such as temperature, light, and pH. However, these approaches are limited in terms of penetration depth and precise controllability, posing challenges for practical clinical applications.

To overcome these limitations, the research team focused on electrical stimulation, which offers high controllability and repeatability. They designed a composite hydrogel system, “HTZ@D,” by integrating biocompatible polysaccharides, natural substances, and human-derived metal ions. The system successfully releases the loaded anticancer drug, doxorubicin, only when subjected to a low-level alternating electrical stimulus of approximately 3V.

According to the study, the HTZ@D system demonstrated excellent stability, with drug leakage limited to approximately 8% over 14 days in the absence of electrical stimulation. In contrast, when electrical stimulation was applied, the system maintained the drug concentration within the optimal therapeutic range (10–100 ng/mL) for more than 14 days with high precision.

In animal experiments, the system selectively eliminated cancer cells while causing minimal impact on normal cells. It not only effectively suppressed tumor growth but also exhibited multifaceted anticancer effects, including enhanced immune cell activation and inhibition of tumor angiogenesis. These results demonstrate both superior safety and efficacy compared to conventional chemotherapy.

The research findings were published in Biomaterials (IF=12.9), a leading international journal in the field of biomaterials.

Professor Na Geon, the corresponding author, stated, “This study is significant in that it presents a foundational platform technology capable of realizing personalized precision medicine by enabling precise control over drug administration timing and dosage through electrical stimulation. It is expected to not only reduce the side effects of chemotherapy and improve patients’ quality of life but also alleviate the burden of repeated treatments and contribute to reducing medical costs.”

The research team plans to further advance the technology by developing a fully implantable therapeutic platform based on a wireless electrical stimulation system that can operate without external devices. In addition, they aim to expand its application beyond anticancer drugs to various intractable diseases, including inflammatory conditions and tissue regeneration, while accelerating efforts toward commercialization following long-term safety and toxicity validation.

(Figure 1) Schematic illustration of an electrically responsive hyaluronic acid–based hydrogel enabling metronomic chemotherapy through electrically controlled release of the anticancer drug doxorubicin (Doxorubicin)

This figure illustrates the operating mechanism of the hydrogel (HTZ@D), which releases anticancer drugs in response to electrical stimulation. When electrical stimulation is applied, the internal bonding structure of the hydrogel changes, triggering drug release; in the absence of stimulation, release is suppressed, enabling precise control. This allows for the implementation of “metronomic therapy,” which maintains a consistent drug concentration in the body. In addition, it demonstrates a mechanism that maximizes anticancer efficacy by enhancing immune activation and inhibiting angiogenesis within the tumor microenvironment.

(Figure 2) Evaluation of the physical properties of HTZ and HTZ@D hydrogels and their electrically stimulated drug release behavior

This figure presents the analysis of the physical properties of the developed hydrogel and its ability to control drug release in response to electrical stimulation.
 (A) The uniform encapsulation of the anticancer drug doxorubicin within the hydrogel was confirmed through fluorescence signal distribution.
 (B) An LED illumination experiment visually demonstrated the hydrogel’s excellent electrical conductivity and efficient transmission of electrical stimulation.
 (C) The results show that “on–off” precise control of drug release is possible, with immediate regulation depending on the presence or absence of electrical stimulation.

(Figure 3) Device for the electrically stimulated drug delivery system, images of HTZ@D, and evaluation of plasma doxorubicin concentration changes in mice following device implantation and stimulation

This figure presents the practical implementation of the electrically stimulated drug delivery device and its effectiveness in regulating drug concentration in vivo.

(A) It shows the structure of the device fabricated using 3D printing technology, in which the HTZ@D hydrogel is embedded. The system is designed to deliver electrical stimulation through platinum electrodes.

(B) In experiments with a mouse model following device implantation, the electrically stimulated group maintained sustained plasma levels of doxorubicin. Notably, a 10-minute stimulation produced stable drug concentrations within the effective therapeutic range. In contrast, under non-stimulated conditions, drug levels rapidly declined. These results demonstrate that repeated control of drug release via electrical stimulation enables the realization of metronomic therapy.