Rujiang Ma

Glucose-Responsive Micelles from Self-Assembly of Poly(ethylene glycol)-b-Poly(acrylic acid-co-acrylamidophenylboronic acid) and the Controlled Release of Insulin

Poly(ethylene glycol)-block-poly(acrylic acid-co-acrylamidophenylboronic acid) [PEG(114)-b-(PAA(63)-co-PAAPBA(107))] was synthesized by the modification of poly(ethylene glycol)-block-poly(acrylic acid) (PEG(114)-b-PAA(170)) with 3-aminophenylboronic acid (APBA). Glucose-responsive PEG(114)-b-(PAA(63)-co-PAAPBA(107)) self-assembled into core-shell micelles with the hydrophobic core composed of PAAPBA and hydrophilic shell composed of PEG in aqueous solution. The swelling and disaggregating behaviors of micelles responding to glucose were investigated by using light scattering in aqueous solution at pH 7.4. Characterization of insulin-loaded micelles and their drug release in solutions with various glucose concentrations were further studied. The results demonstrated that the drug release rate can be controlled by variation of glucose concentration.

Cooperative Macromolecular Self-Assembly toward Polymeric Assemblies with Multiple and Bioactive Functions

In the past decades, polymer based nanoscale polymeric assemblies have attracted continuous interest due to their potential applications in many fields, such as nanomedicine. Many efforts have been dedicated to tailoring the three-dimensional architecture and the placement of functional groups at well-defined positions within the polymeric assemblies, aiming to augment their function. To achieve such goals, in one way, novel polymeric building blocks can be designed by controlled living polymerization methodology and advanced chemical modifications. In contrast, by focusing on the end function, others and we have been practicing strategies of cooperative self-assembly of multiple polymeric building blocks chosen from the vast library of conventional block polymers which are easily available. The advantages of such strategies lie in the simplicity of the preparation process and versatile choice of the constituent polymers in terms of their chemical structure and functionality as well as the fact that cooperative self-assembly based on supramolecular interactions offers elegant and energy-efficient bottom-up strategies. Combination of these principles has been exploited to optimize the architecture of polymeric assemblies with improved function, to impart new functionality into micelles and to realize polymeric nanocomplexes exhibiting functional integration, similar to some natural systems like artificial viruses, molecular chaperones, multiple enzyme systems, and so forth. In this Account, we shall first summarize several straightforward designing principles with which cooperative assembly of multiple polymeric building blocks can be implemented, aiming to construct polymeric nanoassemblies with hierarchal structure and enhanced functionalities. Next, examples will be discussed to demonstrate the possibility to create multifunctional nanoparticles by combination of the designing principles and judiciously choosing of the building blocks. We focus on multifunctional nanoparticles which can partially address challenges widely existing in nanomedicine such as long blood circulation, efficient cellular uptake, and controllable release of payloads. Finally, bioactive polymeric assemblies, which have certain functions closely mimicking those of some natural systems, will be used to conceive the concept of functional integration.

Phenylboronic Acid-Based Complex Micelles with Enhanced Glucose-Responsiveness at Physiological pH by Complexation with Glycopolymer

Polymeric nanoparticles with glucose-responsiveness under physiological conditions are of great interests in developing drug delivery system for the treatment of diabetes. Herein, glucose-responsive complex micelles were prepared by self-assembly of a phenylboronic acid-contained block copolymer PEG-b-P(AA-co-APBA) and a glycopolymer P(AA-co-AGA) based on the covalent complexation between phenylboronic acid and glycosyl. The formation of the complex micelles with a P(AA-co-APBA)/P(AA-co-AGA) core and a PEG shell was confirmed by HNMR analysis. The glucose-responsiveness of the complex micelles was investigated by monitoring the light scattering intensity and the fluorescence (ARS) of the micelle solutions. The complex micelles displayed an enhanced glucose-responsiveness compared to the simple PEG-b-P(AA-co-APBA) micelles and the sensitivity of the complex micelles to glucose increased with the decrease of the amount of P(AA-co-AGA) in the compositions. The cytotoxicity of the polymers and the complex micelles was also evaluated by MTT assay. This kind of complex micelles may be an excellent candidate for insulin delivery and may find application in the treatment of diabetes.

