Bacterial interference is an alternative strategy to fight against device-associated bacterial infections. Pursuing this strategy, a non-pathogenic bacterial biofilm is used as a live, protective barrier to fence off pathogen colonization. In this work, biofilms formed by probiotic Escherichia coli strain Nissle 1917 (EcN) are investigated for their potential for long-term bacterial interference against infections associated with silicone-based urinary catheters and indwelling catheters used in the digestive system, such as feeding tubes and voice prostheses. We have shown that EcN can form stable biofilms on silicone substrates, particularly those modified with a biphenyl mannoside derivative. These biofilms greatly reduced the colonization by pathogenic Enterococcus faecalis in Lysogeny broth (LB) for 11 days.Statement of SignificanceBacterial interference is an alternative strategy to fight against device-associated bacterial infections. Pursuing this strategy, we use non-pathogenic bacteria to form a biofilm that serves as a live, protective barrier against pathogen colonization. Herein, we report the first use of preformed probiotic E. coli Nissle 1917 biofilms on the mannoside-presenting silicone substrates to prevent pathogen colonization. The biofilms serve as a live, protective barrier to fence off the pathogens, whereas current antimicrobial/antifouling coatings are subjected to gradual coverage by the biomass from the rapidly growing pathogens in a high-nutrient environment. It should be noted that E. coli Nissle 1917 is commercially available and has been used in many clinical trials. We also demonstrated that this probiotic strain performed significantly better than the non-commercial, genetically modified E. coli strain that we previously reported.Download high-res image (189KB)Download full-size image

In this work, an amphiphilic copolymer, PCL-SS-P(PEGMA-co-MAEBA), which contained a disulfide joint in backbone was designed and synthesized. The subsequent micelles that self-assembled from the copolymers were cross-linked by hydrazone, resulting in novel stimuli-responsive degradable micelles with a reversible cross-linked shell. By way of the hydrazone cross-linking of the micellar shell, SCMs owned a good stability against the extensive dilution by water or organic solvent. Doxorubicin (DOX) was used as the model drug for studying the in vitro release profiles of the SCMs. In normal physiological conditions at pH 7.4, a quite slow speed was observed with DOX release (only 23% after 72 h); when conditions were changed to pH 5.0, the SCMs successfully de-crosslinked, DOX release was accelerated (62%). Moreover, drug release was further promoted and reached 87% when 10 mM GSH was present, which was primarily due to the breakage of the disulfide joint. The intracellular uptake assay proved that DOX from DOX-loaded SCMs could be efficiently delivered into HepG2 cells after 12 h incubation. MTT assays confirmed that DOX-loaded SCMs owned a high cytotoxicity against HepG2 cells. These redox-responsive, degradable SCMs could be a potential candidate for efficient insoluble anticancer drug delivery and therapy.

•We designed and synthesized the sequence-defined polymers with CRC-motif by NCL reaction.•The amphiphilic polymers were coated with active targeting ligand and shield segments.•The CRC-motif modified polymers could self-assemble into polymeric micelles.•Twin disulfides could be formed, leading to improved siRNA silencing efficiency.•The polymer modified with CRC-motif could be a promising siRNA carrier.The sequence-defined polycationic polymers with or without Cys-Arg-Cys motifs conjugated with targeting and shielding segments were synthesized as siRNA carriers via native chemical ligation (NCL) reaction. After purification, the structures and physicochemical characteristics were determined by a variety of experimental techniques. The particle size of siRNA/CRC-polymer polyplex was much smaller than that of polyplex without CRC motifs. The buffer capacity and siRNA binding ability of CRC motifs modified polymers were significantly improved, resulting from the twin disulfides and hexatomic ring formulation. The critical micelle concentrations of the polymers were < 10 mg/L, indicating formation of polymeric micelles and sufficient stability of the system. The CRC motifs modified polymers with folate targeted ligands exhibited a strongly enhanced cellular uptake than the negative control and the unmodified analogues. The results of gene transfection showed that the folate-PEG-ligated polymer modified with CRC motifs had much better gene transfection compared to the alanine-ended control and other analogues. Furthermore, they showed barely cytotoxicity. By the way, there was no distinctly improvement for pDNA transfection. All above results suggested that folate-PEG-ligated polymers modified with CRC motifs and their self-assembly polymeric micelles could be promising non-viral siRNA carriers.The folate-PEG-ligated CRC-polymer with twin disulfides and its self-assembly polymeric micelle could be a promising non-viral carrier for siRNA delivery.Download high-res image (170KB)Download full-size image

