Drug Leakage Limits Intratumoral Drug Exposure and Efficacy: Influence of Tumor Mechanical Heterogeneity.

Intratumoral administration is widely used to achieve high local drug delivery while minimizing systemic toxicity. However, the fundamental assumption that locally injected agents remain within tumor tissue has rarely been quantitatively examined. Here, we show that drug leakage from the tumor surface can reduce leakage-adjusted local retention and limit therapeutic efficacy after intratumoral injection. Using multiple tumor models, conventional needle injection frequently resulted in drug escape from the tumor surface, leading to reduced leakage-adjusted retention and diminished therapeutic efficacy. Mechanical measurements revealed pronounced differences in tissue stiffness across tumor types, suggesting that tumor mechanical properties may contribute to differences in drug leakage and local retention. Histological analysis further showed that guided jet injection induces structural remodeling within tumor tissue, creating transient interstitial spaces that may facilitate intratumoral fluid propagation. Consistent with these structural observations, three-dimensional imaging demonstrated distinct cavity-formation patterns between conventional needle injection and guided jet delivery. Together, these findings indicate that drug leakage is an underrecognized physical limitation of intratumoral drug delivery and that tumor mechanical heterogeneity is associated with local retention. This study provides a rationale for improving local drug delivery through mechanically guided injection strategies.