Injectable Hydrogels for Local Pharmacokinetic Control in Solid Tumors: From Passive Reservoirs to Stimulus-Responsive Exposure Systems.

Solid tumors remain difficult therapeutic targets because inadequate and heterogeneous intratumoral exposure, rapid local clearance, and postoperative recurrence can limit durable tumor control. Injectable hydrogels provide locoregional platforms that prolong drug residence within tumors or resection cavities while reducing systemic distribution. However, prolonged retention alone does not justify classifying these systems as pharmacokinetic organlike regulators. Here, we synthesize the literature on injectable hydrogels for solid tumor therapy and distinguish passive long-acting reservoirs from stimulus-responsive local pharmacokinetic regulators using three operational criteria: partial decoupling of local exposure from systemic circulation, context-dependent release or degradation in response to tumor cues, and measurable pharmacokinetic outputs linked to the tissue state or therapeutic response. Preclinical evidence indicates that hydrogel depots can increase local residence time, reduce systemic exposure, remodel the tumor immune microenvironment, and suppress recurrence. Nevertheless, most systems remain better supported as sustained local reservoirs than as fully validated systems with PK organ-like potential. Key gaps include limited matched tumor and plasma pharmacokinetic data, insufficient PK/PD modeling, nonstandardized recurrence end points, and limited clinical validation. This review provides an exposure-centered framework for defining evidence required to support PK-organ-like claims.