Co-delivery of antigen-encoding plasmid DNA (pDNA) and immune-modulatory molecules has importance in advancing gene-based immunotherapy and vaccines. Here novel star polymer nanocarriers were synthesized for co-delivery of pDNA and imiquimod (IMQ), a poorly soluble small-molecule adjuvant, to dendritic cells. Computational modeling and experimental results revealed that the polymers formed either multimolecular or unimolecular core-shell-type micelles in water, depending on the nature of the outer hydrophilic shell. Micelles loaded with both IMQ and pDNA were able to release IMQ in response to intracellular pH of the endo-lysosome and transfect mouse dendritic cells (DC2.4 line) in vitro. Importantly, IMQ-loaded micelle/pDNA complexes displayed much enhanced transfection efficiency than IMQ-free complexes. These results demonstrate the feasibility of co-delivery of pDNA and IMQ to antigen-presenting cells by multifunctional polymer nanocarriers with potential use in gene-based vaccine approaches.Download high-res image (251KB)Download full-size image

The development of an in situ formed pH-responsive theranostic nanocomposite for anticancer drug delivery and computed tomography (CT) imaging was reported. β-cyclodextrin-{poly(lactide)-poly(2-(dimethylamino) ethyl methacrylate)-poly[oligo(2-ethyl-2-oxazoline)methacrylate]}21 [β-CD-(PLA-PDMAEMA-PEtOxMA)21] unimolecular micelles served as a template for the in situ formation of gold nanoparticles (GNPs) and the subsequent encapsulation of doxorubicin (DOX). The formation of unimolecular micelles, microstructures and the distributions of GNPs and DOX were investigated through the combination of experiments and dissipative particle dynamics (DPD) simulations. β-CD-(PLA-PDMAEMA-PEtOxMA)21 formed spherical unimolecular micelles in aqueous solution within a certain range of polymer concentrations. GNPs preferentially distributed in the PDMAEMA area. The maximum wavelength (λmax) and the size of GNPs increased with increasing concentration of HAuCl4. DOX preferentially distributed in the PDMAEMA mesosphere, but penetrated the inner PLA core with increasing DOX concentration. DOX-loaded micelles with 41–61% entrapment efficiency showed fast release (88% after 102 h) under acidic tumor conditions. Both in vitro and in vivo experiments revealed superior anticancer efficacy and effective CT imaging properties for β-CD-(PLA-PDMAEMA-PEtOxMA)21/Au/DOX. We conclude that the reported unimolecular micelles represent a class of versatile smart nanocarriers for theranostic application.Statement of SignificanceDeveloping polymeric nanoplatforms as integrated theranostic vehicles for improving cancer diagnostics and therapy is an emerging field of much importance. This article aims to develop an in situ formed pH-responsive theranostic nanocomposite for anticancer drug delivery and computed tomography (CT) imaging. Specific emphases is on structure-properties relationship. There is a sea of literature on polymeric drug nanocarriers, and a couple of polymer-stabilized gold nanoparticles (GNPs) systems for cancer diagnosis are also known. However, to our knowledge, there has been no report on polymeric unimolecular micelles capable of dual loading of GNPs without external reducing agents and anticancer drugs for cancer diagnosis and treatment. To this end, the target of the current work was to develop an in situ formed nanocarrier, which actively dual wrapped CT contrast agent GNPs and hydrophobic anticancer drug doxorubicin (DOX), achieving high CT imaging and antitumor efficacy under in vitro and in vivo acid tumor condition. Meanwhile, by taking advantage of dissipative particle dynamics (DPD) simulation, we further obtained the formation process and mechanism of unimolecular micelles, and detailed distributions and microstructures of GNPs and DOX on unimolecular micelles. Taken together, our results here provide insight and guidance for the design of more effective nanocarriers for cancer theranostic application.Download high-res image (112KB)Download full-size image

