Conventional cancer therapy exploits sensitivity of dividing cells to DNA damage leading to apoptosis and tumor kill. Off-target normal tissue toxicity limits the maximum tolerated dose (MTD) and potential tumor ablation. We developed a targeted nanoparticle therapeutic platform that maximizes delivery of small molecules to tumor cells, including across the blood-brain barrier that normally prevents effective therapy with such agents. The core technology is a novel nanoparticle formulation that maximizes bioavailability and preferentially targets tumor cells while minimizing delivery to normal cells. Plasma irinotecan levels remain readily detectable for at least 48 hours, while free irinotecan is no longer detectable at 2 hours. Nanoparticles are readily imaged in tumor cells when virtually none are detectable in normal tissues. Targeting is achieved with antibodies that cause the nanoparticles to preferentially bind to tumor cells versus normal by a factor of at least 10. Levels of drug by quantitative mass spectroscopy are at least 15-fold greater in tumor vs normal tissue. As a result, the minimum effective dose (MED) is typically reduced ten-fold. Typical payloads include irinotecan, doxorubicin, and gemcitabine. Targeting antibodies include CD276 (B7H3) and CD99 (MIC2) for solid tumors. Compared to antibody-drug conjugates (ADCs), far greater drug doses per antibody molecule are delivered. In addition, the nanoparticles readily pass through the blood-brain barrier at least 15 times better than free drug alone. Consequently, the platform technology shows promise for treatment of both extra-cranial and intra-cranial tumors. In pre-clinical animal studies, survival of human PDX glioblastoma (GBM) bearing mice was prolonged by at least three-fold compared to free-drug treated animals when treated at a sub-optimal dose of 10mg/kg of irinotecan thrice weekly. Ewing sarcoma bearing mice showed indefinite survival at 2 mg/kg bi-weekly dosing, even for relapsed, treatment-resistant tumors. Treatment of hepatocellular carcinoma bearing mice biweekly at 5mg/kg resulted in no detectable tumor and 100% survival at 80 days, when all free irinotecan treated mice at the same dose were dead, with control animals dead at 50 days. Similarly, prostate cancer bearing mice treated at the same dose and regimen were all alive at 58 days when all untreated tumor bearing mice were dead. A similar result was obtained with ovarian cancer and the same treatment regimen, but tumor growth in treated animals was observed at 58 days when all untreated animals were dead. Perhaps most significantly, treated mice bearing pancreatic cancer showed 100 % survival at 80 days when all untreated animals were dead at day 59. At no time did any animal show evidence of treatment-related toxicity. Taken together, these results support a non-toxic cancer treatment approach with existing small molecule therapy that preferentially delivers drug to tumor with markedly improved efficacy. Citation Format: HyungGyoo Kang, Bryon Upton, Paul Scott, Mark Lewis, Jon Nagy, Timothy Triche. Targeted nanospheres for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 825.