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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.

The tumor-targeted, nanoparticle delivery technology has shown the possibility of increasing the delivered dose of virtually any small therapeutics to tumor cells while limiting the drug uptake by normal tissues, thereby greatly increasing the effective MTD. By refining the early formulations and after extensive testing, we developed a novel targeted liposomal nanoparticle, Targeted NanoSpheres (TNS). We showed this novel nano-formulated platform can overcome many deficiencies of conventional nanoparticles and therefore has enhanced potential as an effective delivery vehicle for virtually any type of cancer for which a suitable tumor cell surface antigen is present. We have developedNV103, a first-in-class anti-CD99 TNS (CD99-TNS/Irinotecan), for the treatment of Ewing Sarcoma (EWS), a highly lethal pediatric and young adult bone and soft tissue tumor driven by a fusion protein, typically EWS/FLI1 in over 85% of cases. Cancer cells have the ability to develop resistance to the chemotherapy. Our present salvage/rescue study with NV103 showed that NV103 can overcome irinotecan resistance of Ewing tumor with simple change of dose schedule (dose intensification), not increasing the dose. The results from our salvage/rescue studies with NV103 suggested that successful dose intensification schedules with NV103 could be used to treat relapsed or resistant patients in future clinical trials. Furthermore, Targeted Nanosphere (TNS) can be used to overcome drug resistance of various cancers.This platform is also being investigated for other types of cancer that either express CD99, or other tumor antigens like GD2 and B7-H3. Citation Format: HyungGyoo Kang, Jon Nagy, Bryon Upton, Racheal Upton, Timothy Triche, Timothy Triche. Targeted NanoSpheres (TNS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 312.

Osteosarcoma is the most common primary malignancy of bone in children, adolescents, and adults. Despite extensive surgery and adjuvant aggressive high-dose systemic chemotherapy with potentially severe bystander side effects, cure is attainable in about 70% of patients with localized disease and only 20%–30% of those patients with metastatic disease. Targeted therapies clearly are warranted in improving our treatment of this adolescent killer. However, a lack of osteosarcoma-associated/specific markers has hindered development of targeted therapeutics. We describe a novel osteosarcoma-associated cell surface antigen, ALCAM. We, then, create an engineered anti-ALCAM-hybrid polymerized liposomal nanoparticle immunoconjugate (α-AL-HPLN) to specifically target osteosarcoma cells and deliver a cytotoxic chemotherapeutic agent, doxorubicin. We have demonstrated thatα-AL-HPLNs have significantly enhanced cytotoxicity over untargeted HPLNs and over a conventional liposomal doxorubicin formulation. In this way,α-AL-HPLNs are a promising new strategy to specifically deliver cytotoxic agents in osteosarcoma.