The synthesis of a series of PDEAEMA-based pH-sensitive amphiphilic pentablock copolymers poly(methyl methacrylate)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(ethylene glycol)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(methyl methacrylate) [PEG-b-(PDEAEMA-b-PMMA)2] with different compositions proceeded via the combination of a bromination reaction and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). All the copolymers were characterized by 1H NMR and gel permeation chromatography (GPC). The amphiphilic copolymers can self-assemble into micelles in aqueous solution, and the CMC values were comparatively low (2.40–2.80 mg L−1). The pKb buffering region, particle sizes, zeta potentials and optical transmittance were measured to investigate the pH-sensitivity of the polymeric micelles. The size and morphology of the self-assembled blank and DOX-loaded micelles were determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The in vitro release rate was sharply increased by decreasing the pH from 7.4 to 5.0, due to the swelling of micelles at lower pH caused by the protonation of tertiary amine groups of PDEAEMA. The in vitro cytotoxicity of DOX-loaded micelles against Hela cells were measured and compared with free DOX, suggesting that the blank micelles provide low cytotoxicity and the DOX-loaded micelles provided high cytotoxicity nearly that of free DOX. The results indicate that this new kind of amphiphilic copolymers could serve as promising nanocarriers for controlled anticancer drug delivery.

•A new type of topological descriptors suitable for polymeric structures•Optimum QSAR models between diverse polymeric structures and micellar properties•Key characteristics influencing drug loading capacity and CMC of studied micellesPolymeric micelles are a type of complex chemical product with multiple phases and components, and polymeric molecular structures are among the main factors influencing the micellar properties. In this study, based on block unit autocorrelation (BUA) descriptors, we employed a genetic function approximation (GFA) algorithm and multiple linear regression (MLR) to develop quantitative structure–property relationship (QSPR) models between the multi-topological structures of polymers and micellar properties including drug loading capacity (LC) and critical micelle concentration (CMC), generating an LC optimization model with five descriptors (n = 60, R2 = 0.813, Q2LOO-CV = 0.663, Q25-fold = 0.636, F = 46.880 (p < 0.001), Q2ext = 0.830, Q2y-rand = 0.0004) and a CMC optimization model with six descriptors (n = 22, R2 = 0.897, Q2LOO-CV = 0.702, F = 21.765 (p < 0.001), Q2ext = 0.717, Q2y-rand = 0.0009). Based on the model analysis, the factors mainly influencing LC are the lowest unoccupied molecular orbital (LUMO) energy, dipole, electrostatic energy and electronic energy, which are related to the electronic energy level, electron distribution and interaction of electrons in molecules. The main factors affecting CMC are the energies of interactions between polymers and water, charges and branching of polymer structures. The conclusions obtained may help establish the regulatory mechanism between polymer structures and micellar properties and offer guidance for the design and development of polymeric carrier materials.

•We designed and synthesized three kinds of polymers with different topological structures.•The pH-sensitive core/shell micelles could be used as anticancer drug carriers.•Decreasing the pH value could increase the drug release rate from the system.•Drug release mechanism was investigated to study the structure-property relationships.•Anti-cancer effect of the drug-loaded system was better than the free drugs.Multifunctional core/shell micelles were self-assembled from triblock copolymers poly(ethylene glycol) methyl ether-b-peptide-g-cholesterol (mPEG-b-P-g-Chol) and used as the doxorubicin delivery carriers for cancer chemotherapy. The copolymers were designed and synthesized successfully based on peptides containing histidine residues (pH-trigger) with different topological structures. The peptides were modified by mPEG (hydrophilic) and cholesterol motifs (hydrophobic) on the terminus, resulting in pH-sensitive amphiphilic copolymers. The critical micelle concentrations (CMCs) of the micelles were determined as 4.79, 2.50 and 1.86 mg/L for the linear, Y-shape and fork-shape copolymers, respectively, demonstrating the formation of micelle even at low concentration. The pKb values of three copolymers were found to be around 6.1–6.3 by potentiometric titration test, showing the satisfied pH-sensitivity. The average diameter and zeta potential of blank micelles were 170 nm and +20 mV at pH 7.4, and increased to 250 nm and +35 mV at pH 5.0. DOX was loaded into the core of polymeric micelles by dialysis method, and the drug loading capacity slightly increased when the copolymer topological structure changed from linear to Y- and fork-shape. The drug release rate from the system was obviously influencing by the pH values according to the results of in vitro DOX release experiment. Moreover, to investigate the structure-property relationship, the drug release mechanism was preliminarily explored by the semi-empirical equations. Toxicity test showed that three copolymers had bare toxicity whereas the DOX-loaded micelles remained high cytotoxicity for tumor cells. The results indicate the synthesized copolymers might be a potential hydrophobic drug delivery carrier for cancer targeting therapy with controlled drug release.The pH-sensitive core/shell polymeric micelles, self-assembled from the pH-sensitive amphiphilic copolymers, might be a potential sustained-controlled drug delivery system for cancer therapy.