A glucose-responsive complex polymeric micelle enabling repeated on–off release and insulin protection

We developed a glucose-responsive complex polymeric micelle (CPM) through the self-assembly of two types of diblock copolymers, poly(ethylene glycol)-b-poly(aspartic acid-co-aspartamidophenylboronic acid) (PEG-b-P(Asp-co-AspPBA)) and poly(N-isopropylacrylamide)-b-poly(aspartic acid-co-aspartamidophenylboronic acid) (PNIPAM-b-P(Asp-co-AspPBA)). By controlling the weight ratio between PNIPAM and PEG (WPNIPAM/WPEG = 6/4), the block copolymers form complex micelles with a novel core–shell–corona structure. By following this structure, the continuous PNIPAM shell collapsed on the glucose-responsive P(Asp-co-AspPBA) core. As a result, the CPM exhibits a reversible swelling in response to changes in the glucose concentration, enabling the repeated on–off release of insulin regulated by glucose level. Furthermore, the CPM could effectively protect the encapsulated insulin against protease degradation. Therefore, this glucose-responsive CPM provides a simple and powerful strategy to construct a self-regulated insulin delivery system for diabetes treatment.

In Vivo Biodistribution of Mixed Shell Micelles with Tunable Hydrophilic/Hydrophobic Surface

The miserable targeting performance of nanocarriers for cancer therapy arises largely from the rapid clearance from blood circulation and the major accumulation in the organs of the reticuloendothelial system (RES), leading to inefficient enhanced permeability and retention (EPR) effect after intravenous injection (i.v.). Herein, we reported an efficient method to prolong the blood circulation of nanoparticles and decrease their deposition in liver and spleen. In this work, we fabricated a series of mixed shell micelles (MSMs) with approximately the same size, charge and core composition but with varied hydrophilic/hydrophobic ratios in the shell through spontaneously self-assembly of block copolymers poly(ethylene glycol)-block-poly(l-lysine) (PEG-b-PLys) and poly(N-isopropylacrylamide)-block-poly(aspartic acid) (PNIPAM-b-PAsp) in aqueous medium. The effect of the surface heterogeneity on the in vivo biodistribution was systematically investigated through in vivo tracking of the (125)I-labeled MSMs determined by Gamma counter. Compared with single PEGylated micelles, some MSMs were proved to be significantly efficient with more than 3 times lower accumulation in liver and spleen and about 6 times higher concentration in blood at 1 h after i.v.. The results provide us a novel strategy for future development of long-circulating nanocarriers for efficient cancer therapy.

Fabrication of Complex Micelles with Tunable Shell for Application in Controlled Drug Release

At room temperature, diblock copolymers of PLA-b-PNIPAM and PEG-b-PLA self-assembled into complex micelles with a PLA core and a mixed PEG/PNIPAM shell. By increasing the temperature, these complex micelles could be converted into a core-shell-corona structure composed of a PLA core, a collapsed PNIPAM shell and a soluble PEG corona, and the PEG chains stretched from the inner core to outside, leading to the formation of PEG channels. The PEG channels could be used for the exchange of substance between the core and the external environment. Compared with core-shell micelles, complex micelles with a core-shell-corona structure could avoid the burst diffusion in the release of ibuprofen and inhibit the degradation of PLA by lipase to a certain extent.

pH/Sugar Dual Responsive Core-Cross-Linked PIC Micelles for Enhanced Intracellular Protein Delivery

