High-Performance Concurrent Chemo-Immuno-Radiotherapyfor the Treatment of Hematologic Cancer through Selective High-AffinityLigand Antibody Mimic-Functionalized Doxorubicin-Encapsulated Nanoparticles

摘要

Non-Hodgkin lymphoma is one of the most common types of cancer. Relapsed and refractory diseases are still common and remain significant challenges as the majority of these patients eventually succumb to the disease. Herein, we report a translatable concurrent chemo-immuno-radiotherapy (CIRT) strategy that utilizes fully synthetic antibody mimic Selective High-Affinity Ligand (SHAL)-functionalized doxorubicin-encapsulated nanoparticles (Dox NPs) for the treatment of human leukocyte antigen-D related (HLA-DR) antigen-overexpressed tumors. We demonstrated that our tailor-made antibody mimic-functionalized NPs bound selectively to different HLA-DR-overexpressed human lymphoma cells, cross-linked the cell surface HLA-DR, and triggered the internalization of NPs. In addition to the direct cytotoxic effect by Dox, the internalized NPs then released the encapsulated Dox and upregulated the HLA-DR expression of the surviving cells, which further augmented immunogenic cell death (ICD). The released Dox not only promotes ICD but also sensitizes the cancer cells to irradiation by inducing cell cyclearrest and preventing the repair of DNA damage. In vivo biodistributionand toxicity studies confirm that the targeted NPs enhanced tumoruptake and reduced systemic toxicities of Dox. Our comprehensive invivo anticancer efficacy studies using lymphoma xenograft tumor modelsshow that the antibody-mimic functional NPs effectively inhibit tumorgrowth and sensitize the cancer cells for concurrent CIRT treatmentwithout incurring significant side effects. With an appropriate treatmentschedule, the SHAL-functionalized Dox NPs enhanced the cell killingefficiency of radiotherapy by more than 100% and eradicated more than80% of the lymphoma tumors.