Multilamellar nanoparticles (NPs) are spontaneously formed when mixing two components with opposite charges, meaningful for drug delivery. However, details of NPs association and mechanisms of this process remain largely unknown, due to the limitation of experimental technique. In this work, we use dissipative particle dynamics (DPD) simulation for the first time to determine the structure–property relationships of multilamellar NPs formed by charged blends. As a case study, a system with polyanionic fondparinux (Fpx) and cationic derivatives squalenoyl (CSq, including Sq+ and Sq++) in aqueous media is investigated, with a focus on the optimized formation condition and mechanism of regular spherical multilamellar NPs. In particular, we find that highly ordered multilamellar structures tend to form when the nonbonded interaction between Fpx–CSq and hydrophobic interaction contributed by CSq are well-balanced. The DPD results strongly agree with corresponding experimental results of this novel nanoparticulate drug carrier. This study could help develop promising multilamellar NPs formed by charged blends through self-assembly for drug delivery.

Well-defined A3(BC)3 type amphiphilic miktoarm star polymers poly(ε-caprolactone)3-[poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate)]3 [(PCL)3-(PDEAEMA-b-PPEGMA)3] and their pH-sensitive self-assembled polymeric micelles were developed as anticancer vehicles for improved cancer therapy. These miktoarm star polymers were synthesized by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and characterized by GPC and 1H NMR measurement. The CMC values of the miktoarm star polymers in aqueous solution were extremely low (0.0029–0.0035 mg mL−1), suggesting that the micelles are relatively stable in solution. The self-assembled blank and doxorubicin (DOX)-loaded micelles were spherical in morphology with average sizes of 110–240 nm depending on the architecture of the copolymers, which were determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS). When decreasing pH from 7.4 to 5.0, the micelles underwent globule–uneven–extended conformational transitions, and in vitro drug release rates were significantly accelerated, owing to the swelling of micelles at lower pH conditions caused by the protonation of tertiary amine groups of DEAEMA. Moreover, the drug release profiles at different pH values were well fitted by a semi-empirical equation. The in vitro cytotoxicity of DOX-loaded micelles against HepG2 cells suggested that DOX-loaded (PCL)3-(PDEAEMA-b-PPEGMA)3 micelles exhibited similar anti-tumor activities to free DOX, with at least 80% decrease in cell viability after 48 h incubation. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles. The results demonstrated that the pH-responsive (PCL)3-(PDEAEMA-b-PPEGMA)3 micelles could be used as latent vehicles for delivering hydrophobic anticancer drugs with controlled and sustained release behavior.

How to control the release of drugs from pH-sensitive polymeric micelles is an issue of common concern, which is important to the effectiveness of the micelles. The components and properties of polymers can notably influence the drug distributions inside micelles which is a key factor that affects the drug release from the micelles. In this work, the dissipative particle dynamics simulation method is first used to study the structural transformation of micelles during the protonation process and the drug release process from micelles with different drug distributions. And then the effects of polymer structures, including different lengths of hydrophilic blocks, pH-sensitive blocks and hydrophobic blocks, on drug release are also studied. In the end, several corresponding design principles of pH-sensitive polymers for drug delivery are proposed according to the simulation results. This work is in favor of establishing qualitative rules for the design and optimization of congener polymers for desired drug delivery, which is of great significance to provide a potential approach for the development of new multiblock pH-sensitive polymeric micelles.Keywords: dissipative particle dynamics simulation; drug diffusion; drug distribution; drug release; pH-sensitive polymer

