Malignant tumors are one of the leading causes of death worldwide [1,2]. Surgery is often the primary treatment option, particularly for solid tumors. However, the main drawback of this surgery is the risk of recurrence. Microscopic cancer cells may remain in the body even after a tumor is surgically excised, potentially forming new tumors and leading to disease recurrence [[3], [4], [5]]. Chemotherapy is commonly used to eradicate any remaining cancer cells post-surgery [6]. Regrettably, only a small percentage of intravenously administered anti-cancer drugs reach the tumor site. Additionally, these drugs are rapidly metabolized and expelled from the body, consequently requiring high doses to achieve therapeutic efficacy [[7], [8], [9]]. However, chemotherapeutic drugs can damage healthy cells, resulting in side effects such as fatigue, nausea, hair loss, and infection [10,11].

Local drug delivery systems (LDDS), such as hydrogels, implants, and wafers, minimize systemic side effects and improve therapeutic efficacy by directly delivering high concentrations of drugs to specific areas, such as surgical sites [[12], [13], [14]]. However, LDDS present several challenges. Drugs encapsulated within an LDDS can initially be released in large amounts (termed an initial burst release), leading to excessively high local concentrations and potential side effects [15,16]. Furthermore, typical LDDS cannot be controlled or adjusted in response to changes in the patient's condition after administration. These limitations can reduce the efficacy of treatment and increase the risk of side effects [17]. In addition, LDDS cannot be refilled once the drug is dispensed; thus, a new LDDS must be implanted, which is inconvenient for the patient [18].

Therefore, a reservoir that replenishes drugs in vivo via the bloodstream serves as a promising alternative [[18], [19], [20]].

Drugs injected into the blood circulate throughout the body and are captured in reservoirs at target sites. They are subsequently released slowly, allowing high concentrations of the drug to be delivered to the target site through a”capture and release” process. The reservoir in the body allows the drug to be replenished repeatedly, and the drug regimen can be easily adjusted according to the patient's condition. The binding and release of the drug from the reservoir are important aspects. The bond between the reservoir and the drug must be strong enough to capture the drug from the blood but a bond that is too strong has the disadvantage that the drug cannot be released after capture. Existing reservoir-drug binding technologies typically use strong binding, such as click chemistry and host-guest reactions, to capture drugs in reservoirs. This ensures effective drug capture. However, because strong binding does not lead to drug release after capture, prodrugs with linkers are usually used to bind to the reservoir, and the linker is subsequently cleaved to release the active drug. However, there are drawbacks to this approach, such as limited efficacy and limited drug classes available [18,21].

To address this issue, reservoirs inspired by albumin-drug binding were prepared to allow proper capture and release of the drug in vivo. Once a drug enters the bloodstream, it either remains “free” or binds to various plasma proteins [22,23]. Albumin, the most abundant protein in the plasma, can bind to many drugs, including warfarin, doxorubicin, indocyanine green, and diazepam. The drug forms a reversible complex with albumin, which circulates throughout the bloodstream, where the drug slowly dissociates from the albumin. The gradual release of the drug from the drug-albumin complex can prolong its effects [[24], [25], [26], [27]]. For example, indocyanine green, a dye used in medical imaging and diagnostics, binds to albumin. This binding extends the circulation time of the dye in the bloodstream, allowing it to be used as a contrast agent for extended periods during imaging procedures [28,29]. Albumin can bind to drugs even though there are other endogenous substances in the body that can bind to albumin. Albumin has multiple binding sites and several substances can bind to these sites simultaneously. [25,30]. Because the binding between albumin and a drug is a dynamic reaction, it is balanced depending on the concentration and affinity of the drug [31,32]. Therefore, albumin-drug binding can be effective even in the blood.

A high-concentration albumin hydrogel was developed that can capture and release drugs from blood by utilizing the drug-binding properties of albumin, a natural protein found in the body. In a previous study, thiol-modified albumin and 4-arm PEG-maleimide were used to prepare albumin hydrogels that encapsulated gold nanorods and Chlorella [33]. In this study, hydrogels were prepared using azide-modified albumin and 4-arm PEG-DBCO. Albumin hydrogels can be easily prepared via click chemistry between azide-modified albumin and 4-arm PEG-DBCO, forming injectable hydrogels in less than one minute. The albumin concentration in the hydrogel reaches up to 40 mg/mL, which enhances its drug-binding capacity.

Consequently, when a drug such as indocyanine green or doxorubicin is administered to the blood, the albumin hydrogel effectively captures the drug through albumin-drug binding (Scheme). Because this binding is reversible, it allows for gradual drug release and the possibility of continuous drug refilling. This drug capture and release method using an albumin hydrogel can be easily fabricated without requiring drug modification, thus maintaining drug activity and offering the advantage of applicability to various drugs. Moreover, it allows high concentrations of drugs to be repeatedly delivered to the desired area, potentially enhancing therapeutic effects and reducing toxicity.

Tumor cells rapidly proliferate, necessitating increased nutrients and oxygen, leading to the secretion of angiogenic factors, such as VEGF and ANG1. This results in the formation of abnormal and inefficient blood vessels, which cause hypoxia and nutrient deficit [34,35]. Hydrogels, particularly hydrophilic ones, can absorb considerable amounts of water because of the free penetration of water into their network [36]. When the hydrogel is injected into a tumor, it swells and establishes contact with both the blood vessels of the tumor and the surrounding normal tissue. This allows the hydrogel to capture drugs from nearby blood vessels and subsequently release them into the tumor.

When the albumin hydrogel was implanted at a tumor or the surgical site, it inhibited tumor growth and recurrence by continuously capturing and releasing the drug. Therefore, the drug-binding properties of the high-concentration albumin hydrogel make it a novel and continuously refillable reservoir for local drug delivery.

Scheme. Scheme illustration showing drug capture and release in albumin hydrogels.