pH-Sensitive Block Copolymer Vesicles with Variable Trigger Points for Drug Delivery

Abstract

We have previously reported the preparation of a novel pH-sensitive and biocompatible polymer vesicle in pure water based on the spontaneous self-assembly of a diblock copolymer, PMPC-b-PDPA, where PMPC is poly[2-(methacryloyloxy)ethyl phosphorylcholine] and PDPA is poly[2-(diisopropylamino)ethyl methacrylate] (J. Am. Chem. Soc.200512717982). Herein, we intend to report the strategy for controlling the pH trigger points of association/dissociation of pH-responsive polymer vesicles for anticancer drug delivery. We introduced a reactive block, poly[2-(dimethylamino)ethyl methacrylate] (PDMA) into the above diblock copolymer to form reactive PMPC-b-PDMA-b-PDPA and PMPC-b-PDPA-b-PDMA triblock copolymers, as well as PMPC-b-P(DMA-stat-DPA) block-statistical copolymer by atom transfer radical polymerization (ATRP) in methanol at room temperature. As a result of different block length of PDPA, the introduction of PDMA chain at different positions, and different initial copolymer concentrations, those block copolymer vesicles showed tunable pH trigger points and various isoelectric points (IEPs) in aqueous solution. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) studies confirmed that the block copolymers with relatively long PDPA block form polymer vesicles by simply tuning the solution pH in pure water. Above pH 6.2, the PDPA block becomes hydrophobic so it forms the vesicle membrane. In all cases, the hydrophilic PMPC chains form the vesicle coronas. The PDMA chains are designed in three different positions. In PMPC-b-PDMA-b-PDPA vesicles, the PDMA chains form the middle shell between the PDPA vesicle membrane and the PMPC vesicle corona. In PMPC-b-PDPA-b-PDMA vesicles, the PDMA can mix with PMPC to serve as mixed coronas. In PMPC-b-P(DMA-stat-DPA) vesicles, the reactive PDMA chains can be incorporated into the vesicle membrane, which provides an effective strategy regarding the immobilization of vesicles by selective quaternization of PDMA with a bifunctional cross-linker, such as 1,2-bis(2-iodoethoxy)ethane (BIEE). The degree of cross-linking can be tuned by varying the molar ratio of PDMA to BIEE, which was further investigated by 1H NMR, DLS, and TEM, suggesting tunable permeability of vesicle membrane. The triblock copolymer vesicles were able to encapsulate anticancer drugs such as DOX, exhibiting obviously retarded release profile at physiological conditions.

Investigation on the self-assembled behaviors of C18unsaturated fatty acids in arginine aqueous solution

“…The unloaded free drug was removed by dialysis using a dialysis membrane bag with molecular weight cut-off of $3500 Da according to a reported procedure. 50 The dialysis membrane bag of 5 mL drug-loaded vesicles was immersed in 500 mL of phosphate buffer solution (PBS) and dialyzed at room temperature with 200 rpm of stirring. Fresh PBS (3 mL) was added 6 times in 2 hours (20 min each).…”

Self-assembly and disassembly of stimuli responsive tadpole-like single chain nanoparticles using a switchable hydrophilic/hydrophobic boronic acid cross-linker

“…SCNPs can not only mimic the delicate controlled folding process of proteins with controlled size and morphology, [31][32][33] but can also self-assemble into more complexed 3D structures. 34 Furthermore stimuli-responsive polymeric nanoparticles, also called "smart" or "intelligent" nanoparticles that are capable of conformational and chemical changes by adapting the external stimuli 35,36 have increasingly attracted interest due to their diverse range of applications in delivery and release of drugs, 37,38 diagnostics, 39 sensors. 40 Dynamic covalent chemistry is a very suitable candidate for building intelligent materials which can be responsive to the environmental changes, such as pH or input stimuli.…”

Amphiphilic diblock copolymers bearing pendant aromatic acetal groups: Synthesis and tunable pH‐triggered assembly/disassembly transition behavior

“…Traditional pH-sensitive polymers are usually polymerized with some pH-sensitive monomers, such as 2-(diethyl amino) ethyl methacrylate (DEA), 2-(dimethylamino) ethyl methacrylate (DMA), and so on. [14][15][16][17] The response mechanism of these polymers is the occurrence of protonation or deprotonation during the pH value of the surroundings changes. Given that the protonation or deprotonation occurs instantaneously, the pH-triggered phase transition processes of these polymers are uncontrollable.…”

“…Afterwards, the terminal bromine was substituted by azido groups via azidation reaction in the presence of ScCl as a catalyst. Figure 2(b) shows the typical FTIR spectrum of the azidation product (FTIR spectra of mPEG 17 -N 3 and mPEG 114 -N 3 are shown in Supporting Information Fig. S6(a,b), respectively), where the appearance of characteristic absorption peak of azido group at 2111 cm 21 suggests that the azido groups have been introduced successfully.…”

“…This is because as the acetal groups hydrolyzed, the content of aromatic groups in micelles core decreased, and led to the reduction of the interactions between hydrophobic segments (especially p-p interaction). Interestingly, when the hydrolysis were conducted for a sufficiently long time, no size data can be recorded by DLS for PDAEP 15 -b-PEG 17 and PDAEP 15 -b-PEG 43 micelles, and the D z of PDAEP 15 -b-PEG 114 was determined to be 3 nm. We inferred that at this time, the diblock copolymers micelles were converted to water soluble unimers.…”