Typical cholesterol modified amphiphilic copolymers poly((hydroxyethyl methylacrylate)-co-(2-(diethylamino)ethyl methacrylate))-b-poly(poly(ethylene glycol) methyl ether methacrylate) (Chol-g-P(HEMA-co-DEAEMA)-b-PPEGMA) with specific pH-sensitive/hydrophilic/hydrophobic structures containing different ratios of pH-sensitive PDEAEMA segments were designed and synthesized via the combination of activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and alcoholysis reaction, and their self-assembled three-layered micelles were used as doxorubicin (DOX) delivery carriers. The structures of the polymers were determined by 1H NMR and GPC. The critical micelle concentrations (CMC) of the polymers at different pH values were confirmed by fluorescence spectroscopy, resulting in 9.33 mg L−1 and 13.18 mg L−1 for two polymers even at weakly acidic conditions (pH 6.0). The pKb values, particle sizes and zeta potentials of the polymers in the solutions with different pH values were studied in order to investigate the pH-sensitivity of the polymers. The morphological shapes of the polymers were detected by transmission electron microscopy (TEM). As the pH decreased, the sizes and zeta potentials of the polymeric micelles increased markedly. DOX was loaded in the micelles by the dialysis method, and the in vitro release rate was enhanced sharply with the solution pH of 6.0 when compared to pH of 7.4 for both of the polymers. The cytotoxic effects for HepG2 cells were measured and compared with free DOX, resulting in low and high cytotoxicity for polymers and DOX-loaded micelles, respectively. All the results demonstrated that these pH-sensitive micelles could be used as the potential anti-cancer drug carriers.

Dissipative particle dynamics (DPD) simulation was applied to investigate the microstructures of the micelles self-assembled from pH-sensitive four-arm star triblock poly(ε-caprolactone)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (4AS-PCL-b-PDEAEMA-b-PPEGMA). In the optimized system, the micelles have a core–mesosphere–shell three-layer structure. The drug-loading process and its distribution at different formulations in the micelles were studied. The results show that DOX molecules distributed in the core and the interface between the core and the mesosphere, suggesting the potential encapsulation capacity of DOX molecules. More drugs were loaded in the micelles with the increase in DOX, and the size of micelles became larger. However, some openings start to generate on the PEG shell when the DOX reaches a certain concentration. By changing the pH values of the system, different morphologies of the micelles were acquired after the pH-sensitive blocks PDEAEMA were protonated, the mechanism of which was also analyzed through correlating functions. The results indicated that the sudden increase in solubility parameter of the pH-sensitive blocks and the swelling of the micelles were the key factors on the change of morphologies. Furthermore, with the decrease in pH value, the number and size of the cracks on the surface of the micelles were larger, which may have a direct effect on the drug release. In conclusion, 4AS-PCL-b-PDEAEMA-b-PPEGMA has great promising applications in delivering hydrophobic anticancer drugs for improved cancer therapy.

The entrapment efficiency of a drug into self-assembled polymeric micelles is commonly found to be extremely low. Drug diffusion into the core of micelles is an important process that affects the micelle loading capacity and efficiency of hydrophobic drugs. Herein, dissipative particle dynamics (DPD) simulations are carried out to study drug diffusion abilities into the core of micelles after the core–shell structure of the micelle is formed, which is the key issue that affects drug loading efficiency. Topological structures of the drug, the hydrophobic block length of the polymer, as well as the compatibility between the drug and the hydrophobic block have significant effects on drug loading efficiencies and drug distributions inside micelles. In particular, the interaction parameter of 10 between the drug and hydrophobic block A results in 100% drug loading efficiency and a very homogeneous distribution of drug molecules in the core of the micelles. We also provide an insight into the relationship between drug loading efficiency and micelle stability, which can facilitate the development of stable drug loaded micelles. The present study provides a mechanistic study of micellar drug loading on the microscale level, which may provide ideas for future experimental preparation of stable drug loaded micelles with high drug loading efficiencies.

