Summary of Nanodrugs and Nanoimaging Agents
Nano bioconjugates were engineered based on a natural biodegradable nanoplatform. The drug/imaging agents are specifically delivered crossing multiple bio-barriers such as the BBB and the cancer cell membrane to deliver the anti-cancer drugs to the cytoplasm/nuclei of the tumor cells using one or several targeting monoclonal antibodies or peptides. This controllable unique drug releases tumor growth inhibiting agents specifically into cancer cells without affecting normal surrounding cells. Minimal toxicity was demonstrated for nanodrug tumor delivery for temozolomide, platinum drugs and doxorubicin.
MRI Virtual Biopsy for Brain Lesions Is Used When it Is Impossible to Obtain Brain Tissue for Diagnosis
Discovery of the New Cancer Biomarker, Laminin 411
Institute researchers used leading-edge gene-sequencing analysis to discover a new cancer biomarker: laminin-411. Human gliomas and invasive breast cancer excessively produce laminin-411, which plays an important role in the ability of tumor cells to spread and grow (Cancer Res. 2001;61:5601-5610. Breast Cancer Res. 2005;7:411-421.). This biomarker was later analyzed in a number of human gliomas and showed a significant correlation with glial tumor grade, time to recurrence and patients' survival times (Cancer. 2004;101:604-612.). Inhibition of this marker and drug delivery into the brain in vivo was developed, and glioma tumor reduction was achieved (PNAS USA. 2010;107:18143-18148.). This test is being used to evaluate the biological behavior of gliomas in order to better plan individualized therapeutic treatment and follow-up regimens for each patient. An ongoing clinical trial is underway in the Neurosurgery Department and Department of Pathology and Laboratory Medicine at Cedars-Sinai for laminin-411 as a glial tumor biomarker (about 400 patients have been evaluated).
The Ljubimova Laboratory has also broken new ground, the team has developed nanomedicine technology to inhibit the synthesis of cancer-specific extracellular matrix protein, laminin-411, and to engineer a novel drug delivery system to reduce gliomas in the brain in vivo.
In a panel of 226 patient brain glioma samples, the Ljubimova Lab found a clinical correlation between the expression of tumor vascular laminin-411 (α4β1γ1) with higher tumor grade and with expression of cancer stem cell (CSC) markers including Notch pathway members, CD133, Nestin and c-Myc. Laminin-411 overexpression also correlated with higher recurrence rate and shorter survival of GBM patients. The lab also showed that depletion of laminin-411 α4 and β1 chains with CRISPR/Cas9 in human GBM cells led to reduced growth of resultant intracranial tumors in mice, and significantly increased survival of host animals compared to mice with untreated cells. Inhibition of laminin-411 suppressed Notch pathway in normal and malignant human brain cell types. A nano bioconjugate potentially suitable for clinical use and capable of crossing BBB was designed to block laminin-411 expression. Nano bioconjugate treatment of mice carrying intracranial GBM significantly increased animal survival and inhibited multiple CSC markers including the Notch axis. This study describes an efficient strategy for GBM treatment via targeting a critical component of the tumor microenvironment largely independent of heterogeneous genetic mutations in glioblastoma.
Immunotherapy is one of the fastest developing approaches in clinical oncology with successful treatment of different cancers. However, the unique immune environment of the central nervous system needs consideration when pursuing immunotherapeutic approaches for gliomas. Treatment options are limited, in part because of inefficient drug delivery across the BBB.
The Ljubimova Laboratory developed new nano immunoconjugates (NICs) based on natural biopolymer scaffold, poly(-L-malic acid), with covalently attached a-CTLA-4 and/or a-PD-1 for delivery across the BBB and activation of local brain anti-tumor immune response. NIC treatment of mice bearing intracranial GL261 GBM resulted in an increase of anti-tumor immune cells such as CD8+ T cells, IFN+ natural killers and natural killer T cells and macrophages with a decrease of regulatory T cells (Tregs) in the brain tumor area. Survival of GBM-bearing mice treated with combination of NICs was significantly longer compared to animals treated by single checkpoint inhibitor-bearing NICs or free a-CTLA-4 and a-PD-1. Our study demonstrates trans-BBB delivery of nanopolymer-conjugated checkpoint inhibitors as an effective treatment of GBM via activation of both systemic and local privileged brain tumor immune response.
Crosstalk between CK2 and EGFR/EGFRvIII pathways was found by blocking two glioma specific markers. The active drug component blocks several cancer-specific tumor markers at the same time for multiple tumors: EGFR/EGFRvIII-wild/mutated epidermal growth factor receptor, CK2, a master signaling regulator serine-threonine protein kinase, and HER2/neu. A significant survival increase has been shown in tumor-bearing animals (preclinical data) after drug administration. Using this technology, it is possible to block a combination of several unique markers for each patient at the same time, providing a synergistic effect. (From J Cont Release. 2016;28(244):14-23.)