Redox‐ and Temperature‐Controlled Drug Release from Hollow Mesoporous Silica Nanoparticles

A controlled drug‐delivery system has been developed based on mesoporous silica nanoparticles that deliver anticancer drugs into cancer cells with minimized side effects. The copolymer of two oligo(ethylene glycol) macromonomers cross‐linked by the disulfide linker N,N′‐bis(acryloyl)cystamine is used to cap hollow mesoporous silica nanoparticles (HMSNs) to form a core/shell structure. The HMSN core is applied as a drug storage unit for its high drug loading capability, whereas the polymer shell is employed as a switch owing to its redox/temperature dual responses. The release behavior in vitro of doxorubicin demonstrated that the loaded drugs could be released rapidly at higher temperature or in the presence of glutathione (GSH). Thus, the dual‐stimulus polymer shell exhibiting a volume phase transition temperature higher than 37 °C can effectively avoid drug leakage in the bloodstream owing to the swollen state of the shell. Once internalized into cells, the carriers shed the polymer shell because of cleavage of the disulfide bonds by GSH, which results in the release of the loaded drugs in cytosol. This work may prove to be a significant development in on‐demand drug release systems for cancer therapy.     

pH‐ and β‐cyclodextrin‐responsive micelles based on polyaspartamide derivatives as drug carrier

A novel kind of graft polymer poly(aspartic acid)‐ethanediamine‐g‐adamantane/methyloxy polyethylene glycol (Pasp‐EDA‐g‐Ad/mPEG) was designed and synthesized for drug delivery in this study. The chemical structure of the prepared polymer was confirmed by proton NMR. The obtained polymer can self‐assemble into micelles which were stable under a physiological environment and displayed pH‐ and β‐cyclodextrin (β‐CD)‐responsive behaviors because of the acid‐labile benzoic imine linkage and hydrophobic adamantine groups in the side chains of the polymer. The doxorubicin (Dox)‐loaded micelles showed a slow release under physiological conditions and a rapid release after exposure to weakly acidic or β‐CD environment. The in vitro cytotoxicity results suggested that the polymer was good at biocompatibility and could remain Dox biologically active. Hence, the Pasp‐EDA‐g‐Ad/mPEG micelles may be applied as promising controlled drug delivery system for hydrophobic antitumor drugs. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 1387–1395     

Carrier‐Free Delivery of Precise Drug–Chemogene Conjugates for Synergistic Treatment of Drug‐Resistant Cancer

Combinatorial antitumor therapies using different combinations of drugs and genes are emerging as promising ways to overcome drug resistance, which is a major cause for the failure of cancer treatment. However, dramatic pharmacokinetic differences of drugs greatly impede their combined use in cancer therapy, raising the demand for drug delivery systems (DDSs) for tumor treatment. By employing fluorescent dithiomaleimide (DTM) as a linker, we conjugate two paclitaxel (PTX) molecules with a floxuridine (FdU)‐integrated antisense oligonucleotide (termed chemogene) to form a drug–chemogene conjugate. This PTX–chemogene conjugate can self‐assemble into a spherical nucleic acid (SNA)‐like micellular nanoparticle as a carrier‐free DDS, which knocks down the expression of P‐glycoprotein and subsequently releases FdU and PTX to exert a synergistic antitumor effect and greatly inhibit tumor growth.     

Disassembly‐Driven Fluorescence Turn‐on of Polymerized Micelles by Reductive Stimuli in Living Cells

Stimuli‐response nanoparticles have emerged as powerful tools for imaging and therapeutic applications. Ideally, they should be assembled from biodegradable materials featuring small size and cooperative response to biological stimuli that trigger particle disassembly and release of an active molecule that could be readily monitored in situ. A concept is developed that consists of organic nanoparticles, assembled from fluorescent amphiphiles and polymerized with a redox‐cleavable cross‐linker. We obtained 20 nm nanoparticles bearing self‐quenched Nile Red dye residues, which can disassemble in living cells into highly fluorescent molecular units owing to an external or internal reductive stimulus. The obtained results pave the way to new stimuli‐responsive nanomaterials for applications in background‐free imaging as well as in drug delivery, as the concept can be further extended to other active molecules including drugs and to cross‐linkers cleavable by other biological stimuli.     