A random hydrophobic/pH-sensitive copolymer brush poly(polylactide methacrylate-co-methacrylic acid)-b-poly(poly(ethylene glycol) methyl ether methacrylate) [P(PLAMA-co-MAA)-b-PPEGMA] and its self-assembled micelles were developed for oral administration of hydrophobic drugs. The polymer was synthesized by the combination of activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and ring opening polymerization (ROP). The CMC of P(PLAMA-co-MAA)-b-PPEGMA in aqueous solution was extremely low (about 1.5 mg L−1). The self-assembled blank and drug-loaded micelles were spherical in morphology and had an average size of 160–220 nm, determined by DLS and SEM. Ibuprofen (IBU) was selected as the model drug and encapsulated into the core of micelles via a dialysis method. The in vitro release behavior of IBU from these micelles was pH-dependent. In simulated gastric fluid (SGF, pH 1.2), the cumulative release of IBU was less than 25% of the initial drug content over 24 h, suggesting that the drug can be well protected from the harsh environment in stomach. While in simulated intestinal fluid (SIF, pH 7.4), the ionization of carboxyl groups of MAA contributed to the swelling of the micelle structure, which could accelerate the IBU release from the micelles. 35–45% of IBU was released in 8 h, 60% in 24 h, and 100% after 56 h for P(PLAMA6.3k-co-MAA3k)-b-PPEGMA4k micelles, and it was 50% in 2 h, 90% in 10 h, and 100% after 14 h for P(PLAMA6.3k-co-MAA4.5k)-b-PPEGMA4k micelles with an increased content of MAA. All the results indicate that the pH-sensitive P(PLAMA-co-MAA)-b-PPEGMA micelles may be a potential oral drug delivery carrier for hydrophobic drugs with sustained release.

The insulin loaded nanoparticles composed of poly (lactic-co-glycolic acid) (PLGA) and hydroxypropyl methylcellulose phthalate (HP55) were prepared via the emulsions solvent diffusion method with two different solvents, namely, DMSO and acetone/water. The microstructures of the nanoparticles were studied by the solubility parameters theory, DSC, FTIR, and the nitrogen adsorption technique. Phase-separated PLGA domains were observed from the nanoparticles prepared with both types of solvents. Mesopores were observed from the nanoparticles prepared with DMSO as the solvent and almost did not exist with acetone/water. An in vitro drug release study showed that the pH-sensitivity of nanoparticles was not only attributed to the pH-dependent dissolubility of HP55 but also to the internal microstructure. The formation of mesopores accelerated the release of insulin, leading to no obvious pH-sensitivity of the nanoparticles prepared with DMSO. However, for the nanoparticles prepared with acetone/water, the release of insulin was pH-dependent. The results demonstrated that solvents played an important role in affecting the microstructures of nanoparticles, which influenced markedly the insulin release behavior.Graphical abstractHighlights► The solvent effect on compatibility of components in nanoparticles has been explored. ► The microstructures of nanoparticles are dependent of different solvents. ► The mesopores accelerated the release of insulin from pH-sensitive nanoparticles. ► The microstructure is an important factor influencing the insulin release behavior.

A novel and well-defined pH-sensitive amphiphilic triblock copolymer brush poly(lactide)-b-poly(methacrylic acid)-b-poly(poly(ethylene glycol) methyl ether monomethacrylate) (PLA-b-PMAA-b-PPEGMA) and its self-assembled micelles were developed for oral administration of hydrophobic drugs. The copolymer and its precursors were synthesized by the combination of activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and ring-opening polymerization (ROP) techniques. The molecular structures and characteristics were confirmed by GPC, 1H NMR, and FT-IR. The critical micelle concentration (CMC) values of PLA-b-PMAA-b-PPEGMA in aqueous medium varied from 1.4 to 2.6 mg/L, and the partition equilibrium constant (Kv) of pyrene in micellar solutions ranged from 2.873 × 105 to 3.312 × 105. The average sizes of the self-assembled blank and drug-loaded micelles were 140–250 nm determined by DLS in aqueous solution. The morphology of the micelles was found to be spherical by SEM. Nifedipine (NFD), a poorly water-soluble drug, was selected as the model drug and wrapped into the core of micelles via dialysis method. The in vitro release behavior of NFD from the micelles was pH-dependent. In simulated gastric fluid (SGF, pH 1.2), the cumulative release percent of NFD was relative low, while in simulated intestinal fluid (SIF, pH 7.4), more than 96% was released within 24 h. All the results showed that the pH-sensitive PLA-b-PMAA-b-PPEGMA micelle may be a prospective candidate as oral drug delivery carrier for hydrophobic drugs with controlled release behavior.

