Chunhua Cai

Dual-drug delivery system based on hydrogel/micelle composites

We present a dual-drug delivery system (DDDS) of hydrogel/polypeptide micelle composites in this work. The DDDS was constructed from aspirin (Asp) dispersed poly(vinyl alcohol) (PVA) or Chitosan (CS)/PVA hydrogel and doxorubicin (DOX) loaded poly(L-glutamic acid)-b-poly(propylene oxide)-b-poly(L-glutamic acid) (GPG) micelles. Independent release behaviors of the two drugs are observed. Asp has a short-term release while DOX has a long-term and sustained release behavior in all the DDDSs. The release of DOX from all the DDDSs is environmentally controlled due to the pH and temperature sensitivity of the GPG micelle. Asp shows the pH controlled release behavior in CS/PVA/micelle DDDS due to the pH sensitivity of CS hydrogel. The releasing profiles were analyzed using a power law equation proposed by Peppas. It reveals that the release of Asp is anomalous transport in all the hydrogel/micelle DDDSs. The release of DOX is Fickian type in PVA/micelle system, and changes to anomalous transport in CS/PVA/micelle system according to the release exponent n.

Drug releasing behavior of hybrid micelles containing polypeptide triblock copolymer

We report a new type of hybrid polymeric micelles for drug delivery applications. These micelles consist of PLGA (PLGA: poly(l-glutamic acid)) and PEG (PEG: polyethylene glycol) mixed corona chains. In acidic condition, PLGA undergoes a transformation from water-soluble random coils to water-insoluble alpha-helix, leading to microphase separation in micelle coronas and formation of PEG channels. These channels connect the inner core and the outer milieu, accelerating the diffusion of drugs from micelles. The micelles were prepared through a co-micellization of PLGA-b-PPO-b-PLGA (PPO: poly(propylene oxide)) and PEG-b-PPO in water. During the self-assembly, the PPO blocks of both block copolymers aggregated into cores that were surrounded by mixed corona chains of PLGA and PEG blocks. We confirmed this structure by using a number of characterization techniques including nuclear magnetic resonance spectroscopy, zeta potential, circular dichroism, and dynamic light scattering. We also performed molecular dynamics (MD) simulations to verify the models of the hybrid micelle structure. One advantage of the hybrid micelles as drug carriers is their tunable release rate without sacrificing colloidal stability. The rate can be tuned by either micelle structures such as the composition of the mixture or external parameters such as pH.

Simulation‐Assisted Self‐Assembly of Multicomponent Polymers into Hierarchical Assemblies with Varied Morphologies

As you like it: The synthesis of supramolecular hierarchical nanostructures with designed morphologies has been realized through computer-simulation-guided multicomponent assembly of polypeptide-based block copolymers and homopolymers. By adjusting the attraction between hydrophobic polypeptide rods, as well as other parameters such as the molar ratio of copolymers and the rigidity of polymers, a variety of morphologies were obtained.

Self-assembly behavior of pH- and thermosensitive amphiphilic triblock copolymers in solution: experimental studies and self-consistent field theory simulations.

We investigated, both experimentally and theoretically, the self-assembly behaviors of pH- and thermosensitive poly(L-glutamic acid)- b-poly(propylene oxide)-b-poly(L-glutamic acid) (PLGA-b-PPO-b-PLGA) triblock copolymers in aqueous solution by means of transmission electron microscopy (TEM), scanning electron microscopy (SEM), dynamic light scattering (DLS), circular dichroism (CD), and self-consistent field theory (SCFT) simulations. Vesicles were observed when the hydrophilic PLGA block length is shorter or the pH value of solution is lower. The vesicles were found to transform to spherical micelles when the PLGA block length increases or its conformation changes from helix to coil with increasing the pH value. In addition, increasing temperature gives rise to a decrease in the size of aggregates, which is related to the dehydration of the PPO segments at higher temperatures. The SCFT simulation results show that the vesicles transform to the spherical micelles with increasing the fraction or statistical length of A block in model ABA triblock copolymer, which corresponds to the increase in the PLGA length or its conformation change from helix to coil in experiments, respectively. The SCFT calculations also provide chain distribution information in the aggregates. On the basis of both experimental and SCFT results, the mechanism of the structure change of the PLGA- b-PPO- b-PLGA aggregates was proposed.

Morphology Transformation of Hybrid Micelles Self-Assembled from Rod–Coil Block Copolymer and Nanoparticles

Hybrid polymeric micelles self-assembled from a mixture containing poly(γ-benzyl-L-glutamate)-block-poly(ethylene glycol) (PBLG-b-PEG) block copolymer and gold nanoparticles (AuNPs) were prepared. The effect of AuNPs on the self-assembly behavior of PBLG-b-PEG was studied both experimentally by transmission electron microscopy, scanning electron microscopy, and laser light scattering and computationally using dissipative particle dynamics (DPD) simulations. It was found that, the pure PBLG-b-PEG block copolymer self-assembles into long cylindrical micelles. By introducing AuNPs to the stock block copolymer solution, the formed aggregate morphology transforms to spherical micelles. The DPD simulation results well reproduced the morphological transformations observed in the experiments. And the simulation revealed that the main reason for the aggregate morphology transformation is the breakage of ordered packing of PBLG rods in micelle core by the added nanoparticles. Moreover, from the DPD simulations, the distribution information on nanoparticles was obtained. The nanoparticles were found to prefer to locate near the core/shell interface as well as in the core center of the micelles. The combination of experimental and simulation methods lead to a comprehensive understanding of such a complex self-assembly system.

Hierarchical nanostructures self-assembled from a mixture system containing rod-coil block copolymers and rigid homopolymers.