Synthesis and character of novel polycarbonate for constructing biodegradable multi‐stimuli responsive delivery system

Here, we design a novel triple‐stimuli‐sensitive graft copolymer assembly which responds to the changes in temperature, reducing agent, and light. The graft copolymer consists of thermo‐responsive tetraethylene glycolyl poly(trimethylene carbonate) (P(MTC‐4EG)) as backbone and light‐sensitive poly(2‐nitrobenzyl methacrylate) (PNBM) as side chain linked by an intervening disulfide bond. In aqueous solution, the polymer can self‐assemble into micelle with thermo‐sensitive shell (P(MTC‐4EG)), light‐sensitive core (PNBM), and disulfide linker. The assemblies in response to stimuli were revealed by dynamic light scatting (DLS) and transmission electron microscopy (TEM). The drug release behaviors of Nile Red (NR)‐loaded carriers were also valued with stimuli from temperature, reducing agent, and light. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3583–3592     

Novel Biodegradable Polymer with Redox‐Triggered Backbone Cleavage Through Sequential 1,6‐Elimination and 1,5‐Cyclization Reactions

In the past decade, the self‐immolative biodegradable polymer arose as a novel paradigm for its efficient degradation mechanism and vast potential for advanced biomedical applications. This study reports successful synthesis of a novel biodegradable polymer capable of self‐immolative backbone cleavage. The monomer is designed by covalent conjugations of both pendant redox‐trigger (p‐nitrobenzyl alcohol) and self‐immolative linker (p‐hydroxybenzyl alcohol) to the cyclization spacer (n‐2‐(hydroxyethyl)ethylene diamine), which serves as the structural backbone. The polymerization of the monomer with hexamethylene diisocyanate yields a linear redox‐sensitive polymer that can systemically degrade via sequential 1,6‐elimination and 1,5‐cyclization reactions within an effective timeframe. Ultimately, the polymer's potential for biomedical application is simulated through in vitro redox‐triggered release of paclitaxel from polymeric nanoparticles.     

In Situ Probing Intracellular Drug Release from Redox‐Responsive Micelles by United FRET and AIE

Redox‐responsive micelles are versatile nanoplatforms for on‐demand drug delivery, but the in situ evaluation of drug release is challenging. Fluorescence resonance energy transfer (FRET) technique shows potential for addressing this, while the aggregation‐caused quenching effect limits the assay sensitivity. The aim of the current work is to combine aggregation‐induced emission (AIE) probe with FRET to realize drug release assessment from micelles. Tetraphenylethene (TPE) is selected as AIE dye and curcumin (Cur) is chosen as the model drug as well as FRET receptor. The drug is covalently linked to a block copolymer via the disulfide bond linker and TPE is also chemically linked to the polymer via an amide bond; the obtained amphiphilic polymer conjugate self‐assembles into micelles with a hydrodynamic size of ≈125 nm. Upon the supplement of glutathione or tris(2‐carboxyethyl)phosphine) trigger (10 × 10⁻³m ), the drug release induces the fluorescence increase of both TPE and Cur. Accompanied with the FRET decay, absorption enhancement and particle size increase are observed. The same phenomenon is observed in MCF‐7 cells. The FRET–AIE approach can be a useful addition to the spectrum of available methods for monitoring drug release from stimuli‐responsive nanomedicine.     

In Situ Formation of Polymeric Nanoassemblies Using an Efficient Reversible Click Reaction

Polymer–drug conjugates are promising as strategies for drug delivery, because of their high drug loading capacity and low premature release profile. However, the preparation of these conjugates is often tedious. In this paper, we report an efficient method for polymer–drug conjugates using an ultrafast and reversible click reaction in a post‐polymerization functionalization strategy. The reaction is based on the rapid condensation of boronic acid functionalities with salicylhydroxamates. The polymer, bearing the latter functionality, has been designed such that the reaction with boronic acid bearing drugs induces an in situ self‐assembly of the conjugates to form well‐defined nanostructures. We show that this method is not only applicable for molecules with an intrinsic boronic acid group, but also for the other molecules that can be linked to aryl boronic acids through a self‐immolative linker. The linker has been designed to cause traceless release of the attached drug molecules, the efficiency of which has been demonstrated through intracellular delivery.     

