Glioblastoma is the most common and aggressive form of primary brain cancer, with median survival of 16–20 months and a 5‐year survival rates of <5%. Recent advances in immunotherapies have shown that addressing the tumor immune profile by targeting the colony‐stimulating factor 1 (CSF‐1) signaling pathway of tumor‐associated macrophages (TAMs) has the potential to improve glioblastoma therapy. However, such therapies have shown limited successes in clinical translation partially due to lack of specific cell targeting in solid tumors and systemic toxicity. In this study, we present a novel hydroxyl dendrimer‐mediated immunotherapy to deliver CSF‐1R inhibitor BLZ945 (D‐BLZ) from systemic administration selectively to TAMs in glioblastoma brain tumors to repolarize the tumor immune environment in a localized manner. We show that conjugation of BLZ945 to dendrimers enables sustained release in intracellular and intratumor conditions. We demonstrate that a single systemic dose of D‐BLZ targeted to TAMs decreases pro‐tumor expression in TAMs and promotes cytotoxic T cell infiltration, resulting in prolonged survival and ameliorated disease burden compared to free BLZ945. Our results demonstrate that dendrimer‐drug conjugates can facilitate specific, localized manipulation of tumor immune responses from systemic administration by delivering immunotherapies selectively to TAMs, thereby improving therapeutic efficacy while reducing off‐target effects.

Patients with glioblastoma have failed to see improved outcomes despite the discovery of powerful anti-cancer drugs because such therapies do not adequately cross the blood-brain barrier and penetrate into solid tumors to access pathological cells. In addition to these delivery challenges, tumors polarize host macrophages into tumor-associated macrophages (TAMs), which suppress the tumor-killing response and create a growth-conducive immune environment for cancer cells. As a result, TAMs are promising therapeutic targets but translational efforts targeting them have largely failed due to low response rates and high systemic toxicities. Therefore, a vehicle that carries immunotherapies into the brain, deep into solid tumors, and specifically to TAMs while remaining inactive in the body provides a promising clinical strategy. Here, we present hydroxyl-terminated polyamidoamine (PAMAM) dendrimers as novel targeted drug delivery systems to overcome these delivery challenges in the GL261 mouse model of glioblastoma. Upon systemic administration, these dendrimers, without any targeting ligands, are able to cross the blood-brain barrier, distribute uniformly throughout the solid glioblastoma tumor, and localize specifically within TAMs. Dendrimers display high tumor specificity (>5-fold compared to the contralateral hemisphere) and minimal systemic accumulation (< 5% initial dose remaining in livers or kidneys after 24 hours). We then conjugated BLZ945, a potent immunotherapy that prevents tumors from recruiting TAMs, to the dendrimer via pH-sensitive linkers for triggered intratumoral and intracellular release. We find that a single systemic dose of dendrimer-delivered BLZ945 halfway through disease progression prolongs survival by >30% compared to free BLZ945 and untreated cohorts. These survival benefits were accompanied by amelioration of disease progression and improved motor function. Finally, we demonstrate that repeat dosing of dendrimer-delivery BLZ945 in combination with current standard of care temozolomide provides robust, synergistic improvements to survival and disease severity. These studies validate the potential of dendrimers for localized immune manipulation in glioblastoma.

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