Cationic Polypeptide Dendrimers with Concurrent Antibacterial and Anticancer Activities Depending on Topological Structure

Bacterial infections complicate cancer treatment, necessitating agents with concurrent antibacterial and anticancer activities. The rational design of host defense peptide (HDP) mimics that retain this dual efficacy via a membranolytic mechanism represents a critical challenge. In this study, two series of cationic polypeptide dendrimers (Orn_Gn and Lys_Gn, <i>n</i> = 3-5) were constructed and the results demonstrated that their antimicrobial and antitumor efficacy exhibits significant dependence on dendrimer generations and interior size. Among all products, Lys_G5 exhibited the best antitumor activity (IC₅₀ = 64 μg/mL) and considerable antibacterial activity (MIC = 16 μg/mL). Membrane morphology analysis revealed that increasing dendrimer generations induced expansive membranolytic domains, whereas larger interior sizes potentiated the membrane penetration depth. Further, Lys_G5 suppressed tumor progression in vivo (64% reduction in tumor weight, <i>p</i> < 0.001) with negligible damage to healthy tissues. Overall, constructing HDP mimics with optimal dendrimer topology structure is a promising strategy to resolve challenges in the concurrent treatment of bacteria and tumors.