21442-01-3Relevant articles and documents
RETRACTED ARTICLE: Folic acid mediated endocytosis enhanced by modified multi stimuli nanocontainers for cancer targeting and treatment: Synthesis, characterization, in-vitro and in-vivo evaluation of therapeutic efficacy
Efthimiadou,Lelovas,Fragogeorgi,Boukos,Balafas,Loudos,Kostomitsopoulos,Theodosiou,Tziveleka,Kordas
, (2020/01/13)
Polymeric materials are in the epicenter of scientific research the last decade and have been used in a range of pharmaceutical and biological applications. Multifunctional polymeric materials are capable targeting agents, which can be used as controlled drug release vehicles for the enhancement of therapeutic efficacy, as well as for diagnostic purposes. A newer generation of these smart polymeric entities constitutes of smart nanocontainers (NCs), which can navigate the drug to specific areas by avoiding random distribution, and thus resulting in drug toxicity reduction. The combination of pH, thermo and redox sensitivity of the multi stimuli NCs can help to achieve specific release of the drug in the tumor area, where these sensitivity parameters can be observed. Hollow polymeric multi stimuli fluorescent tNCs based on N-(2-Hydroxypropyl)methacrylamide (HPMA) were successfully functionalized with a specific targeting moiety; folic acid, and then characterized morphologically, by scanning electron and transmission electron microscopy, as well as structurally, by Fourier-transform infrared spectroscopy. Their targeting mechanism was investigated in vitro in cervical cancer cell lines and in vivo in tumor bearing mice. According to our results the folic acid functionalized NCs targeted HeLa cells’ surface within the first 30 min of treatment. Human tumor xenografted mice (nonobese diabetic/severe combined immunodeficient) were injected with folate functionalized NCs and their tumor uptake was estimated by γ-imaging at about 3.5%. The targeting efficiency of the folate functionalized NCs was investigated directly in vivo by γ-imaging and indirectly by a tumor efficacy protocol.
Overcoming resistance to rituximab in relapsed non-Hodgkin lymphomas by antibody-polymer drug conjugates actively targeted by anti-CD38 daratumumab
Helman, Karel,Klener, Pavel,Mavis, Cory,Etrych, Tomá?,Janou?ková, Olga,Lidicky, Ond?ej,Machová, Daniela,Pokorná, Eva,Vo?ková, Petra
, p. 160 - 170 (2020/09/07)
B-cell non-Hodgkin lymphomas (B-NHL) represent the most common type of hematologic malignancies in the Western hemisphere. The therapy of all B-NHL is based on the combination of different genotoxic cytostatics and anti-CD20 monoclonal antibody (mAb) rituximab. Unfortunately, many patients relapse after the mentioned front-line treatment approaches. The therapy of patients with relapsed/refractory (R/R) B-NHL represents an unmet medical need. We designed, developed and tested novel actively targeted hybrid mAb-polymer-drug conjugate (APDC) containing anti-CD20, anti-CD38 or anti-CD19 mAbs. Biocompatible copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) with cytostatic agent doxorubicin attached via stimuli-sensitive hydrazone bond were employed for the mAb grafting. Anti-lymphoma efficacy of the APDC nanotherapeutics was evaluated in vivo on a panel of three patient-derived lymphoma xenografts derived from two patients with R/R B-NHL and one patient with so far untreated B-NHL. In both PDX models derived from patients with R/R B-NHL, the targeting with anti-CD38 antibody daratumumab demonstrated highly improved anti-lymphoma efficacy compared to the targeting with anti-CD20 rituximab, two experimental anti-CD19 antibodies and non-targeted controls. The results represent a proof-of-concept of a new algorithm of personalized anti-tumor therapy based on highly innovative APDC biomaterials.
Polyvalent Diazonium Polymers Provide Efficient Protection of Oncolytic Adenovirus Enadenotucirev from Neutralizing Antibodies while Maintaining Biological Activity in Vitro and in Vivo
Francini, Nora,Purdie, Laura,Mantovani, Giuseppe,Alexander, Cameron,Cochrane, Daniel,Illingworth, Sam,Fisher, Kerry,Seymour, Leonard W.,Spain, Sebastian G.
, p. 1244 - 1257 (2019/05/11)
Oncolytic viruses offer many advantages for cancer therapy when administered directly to confined solid tumors. However, the systemic delivery of these viruses is problematic because of the host immune response, undesired interactions with blood components, and inherent targeting to the liver. Efficacy of systemically administered viruses has been improved by masking viral surface proteins with polymeric materials resulting in modulation of viral pharmacokinetic profile and accumulation in tumors in vivo. Here we describe a new class of polyvalent reactive polymer based on poly(N-(2-hydroxypropyl)methacrylamide) (polyHPMA) with diazonium reactive groups and their application in the modification of the chimeric group B oncolytic virus enadenotucirev (EnAd). A series of six copolymers with different chain lengths and density of reactive groups was synthesized and used to coat EnAd. Polymer coating was found to be extremely efficient with concentrations as low as 1 mg/mL resulting in complete (>99%) ablation of neutralizing antibody binding. Coating efficiency was found to be dependent on both chain length and reactive group density. Coated viruses were found to have reduced transfection activity both in vitro and in vivo, with greater protection against neutralizing antibodies resulting in lower transgene production. However, in the presence of neutralizing antibodies, some in vivo transgene expression was maintained for coated virus compared to the uncoated control. The decrease in transgene expression was found not to be solely due to lower cellular uptake but due to reduced unpackaging of the virus within the cells and reduced replication, indicating that the polymer coating does not cause permanent inactivation of the virus. These data suggest that virus activity may be modulated by the appropriate design of coating polymers while retaining protection against neutralizing antibodies.