| 摘要: | B-cell lymphomas represent a large, heterogeneous group of disorders that significantly contribute to cancer morbidity and mortality worldwide. Managing of patients with B-cell lymphoma depends on histologic characteristics, staging, patient age, prognosis, and coexisting comorbidities. Many B-cell lymphoma patients can be successfully treated with current therapeutic approaches. However, patients still suffer from resistance and toxic effects, warranting the development of better and safer therapeutics. Intensive study is ongoing to identify potential targets, find novel drugs or explore sequences of administrations and new combinations for managing of B-cell lymphomas for the healthcare system. This dissertation aimed to combine clinical and preclinical data in specific subgroups of B-cell neoplasms. This dissertation involves the evaluation of novel combination therapeutic approaches and the design of drug-free formulations based on nanotechnology for the treatment of B-cell lymphomas.
In the first part, we used reliable published data to perform a meta-analysis of B-cell lymphomas. The study was a systematic review and meta-analysis which was conducted to identify the addition of an anti-CD20 antibody to a single-agent Bruton tyrosine kinase inhibitor (BTKi) leads to improve outcomes for patients with chronic lymphocytic leukemia (CLL). We searched for relevant publications in the PubMed, Embase, MEDLINE, and Cochrane databases until December 2022. Overall, adding an anti-CD20 antibody to BTKi revealed superior efficacy than BTKi treatment alone in untreated or previously treated CLL patients without affecting the safety of single-agent BTKi.
In the second part, we demonstrated that polypyrrole-polyethyleneimine nanocomplex (PPY-PEI NC), an intelligent nanocomposite polymer immunomodulator, interacts with the tumor microenvironment of B-cell lymphomas. Endocytosis-dependent PPY-PEI NC engulfment led to quick binding in four different B-cell lymphoma cells. In vitro, the PPY-PEI NC efficiently reduced malignant B-cell aggregations, followed by cytotoxicity induced by apoptosis initiation. PPY-PEI NC-induced cell apoptosis was characterized by mitochondrial swelling, antiapoptotic protein downregulation, and caspase-dependent apoptosis. Following the destabilization of Mcl-1, Bcl-2, and loss of mitochondrial transmembrane potential, deregulated AKT and ERK signaling caused glycogen synthase kinase-3β-mediated cell death. Furthermore, PPY-PEI NCs also caused lysosomal membrane permeabilization while suppressing endosomal acidification, which helped to protect cells from lysosomal apoptosis partly. In an ex vivo mixed culture system containing lymphoma cells and healthy leukocytes, PPY-PEI NCs preferentially uptook and eliminated exogenous cancer B-cells. While PPY-PEI NCs had negligible toxic effects in wild-type mice, they efficiently inhibited the formation of B-cell lymphoma-driven tumors in a subcutaneous lymphoma xenograft model for a long time. This research investigates a prospective PPY-PEI NC-based anti-lymphoma drug against B-cell malignancies.
The findings in this thesis suggest that the combination between BTKi and anti-CD20 is a potential target for clinical drug application, and PPY-PEI NC is a potential candidate for kinase inhibitors in B-cell lymphomas. |