A novel pH-sensitive amphiphilic copolymer brush poly(methyl methacrylate-co-methacrylic acid)-b-poly(poly(ethylene glycol) methyl ether monomethacrylate) [P(MMA-co-MAA)-b-PPEGMA] was defined and synthesized by atom transfer radical polymerization (ATRP) technique. The molecular structures and characteristics of this copolymer and its precursors were confirmed by 1H NMR, FT-IR, and GPC. The CMC of P(MMA-co-MAA)-b-PPEGMA in aqueous medium was determined to be 1−4 mg/L. This copolymer could self-assemble into micelles in aqueous solution with an average size of 120−250 nm determined by DLS. The morphologies of the micelles were found to be spherical by SEM and TEM. Ibuprofen (IBU), a poorly water-soluble drug, was selected as the model drug and wrapped into the core of micelles via dialysis method. Drug entrapment efficiency reached to 90%. The in vitro release behavior of IBU from these micelles was pH-dependent. The cumulative release percent of IBU was less than 20% of the initial drug content in simulated gastric fluid (SGF, pH 1.2) over 12 h, but 90% was released in simulated intestinal fluid (SIF, pH 7.4) within 6 h. The release profiles showed that the P(MMA-co-MAA)-b-PPEGMA micelles could inhibit the premature burst drug release under the intestinal conditions. All the results indicate that the P(MMA-co-MAA)-b-PPEGMA micelle may be a potential oral drug delivery carrier for poorly water-soluble drugs.

Unimolecular polymeric micelles have several features, such as thermodynamic stability, small particle size, biocompatibility, and the ability to internalize hydrophobic molecules. These micelles have recently attracted significant attention in various applications, such as nano-reactors, catalysis, and drug delivery. However, few attempts have explored the formation mechanisms and conditions of unimolecular micelles due to limited experimental techniques. In this study, a unimolecular micelle system formed from β-cyclodextrin-graft-{poly(lactide)-block-poly(2-(dimethylamino) ethyl multimethacrylate)-block-poly[oligo (2-ethyl-2-oxazoline) methacrylate]} β-CD-g-(PLA-b-PDMAEMA-b-PEtOxMA) star-like block copolymers in aqueous media was investigated by dissipative particle dynamics (DPD) to explore the formation process of unimolecular micelles. The simulation results showed that using longer hydrophobic or pH-sensitive chains, shorter hydrophilic backbones, smaller hydrophilic side chain grafting density, and fewer polymer arms resulted in micellar aggregation. Furthermore, this unimolecular polymeric micelle could be used for encapsulating gold nanoparticles, whose mesoscopic structure was also explored. The gold nanoparticles tended to distribute in the middle layer formed by PDMAEMA, and the unimolecular micelles were capable of impeding gold nanoparticle aggregation. This study could help understand the formation mechanism of unimolecular micelles formed from star-like block copolymers in dilute solutions and offer a theoretical guide to the design and preparation of promising unimolecular polymeric micelles with targeting properties.

Well-defined A3(BC)3 type amphiphilic miktoarm star polymers poly(ε-caprolactone)3-[poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate)]3 [(PCL)3-(PDEAEMA-b-PPEGMA)3] and their pH-sensitive self-assembled polymeric micelles were developed as anticancer vehicles for improved cancer therapy. These miktoarm star polymers were synthesized by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and characterized by GPC and 1H NMR measurement. The CMC values of the miktoarm star polymers in aqueous solution were extremely low (0.0029–0.0035 mg mL−1), suggesting that the micelles are relatively stable in solution. The self-assembled blank and doxorubicin (DOX)-loaded micelles were spherical in morphology with average sizes of 110–240 nm depending on the architecture of the copolymers, which were determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS). When decreasing pH from 7.4 to 5.0, the micelles underwent globule–uneven–extended conformational transitions, and in vitro drug release rates were significantly accelerated, owing to the swelling of micelles at lower pH conditions caused by the protonation of tertiary amine groups of DEAEMA. Moreover, the drug release profiles at different pH values were well fitted by a semi-empirical equation. The in vitro cytotoxicity of DOX-loaded micelles against HepG2 cells suggested that DOX-loaded (PCL)3-(PDEAEMA-b-PPEGMA)3 micelles exhibited similar anti-tumor activities to free DOX, with at least 80% decrease in cell viability after 48 h incubation. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles. The results demonstrated that the pH-responsive (PCL)3-(PDEAEMA-b-PPEGMA)3 micelles could be used as latent vehicles for delivering hydrophobic anticancer drugs with controlled and sustained release behavior.