Malignant gliomas are the most common and aggressive form of primary brain tumors, with a median survival of 15–20 months for patients receiving maximal interventions. Advances in nanomedicine have provided tumor‐specific delivery of chemotherapeutics to potentially overcome their off‐target toxicities. Recent advances in dendrimer‐based nanomedicines have established that hydroxyl‐terminated poly(amidoamine) dendrimers can intrinsically target neuroinflammation and brain tumors from systemic administration without the need for targeting moieties. The size of nanocarriers is a critical parameter that determines their tumor‐targeting efficiency, intratumor distribution, and clearance mechanism. In this study, we explore the dendrimer size effects on brain tumor targeting capability in two clinically relevant orthotopic brain tumor models, the 9L rat and GL261 mouse models, which capture differing aspects of gliomas. We show that increasing dendrimers from Generation 4 to Generation 6 significantly enhances their tumor accumulation (~10‐fold greater at 24 hr), tumor specificity (~2–3 fold higher), and tumor retention. The superior tumor targeting effect of G6 dendrimers is associated with its reduced renal clearance rate, resulting in longer circulation time compared to G4 dendrimers. Additionally, the increase in dendrimer generation does not compromise its homogeneous tumor distribution and intrinsic targeting of tumor‐associated macrophages. These results validate the potential for these dendrimers as an effective, clinically translatable platform for effectively targeting tumor‐associated macrophages in malignant gliomas.

中文翻译：

---

树状体大小对全身给药后原位肿瘤模型中选择性脑肿瘤靶向的影响。


恶性神经胶质瘤是原发性脑肿瘤中最常见和最具侵袭性的形式，接受最大程度干预的患者的中位生存期为 15-20 个月。纳米医学的进步提供了肿瘤特异性化疗药物的递送，以潜在地克服其脱靶毒性。基于树枝状聚合物的纳米药物的最新进展已经证实，羟基封端的聚（酰胺基胺）树枝状聚合物可以通过全身给药内在地靶向神经炎症和脑肿瘤，而不需要靶向部分。纳米载体的尺寸是决定其肿瘤靶向效率、瘤内分布和清除机制的关键参数。在这项研究中，我们在两种临床相关的原位脑肿瘤模型（9L 大鼠和 GL261 小鼠模型）中探讨了树枝状大分子大小对脑肿瘤靶向能力的影响，这两种模型捕获了胶质瘤的不同方面。我们发现，从第 4 代到第 6 代不断增加的树枝状聚合物显着增强了它们的肿瘤积累（24 小时时增加约 10 倍）、肿瘤特异性（增加约 2-3 倍）和肿瘤保留。 G6 树枝状聚合物卓越的肿瘤靶向作用与其降低的肾清除率有关，从而导致与 G4 树枝状聚合物相比更长的循环时间。此外，树枝状聚合物生成的增加不会损害其均匀的肿瘤分布和肿瘤相关巨噬细胞的内在靶向性。这些结果验证了这些树枝状聚合物作为有效的临床可转化平台的潜力，可有效靶向恶性胶质瘤中的肿瘤相关巨噬细胞。