ABSTRACT
CXC chemokine receptor 4 (CXCR4) is overexpressed by a broad range of hematological disorders, and its interaction with CXC chemokine ligand 12 (CXCL12) is of central importance in the retention and chemoprotection of neoplastic cells in the bone marrow and lymphoid organs. In this article, we describe the biological evaluation of a new CXCR4-targeting and -antagonizing molecule (BAT1) that we designed and show that, when incorporated into a liposomal drug delivery system, it can be used to deliver cancer therapeutics at high levels to chronic lymphocytic leukemia (CLL) cells. CXCR4 targeting and antagonism by BAT1 were demonstrated alone and following its incorporation into liposomes (BAT1-liposomes). Antagonism of BAT1 against the CXCR4/CXCL12 interaction was demonstrated through signaling inhibition and function blocking: BAT1 reduced ERK phosphorylation and cell migration to levels equivalent to those seen in the absence of CXCL12 stimulation (P < .001). Specific uptake of BAT1-liposomes and delivery of a therapeutic cargo to the cell nucleus was seen within 3 hours of incubation and induced significantly more CLL cell death after 24 hours than control liposomes (P = .004). The BAT1 drug-delivery system is modular, versatile, and highly clinically relevant, incorporating elements of proven clinical efficacy. The combined capabilities to block CXCL12-induced migration and intracellular signaling while simultaneously delivering therapeutic cargo mean that the BAT1-liposome drug-delivery system could be a timely and relevant treatment of a range of hematological disorders, particularly because the therapeutic cargo can be tailored to the disease being treated.
Subject(s)
Antineoplastic Agents/administration & dosage , DEAD-box RNA Helicases/metabolism , Drug Carriers , Drug Delivery Systems , Liposomes , Receptors, CXCR4/metabolism , Antineoplastic Agents/chemistry , Cell Survival , Chemokine CXCL12/antagonists & inhibitors , DEAD-box RNA Helicases/chemistry , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Drug Carriers/chemistry , Humans , Leukemia/drug therapy , Leukemia/genetics , Leukemia/metabolism , Leukemia/pathology , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Liposomes/chemistry , Lymphocytes/immunology , Lymphocytes/metabolism , Molecular Structure , Molecular Targeted Therapy , Protein Binding , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/chemistryABSTRACT
A bis(cyclam)-capped cholesterol lipid designed to bind C-X-C chemokine receptor type 4 (CXCR4) was synthesised in good overall yield from 4-methoxyphenol through a seven step synthetic route, which also provided a bis(cyclam) intermediate bearing an octaethyleneglycol-primary amine that can be easily derivatised. This bis(cyclam)-capped cholesterol lipid was water soluble and self-assembled into micellar and non-micellar aggregates in water at concentrations above 8 µM. The bioactivity of the bis(cyclam)-capped cholesterol lipid was assessed using primary chronic lymphocytic leukaemia (CLL) cells, first with a competition binding assay then with a chemotaxis assay along a C-X-C motif chemokine ligand 12 (CXCL12) concentration gradient. At 20 µM, the bis(cyclam)-capped cholesterol lipid was as effective as the commercial drug AMD3100 for preventing the migration of CLL cells, despite a lower affinity for CXCR4 than AMD3100.
Subject(s)
Heterocyclic Compounds/chemistry , Lipids/chemical synthesis , Lipids/pharmacology , Receptors, CXCR4/metabolism , Cell Line, Tumor , Chemistry Techniques, Synthetic , Humans , Lipids/chemistry , Signal Transduction/drug effectsABSTRACT
Graphene based nanomaterials are being used experimentally to deliver therapeutic agents to cells or tissues both in vitro and in vivo. However, substantial challenges remain before moving to safe and effective use in humans. In particular, it is recognised that graphene molecules undergo complex interactions with solutes, proteins or cellular systems within the body, and that these interactions impact significantly on the behaviour or toxicity of the molecule. Approaches to overcome these problems include modification of the graphene or its combination with other molecules to accentuate favourable characteristics or modify adverse interactions. This has led to an emerging role for graphene as one part of highly-tailored multifunctional delivery vehicles. This review examines the knowledge that underpins present approaches to exploit graphene in therapeutics delivery, discussing both favourable and unfavourable aspects of graphene behaviour in biological systems and how these may be modified; then considers the present place of the molecule and the challenges for its further development.
