Abstract:
Polymeric assemblies capable of
in-situ constructing redox microenvironments in the hydrophobic domains were designed and fabricated to promote the release of covalently conjugated camptothecin (CPT) drug molecules. The ultraviolet (UV) and redox responsive amphiphilic polyprodrug diblock copolymer, PEG-
b-P(NTMA-
co-CPTM), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, in which the hydrophilic block was polyethylene glycol (PEG) and the hydrophobic block was copolymerized from two kinds of stimuli-responsive methacrylate derivative monomers, UV-responsive NTMA monomer and redox-sensitive CPTM monomer. In the side group of (2-(3-(4, 5-dimethoxy-2-nitrobenzyl)mercapto-propanamido)ethoxycarbonylamino)ethyl methacrylate (NTMA) monomer,
o-nitrobenzyl thioether moiety was introduced to protect the mercapto group; while in the side group of CPTM prodrug monomer, CPT drug moiety was linked to the ethyl group of ethyl methacrylate via disulfide linkage. The chemical and chain structure of the corresponding monomers and diblock polymers were characterized by Nuclear Magnetic Resonance (NMR), High Performance Liquid Chromatography (HPLC), Electron Spray Ionization Mass Spectrometry (ESI-MS) and Gel Permeation Chromatography (GPC). The prepared amphiphilic PEG-
b-P(NTMA-
co-CPTM) diblock polyprodrug copolymer could self-assemble into compound vesicles in aqueous solution, as confirmed by Transmission Electron Microscope (TEM) and Dynamic Light Scattering (DLS) measurements. The dual responsiveness of the P(NTMA-
co-CPTM) compound vesicles and the release of CPT were monitored via Ultraviolet-Visible (UV-Vis) spectroscopy and DLS. It was found that under UV irradiation, in the side chains of P(NTMA-
co-CPTM) blocks, mercapto groups could be decaged due to the photo-cleavage of the
o-nitrobenzyl thioether moieties, thus
in-situ constructing reductive microenvironments in the hydrophobic domains of the compound vesicles. Then, CPT drug molecules were released via the exchange reaction between the decaged mercapto groups and the adjacent disulfide linkages. After being subjected to UV irradiation for 20 min, the cumulative release of CPT drug molecules within 96 h from PEG-
b-P(NTMA-
co-CPTM) compound vesicles was as high as 60%, comparable to the result obtained within the same duration time after addition of 5 mmol/L glutathione (GSH) and without UV irradiation.