Tandem dynamic kinetic resolution and enzymatic polycondensation to synthesize mPEG‐functionalized poly(amine‐co‐ester)‐type chiral prodrugs

Amphiphilic poly(amine‐co‐ester)s, which contain a single effective enantiomer of an asymmetric drug and thus can avoid potentially serious side effects, are difficult to prepare through nonselective chemical routes not only in the process of introducing chiral drugs to the polymer, but also in the synthesis of the polymer's backbone by metal catalysts. A model of racemic mexiletine, an important antiarrhythmic agent, was used to demonstrate the tandem combination of Candida antarctica lipase B (CAL‐B)‐ and Pd/C‐catalyzed dynamic kinetic resolution (DKR) and subsequent CAL‐B‐catalyzed polycondensation, as an efficient protocol to prepare poly(ethylene glycol)‐functionalized poly(amine‐co‐ester)s containing (R)‐mexiletine with 99% ee value. Chemoenzymatic DKR and enzymatic polymerization conditions were optimized, and the optical purity of incorporated (R)‐mexiletine was confirmed through its hydrolysis from polyester. The copolymers can readily self‐assemble into nanometer‐scale‐sized micelles with well‐dispersed spheres, which have a size distribution that can be efficiently adjusted by changing the polymer concentration. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Controlled Supramolecular Self‐Assembly of Super‐charged β‐Lactoglobulin A–PEG Conjugates into Nanocapsules

The synthesis and characterization of a new protein–polymer conjugate composed of β lactoglobulin A (βLG A) and poly(ethylene glycol) PEG is described. βLG A was selectively modified to self‐assemble by super‐charging via amination or succinylation followed by conjugation with PEG. An equimolar mixture of the oppositely charged protein–polymer conjugates self‐assemble into spherical capsules of 80–100 nm in diameter. The self‐assembly proceeds by taking simultaneous advantage of the amphiphilicity and polyelectrolyte nature of the protein–polymer conjugate. These protein–polymer capsules or proteinosomes are reminiscent of protein capsids, and are capable of encapsulating solutes in their interior. We envisage this approach to be applicable to other globular proteins.     

Supramolecular Proteoglycan Aggregate Mimics: Cyclodextrin‐Assisted Biodegradable Polymer Assemblies for Electrostatic‐Driven Drug Delivery

Self‐assembled, noncovalent polymeric biodegradable materials mimicking proteoglycan aggregates were synthesized from inclusion complexes of cationic surfactants with γ‐cyclodextrin and the natural anionic polymer hyaluronan. The amorphous structure of this ternary system was proven by X‐ray diffraction and thermal analysis. Light‐scattering measurements showed that there was a competition between hyaluronic acid and the surfactant for the cyclodextrin cavity. These self‐assembled supramolecular matrices were loaded with both hydrophilic and lipophilic drug substances for dissolution studies. The release of the entrapped drugs was found to be controlled by cations in the surrounding media and by biodegradation. Slow drug release in an ion‐free medium became faster in physiological salt solution in which the macroscopic polymer matrix was disassembled. In contrast, the enzymatic degradation of hyaluronan was hindered in the polymeric matrix. The supramolecular systems consisting of γ‐cyclodextrin as a macrocyclic host, a cationic surfactant guest, and hyaluronic acid as the anionic polymer electrostatically cross‐linked by the inclusion complex of the first two was found to be a novel drug‐delivery system for the controlled release of traditional drugs such as curcumin and ketotifen and proteins such as bovine serum albumin.     

Self‐Assembly of Porphyrin–Paclitaxel Conjugates Into Nanomedicines: Enhanced Cytotoxicity due to Endosomal Escape

Nanomedicines assembled directly from drug molecules possess several advantages, including precise molecular structure and high content of drugs. Herein, porphyrin–paclitaxel conjugates (Py‐s‐s‐PTX) were synthesized by using a disulfide bond as a linker. The Py‐s‐s‐PTX could self‐assemble into nanoparticles (Py‐s‐s‐PTX NPs) with a size of about 100 nm via disulfide‐induced assembly. Py‐s‐s‐PTX NPs are highly stable under biological conditions and could be destroyed in the presence of reducing agents as revealed by dynamic light scattering. The obtained Py‐s‐s‐PTX NPs could be internalized by cancer cells via endocytosis and disassociated in the reducing cytoplasm, thus releasing PTX in cancer cells. Endosomal escape triggered upon irradiation could enhance the cytotoxicity of paclitaxel, and Py‐s‐s‐PTX NPs possess cytotoxicity comparable to that of free PTX. We believe that this disulfide‐assembled nanomedicine represents a new and important development for chemotherapy in cancer therapy.     

