Intratumor performance and therapeutic efficacy of PAMAM dendrimers carried by clustered nanoparticles.

In recent years, small nanoparticles (NPs) with diameter less than 10 nm have aroused considerable interests in biomedical applications. However, their intratumor performance, as well as the antitumor efficacy, has not been well understood due to their size-dependent pharmacokinetics, which presents a formidable challenge for delivering comparable amount of different small NPs to tumor tissues. Utilizing the multistage delivery strategy, we construct G3-, G5-, and G7-iCluster delivery systems by using poly(amidoamine) (PAMAM) dendrimers of different generations (G3-, G5-, and G7-PAMAM) as building blocks. The iCluster nanoparticles showed comparable pharmacokinetics and similar initial tumor deposition due to their similarity in size and surface chemistry. After accumulating at tumor site, individual small dendrimers were released, and thus their intratumor performance was comparatively investigated. Our results indicated that a subtle change in generation markedly affects their intratumor activities. G5-iCluster outperformed G3-iCluster and G7-iCluster in the treatment efficacy in an orthotopic pancreatic tumor model. The mechanistic study revealed that G3-PAMAM showed reduced particle retention in tumor tissue due to its small size and weak cell internalization, while G7-PAMAM was much less penetrative because of its relatively large size and strong particle-cell interaction. In contrast, G5-PAMAM exhibited balanced tumor penetration, cell internalization, and tumor retention. Our finding highlights the huge influence of subtle difference of small NPs in their intratumor performance.