Self-assembly behavior of a mixture system containing rod-coil block copolymers and rigid homopolymers was investigated by using Brownian dynamics simulations. The morphologies of formed hierarchical self-assemblies were found to be dependent on the Lennard-Jones (LJ) interaction εRR between rod blocks, lengths of rod and coil blocks in copolymer, and mixture ratio of block copolymers to homopolymers. As the εRR value decreases, the self-assembled structures of mixtures are transformed from an abacus-like structure to a helical structure, to a plain fiber, and finally are broken into unimers. The order parameter of rod blocks was calculated to confirm the structure transition. Through varying the length of rod and coil blocks, the regions of thermodynamic stability of abacus, helix, plain fiber, and unimers were mapped. Moreover, it was discovered that two levels of rod block ordering exist in the helices. The block copolymers are helically wrapped on the homopolymer bundles to form helical string, while the rod blocks are twistingly packed inside the string. In addition, the simulation results are in good agreement with experimental observations. The present work reveals the mechanism behind the formation of helical (experimentally super-helical) structures and may provide useful information for design and preparation of the complex structures.

Polypeptide self-assemblies: nanostructures and bioapplications

Polypeptide copolymers can self-assemble into diverse aggregates. The morphology and structure of aggregates can be varied by changing molecular architectures, self-assembling conditions, and introducing secondary components such as polymers and nanoparticles. Polypeptide self-assemblies have gained significant attention because of their potential applications as delivery vehicles for therapeutic payloads and as additives in the biomimetic mineralization of inorganics. This review article provides an overview of recent advances in nanostructures and bioapplications related to polypeptide self-assemblies. We highlight recent contributions to developing strategies for the construction of polypeptide assemblies with increasing complexity and novel functionality that are suitable for bioapplications. The relationship between the structure and properties of the polypeptide aggregates is emphasized. Finally, we briefly outline our perspectives and discuss the challenges in the field.

Polypeptide‐Based “Smart” Micelles for Dual‐Drug Delivery: A Combination Study of Experiments and Simulations

A dual-drug-loaded micelle is designed and constructed from a mixture of poly(propylene oxide)-b-poly(γ-benzyl-l-glutamate)-b-poly(ethylene glycol) (PPO-b-PBLG-b-PEG) triblock terpolymers and two model drugs, doxorubicin (DOX) and naproxen (Nap). In the micelles, the DOX is chemically linked to the PBLG backbones through an acid-cleavable hydrazone bond, whereas the Nap is physically encapsulated in the cores. The drug loading and releasing behaviors of the dual-drug-loaded micelles as well as single drug-loaded micelles (DOX-conjugated or Nap-loaded micelles) are studied. The structures of micelles are characterized by means of microscopies and dynamic light scattering, and further examined by dissipative particle dynamics (DPD) simulations. It is revealed that the micelles possess a core-shell-corona structure in which the PPO/Nap, PBLG/DOX, and PEG aggregate to form the core, shell, and corona, respectively. In vitro studies reveal that the release of DOX and Nap is pH- and thermosensitive. Such drug releasing behaviors are also examined by DPD simulations, and more information regarding the mechanism is obtained. In addition, the bio-related properties such as cellular uptake of the micelles and biocompatibility of the deliveries are evaluated. The results show that the dual-drug-loaded micelles are biocompatible at normal physiological conditions and retain the anti-cancer efficiency.

Toroid Formation through Self-Assembly of Graft Copolymer and Homopolymer Mixtures: Experimental Studies and Dissipative Particle Dynamics Simulations

Self-assembly of mixture systems containing poly(acrylic acid)-g-poly(γ-benzyl-L-glutamate) graft copolymers (PAA-g-PBLG) and PBLG homopolymers in aqueous solution was investigated by both experiments and computer simulations. It was found that the aggregate morphologies, such as rods, curved rods, and toroids, could be tuned by the homopolymer content. The toroidal micelles with uniform size were formed when the homopolymer content in the hybrid aggregates is higher. The effect of added water content on the toroid formation process was studied. Rods and curved rods were observed sequentially before formation of toroids. We also performed dissipative particle dynamics (DPD) simulations to verify the structure transition and explore the formation mechanism of the toroidal aggregates. The DPD results are in good agreement with the experimental findings and provide additional information such as chain distribution in aggregates, which is difficult to be gained through experiments. On the basis of the experimental and simulation results, the formation mechanism of the toroidal micelles was suggested.

Drug-carrier/hydrogel scaffold for controlled growth of cells

In this work, a novel functional drug-carrier/hydrogel scaffold was prepared to control the growth of cells for tissue engineering. The drug-carrier/hydrogel scaffold was constructed from a micelle/Ca-alginate microparticles (Alg-MPs)/poly(vinyl alcohol) (PVA) hydrogel composite. In such a system, paclitaxel (PTX) is encapsulated in the micelles formed by poly(L-glutamic acid)-b-poly(propylene oxide)-b-poly(L-glutamic acid) (GPG), while human vascular endothelial growth factor-165 (VEGF(165)) is loaded in the Alg-MPs. The designed function of this scaffold is to encourage the fast growth of cells such as endothelial cells (ECs) in the early period to reduce the rejection and inhibit the growth of cells such as smooth muscle cells (SMCs) in late period to prevent the vascular intimal hyperplasia. The effect of VEGF(165) is to encourage the growth of ECs, while PTX is used to inhibit the growth of smooth muscle cells (SMCs). Structure characterizations show that the drug carriers are well dispersed in the PVA hydrogel. Independent release behaviors of the two drugs are observed. VEGF(165) shows a short-term release behavior, while PTX shows a long-term release behavior from the drug-carrier/hydrogel scaffolds. Further study shows a controllable cell growth behavior on this functional drug-carrier/hydrogel scaffold via the MTT assay.