ABSTRACT
Rare earth metal-mediated group transfer polymerisation enables the synthesis of previously inaccessible block copolymers of 2-vinylpyridine, diethyl vinylphosphonate and the new diallyl vinylphosphonate monomer. This precision polymerisation and the selective cross-linking of allyl side groups via thiol-ene click chemistry leads to the formation of well-defined dual-responsive nanoparticles. We demonstrate that these next generation nanocarriers are pH- and temperature-responsive and are capable of efficiently delivering doxorubicin into the nucleus of cancer cells. High anti-cancer activity could be demonstrated via cytotoxicity tests on breast cancer (MCF-7) and cervical cancer (HeLa) cells. These results validate this modular synthesis route as an ideal platform for the development of sophisticated nanocarriers for future drug delivery applications.
Subject(s)
Antineoplastic Agents/administration & dosage , Doxorubicin/administration & dosage , Drug Carriers/chemistry , Nanoparticles/chemistry , HeLa Cells , Humans , Hydrogen-Ion Concentration , MCF-7 CellsABSTRACT
Utilization of group transfer polymerization for the synthesis of poly(diethyl vinylphosphonate) (PDEVP) allows its controlled end-group functionalization. Thus, a new fluorescent chromophore/PDEVP conjugate is prepared and subjected to biocompatibility tests on two different human cell lines. In contrast to the previous studies, the tagged polymer is not absorbed by cells from the solution and has nearly no impact on cell mortality rate.
Subject(s)
Biocompatible Materials/chemical synthesis , Fluorescent Dyes/chemical synthesis , Organophosphonates/chemical synthesis , Polymers/chemical synthesis , Vinyl Compounds/chemical synthesis , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacology , HEK293 Cells , Humans , Molecular Structure , Organophosphonates/chemistry , Organophosphonates/pharmacology , Polymers/chemistry , Polymers/pharmacology , Structure-Activity Relationship , Vinyl Compounds/chemistry , Vinyl Compounds/pharmacologyABSTRACT
To date, many poly(ethylene glycol) (PEG) and poly(N-isopropylacrylamide) (PNIPAAm) biomolecule conjugates have been described, but they often show long response times, are not bio-inert, or lose function in biological fluids. Herein, we present a modular synthetic approach to generate polyvinylphosphonate biomolecule conjugates. These conjugates exhibit a sharp phase transition temperature even under physiological conditions where few other examples with this property have been described to date. Furthermore, it was feasible to add biological functions to the polymers via the conjugation step. The polyvinylphosphonate cholesterol constructs are attached to the cellular membrane and the folic acid anchored polymers are shuttled into the cells. This is an exceptional finding through a straightforward synthetic approach.
Subject(s)
Fluorescent Dyes/chemistry , Polyvinyls/chemistry , Cell Line , Fluorescent Dyes/metabolism , Folic Acid/chemistry , Humans , Microscopy, Confocal , Phosphorous Acids/chemistry , Polyvinyls/metabolism , SpectrophotometryABSTRACT
C-H bond activation of 2-methoxyethylamino-bis(phenolate)-yttrium catalysts allowed the synthesis of BAB block copolymers comprised of 2-vinylpyridine (2VP; monomerâ A) and diethylvinylphosphonate (DEVP; monomerâ B) as the A and B blocks, respectively, by rare-earth-metal-mediated group-transfer polymerization (REM-GTP). The inherent multi-stimuli-responsive character and drug-loading and -release capabilities were observed to be dependent on the chain length and monomer ratios. Cytotoxicity assays revealed the biocompatibility and nontoxic nature of the obtained micelles toward ovarian cancer (HeLa) cells. The BAB block copolymers effectively encapsulated, transported, and released doxorubicin (DOX) within HeLa cells. REM-GTP enables access to previously unattainable vinylphosphonate copolymer structures, and thereby unlocks their full potential as nanocarriers for stimuli-responsive drug delivery in HeLa cells. The self-evident consequence is the application of these new micelles as potent drug-delivery vehicles with reduced side effects in future cancer therapies.