Regioselective Ring‐Opening Polymerization of a Polyhydroxycarboxylic Acid for the Synthesis of a Nanoscale Carrier Material with pH‐Dependent Stability and Sustained Drug Release

Synthetic polyesters are usually composed of monohydroxycarboxylic acids to avoid the problem of regioselectivity during ring‐opening polymerization. In contrast, the linear polyester BICpoly contains four secondary OH groups and is nevertheless esterified regioselectively at only one of these positions. Neither the synthesis of the tricyclic monomers nor the ring‐opening polymerization requires protecting groups, making BICpoly an attractive novel and biocompatible polymer. BICpoly nanoparticles can be loaded with low‐molecular weight drugs or coated onto surfaces as thin films. The release of loaded compounds makes BICpoly an attractive depot for drug release, as shown herein by loading BICpoly with dyes or the cytostatic drug doxorubicin. BICpoly is distinguishable from other polymers by its characteristic pH‐dependent degradation.     

Novel designed polymer–acyclovir conjugates with linker‐controlled drug release and hepatoma cell targeting

To develop designed polymer–drug conjugates, where the rate of drug liberation and hepatoma cell targeting function could be rationally and widely controlled, we facilely synthesized a series of novel, galactose‐functionalized polymer–acyclovir conjugates with different linkers and first reported the effect of the linker structure including the type of acyclovir‐linked bond (an ester bond or an amide bond) and relative length of the linker between acyclovir and the polymer main chain on release rate and targeting ability of conjugates. In vitro release studies showed that the cumulative released acyclovir from these polymer–acyclovir conjugates was between 24 and 65% in pH 1.2 glycine solution after 7 days. The ester bond more easily underwent hydrolysis than the amide bond. The longer the relative linker length was, the faster the acyclovir was released. The cell recognition experiments visualized using confocal laser scanning microscopy exhibited that the resultant galactose‐functionalized polymer–acyclovir conjugates had evident targeting to hepG2 cells, and targeting ability was also in connection with the relative length of linker. By choosing appropriate linker, cellular internalization of acyclovir could be well achieved. We consider these results to be helpful for the design of multifunctional polymeric prodrugs, in which the required release rate and targeting ability could be rationally controlled by predetermined molecular architecture. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 117–126, 2008     

The Solution Structure and Self‐Association Properties of the Cyclic Lipodepsipeptide Pseudodesmin A Support Its Pore‐Forming Potential

Pseudodesmin A is a cyclic lipodepsipeptide (CLP) of the viscosin group with a moderate in vitro biological activity. For several CLPs, including members of this group, this activity has been related to the ability to form ion pores in cellular membranes. As their size does not allow individual CLPs to span the membrane bilayer, individual monomers must somehow assemble into a larger structure. NMR spectroscopy has been used to demonstrate that in chloroform and other apolar organic solvents, pseudodesmin A monomers assemble into a supramolecular structure. These self‐assembled structures can become sufficiently large to span the membrane bilayer as demonstrated with translational diffusion NMR spectroscopic measurements. With the aim to obtain more insight into the structural nature of this assembly, the solution conformation of pseudodesmin A was first determined by using ROESY (rOe) restraints measured in acetonitrile, in which no self‐association occurs. The structure, which is found to be mostly similar to the previously described crystal structure, is shown to be retained within the supramolecular complex. Intermolecular rOe contacts obtained in chloroform together with chemical shift perturbation data provides structural insight into the organization of the self‐associated complex. Based upon this analysis, a model for the organization of pseudodesmin A monomers in the supramolecular assembly is proposed, which is in agreement with the formation of bilayer spanning hydrophilic pores and provides the basis for a structure–function relationship for this type of CLPs. Finally, it is demonstrated that the differences previously reported between the crystal and solution conformation of the white line inducing principle (WLIP), a close analogue of pseudodesmin A, are the result of the use of dimethyl sulfoxide as solvent, whose strong hydrogen‐bonding capacity induces conformational exchange.     