Herein, a series of biocompatible, robust, pH/sugar-sensitive, core-cross-linked, polyion complex (PIC) micelles based on phenylboronic acid-catechol interaction were developed for protein intracellular delivery. The rationally designed poly(ethylene glycol)-b-poly(glutamic acid-co-glutamicamidophenylboronic acid) (PEG-b-P(Glu-co-GluPBA)) and poly(ethylene glycol)-b-poly(l-lysine-co-ε-3,4-dihydroxyphenylcarboxyl-L-lysine) (PEG-b-P(Lys-co-LysCA)) copolymers were successfully synthesized and self-assembled under neutral aqueous condition to form uniform micelles. These micelles possessed a distinct core-cross-linked core-shell structure comprised of the PEG outer shell and the PGlu/PLys polyion complex core bearing boronate ester cross-linking bonds. The cross-linked micelles displayed superior physiological stabilities compared with their non-cross-linked counterparts while swelling and disassembling in the presence of excess fructose or at endosomal pH. Notably, either negatively or positively charged proteins can be encapsulated into the micelles efficiently under mild conditions. The in vitro release studies showed that the release of protein cargoes under physiological conditions was minimized, while a burst release occurred in response to excess fructose or endosomal pH. The cytotoxicity of micelles was determined by cck-8 assay in HepG2 cells. The cytochrome C loaded micelles could efficiently delivery proteins into HepG2 cells and exhibited enhanced apoptosis ability. Hence, this type of core-cross-linked PIC micelles has opened a new avenue to intracellular protein delivery.

Effect of Coordination on the Glucose-Responsiveness of PEG-b-(PAA-co-PAAPBA) Micelles.

Poly(ethylene glycol)-block-poly(acrylic acid) (PEG-PAA) is modified by 3-aminophenylboronic acid (APBA) with different modification degrees, such as PEG(114) -b-(PAA(0.37) -co-PAAPBA(0.63) )(170) , PEG(114) -b-(PAA(0.23) -co-PAAPBA(0.77) )(170) and PEG(114) -b-(PAA(0.02) -co-PAAPBA(0.98) )(170) . Micelles self-assembled from these three copolymers possess glucose-responsiveness at varying pH values. Micelles self-assembled from PEG(114) -b-(PAA(0.37) -co-PAAPBA(0.63) )(170) have glucose-responsiveness at the physiological pH (7.4), endowing them with potential applications in the treatment of diabetes. (11) B magic-angle spinning nuclear magnetic resonance ((11) B MAS NMR) analysis indicates that interactions between PAAPBA segments and PAA segments induce boron changes from the trigonal planar form to the tetrahedral form, resulting in glucose-responsiveness of PEG(114) -b-(PAA(0.37) -co-PAAPBA(0.63) )(170) micelles at pH 7.4.

A Multifunctional Nanocarrier Based on Nanogated Mesoporous Silica for Enhanced Tumor-Specific Uptake and Intracellular Delivery

A multifunctional drug delivery system based on MCM-41-type mesoporous silica nanoparticles is described that behaves as if nanogates were covalently attached to the outlets of the mesopores through a highly acid-sensitive benzoic-imine linker. Tumor-specific uptake and intracellular delivery results from the pH-dependent progressive hydrolysis of the benzoic-imine linkage that starts at tumor extracellular pH = 6.8 and increases with decreasing pH. The cleavage of the benzoic-imine bond leads to the removal of the polypseudorotaxane caps and subsequent release of the payload drugs at tumor sites. At the same time, the carrier surface becomes positively charged, which further facilitates cellular uptake of the nanocarriers, thus offering a tremendous potential for targeted tumor therapy.

Thermosensitive and pH-sensitive Au-Pd bimetallic nanocomposites.

The bimetallic nanoparticles were protected by a double stimuli-sensitive diblock copolymer, poly(N-isopropylacrylamide)-block-poly(4-vinylpyridine) (PNIPAM-b-P4VP), which was synthesized via the reversible addition-fragmentation chain transfer (RAFT) polymerization. The obtained nanocomposites were made up of bimetallic nanoparticles cross-linked P4VP core and PNIPAM shell. Energy-dispersive X-ray (EDX) spectra and UV-vis transmittance revealed the formed nanoparticles was truly bimetallic particles with incomplete core-shell structures, Au as core and Pd as shell, rather than the physical mixture of monometallic nanoparticles. Laser light scattering (LLS) demonstrated the nanocomposites exhibit both thermo and pH sensitivity. X-ray diffraction (XRD) clearly showed Au formed a high-ordered crystal while Pd fashioned amorphous aggregates. In addition, the bimetallic nanocomposites show special responsiveness for temperature and better catalytic activity than corresponding monometallic nanocomposites.