Wen and Wu et al. show rituximab (anti-CD20) encapsulated in crosslinked, biodegradable, polymeric nanocapsules sustained drug kinetics in the blood, penetrated rodents’ brains, and was not neurotoxic. Compared to free antibody, nanocapsules improved tumor control in an immunodeficient mouse model of CD20+ non-Hodgkin’s lymphoma (NHL) with brain metastases, which was likely mediated via direct apoptosis. Arming nanocapsules with CXCL13 to target CXCR5 on NHL cells increased efficacy, showing systemic and brain tumor elimination in a xenograft humanized NHL mouse model, likely enhanced by human NK/macrophage ADCC.
Contributed by Paula Hochman
Approximately 15-40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolysed, enhancing the CNS levels of the antibody by approximately tenfold with respect to the administration of naked rituximab. When the nanocapsules were functionalized with CXCL13-the ligand for the chemokine receptor CXCR5, which is frequently found on B-cell lymphoma-a single dose led to improved control of CXCR5-expressing metastases in a murine xenograft model of non-Hodgkin lymphoma, and eliminated lymphoma in a xenografted humanized bone marrow-liver-thymus mouse model. Encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of cancers with CNS metastases.
Author Info: (1) Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. UCLA AIDS Institute
Author Info: (1) Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. UCLA AIDS Institute, Los Angeles, CA, USA. (2) Department of Chemical and Biomolecular Engineering, School of Engineering, University of California, Los Angeles, Los Angeles, CA, USA. (3) Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. UCLA AIDS Institute, Los Angeles, CA, USA. (4) Department of Chemical and Biomolecular Engineering, School of Engineering, University of California, Los Angeles, Los Angeles, CA, USA. (5) Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. UCLA AIDS Institute, Los Angeles, CA, USA. (6) Department of Chemical and Biomolecular Engineering, School of Engineering, University of California, Los Angeles, Los Angeles, CA, USA. (7) Department of Pathology and Laboratory Medicine (Neuropathology), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. (8) State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, China. (9) UCLA AIDS Institute, Los Angeles, CA, USA. Division of Haematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. (10) Biopharmaceutical Research and Development Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, China. (11) Institute of Medicinal Plant Development, Chinse Academy of Medical Sciences and Peking Union Medical College, Beijing, China. (12) Institute of Medicinal Plant Development, Chinse Academy of Medical Sciences and Peking Union Medical College, Beijing, China. (13) Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. UCLA AIDS Institute, Los Angeles, CA, USA. (14) Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. UCLA AIDS Institute, Los Angeles, CA, USA. Department of Epidemiology, School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA. (15) UCLA AIDS Institute, Los Angeles, CA, USA. Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. (16) Department of Chemical and Biomolecular Engineering, School of Engineering, University of California, Los Angeles, Los Angeles, CA, USA. luucla@ucla.edu. (17) Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. syuchen@mednet.ucla.edu. UCLA AIDS Institute, Los Angeles, CA, USA. syuchen@mednet.ucla.edu. (18) UCLA AIDS Institute, Los Angeles, CA, USA. masa3k@ucla.edu. Division of Haematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. masa3k@ucla.edu.