A visible light responsive azobenzene‐functionalized polymer: Synthesis,self‐assembly,and photoresponsive properties

A novel visible light responsive random copolymer consisting of hydrophobic azobenzene‐containing acrylate units and hydrophilic acrylic acid units has been prepared. The azobenzene molecule bearing methoxy groups at all four ortho positions is readily synthesized by one‐step conversion of diazotization. The as‐prepared polymer can self‐assemble into nanoparticles in water due to its amphiphilic nature. The tetra‐o‐methoxy‐substituted azobenzene‐functionalized polymer can exhibit the trans‐to‐cis photoswitching under the irradiation with green light of 520 nm and the cis‐to‐trans photoswitching under the irradiation with blue light of 420 nm in both solution and aggregate state. The morphologies of the self‐assembled nanoparticles are revealed by TEM and DLS. The controlled release of loaded molecules from the nanoparticles can be realized by adjusting pH value since the copolymer possesses pH responsive acrylic acid groups. The fluorescence of loaded Nile Red in the nanoparticles can be tuned upon the visible light irradiation. The reversible photoswitching of the azobenzene‐functionalized polymer under visible light may endow the polymer with wide applications without using ultraviolet light at all. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2768–2775     

An Adjustable pH‐Responsive Drug Delivery System Based on Self‐Assembly Polypeptide‐Modified Mesoporous Silica

In this study, an adjustable pH‐responsive drug delivery system using mesoporous silica nanoparticles (MSNs) as the host materials and the modified polypeptides as the nanovalves is reported. Since the polypeptide can self‐assemble via electrostatic interaction at pH 7.4 and be disassembled by pH changes, the modified poly(l ‐lysine) and poly(l ‐glutamate) are utilized for pore blocking and opening in the study. Poly(l ‐lysine)‐MSN (PLL‐MSN) and poly(l ‐glutamate)‐MSN (PLG‐MSN) are synthesized via the ring opening polymerization of N‐carboxyanhydrides onto the surface of mesoporous silica nanoparticles. The successful modification of the polypeptide on MSN is proved by Zeta potential change, X‐ray photoelectron spectroscopy (XPS), solid state NMR, and MALDI‐TOF MS. In vitro simulated dye release studies show that PLL‐MSN and PLG‐MSN can successfully load the dye molecules. The release study shows that the controlled release can be constructed at different pH by adjusting the ratio of PLL‐MSN to PLG‐MSN. Cellular uptake study indicates that the drug is detected in both cytoplasm and nucleus, especially in the nucleus. In vitro cytotoxicity assay indicates that DOX loaded mixture nanoparticles (ratio of PLL‐MSN to PLG‐MSN is 1:1) can be triggered for drug release in HeLa cells, resulting in 88% of cell killing.     

Enzyme‐Instructed Intracellular Molecular Self‐Assembly to Boost Activity of Cisplatin against Drug‐Resistant Ovarian Cancer Cells

Anticancer drug resistance demands innovative approaches that boost the activity of drugs against drug‐resistant cancers without increasing the systemic toxicity. Here we show the use of enzyme‐instructed self‐assembly (EISA) to generate intracellular supramolecular assemblies that drastically boost the activity of cisplatin against drug‐resistant ovarian cancer cells. We design and synthesize small peptide precursors as the substrates of carboxylesterase (CES). CES cleaves the ester bond pre‐installed on the precursors to form the peptides that self‐assemble in water to form nanofibers. At the optimal concentrations, the precursors themselves are innocuous to cells, but they double or triple the activity of cisplatin against the drug‐resistant ovarian cancer cells. This work illustrates a simple, yet fundamental, new way to introduce non‐cytotoxic components into combination therapies with cisplatin without increasing the systemic burden or side effects.     

Photo‐responsive amphiphilic poly(α‐hydroxy acids) with pendent o‐nitrobenzyl ester constructed via copper‐catalyzed azide‐alkyne cycloaddition reaction

Photo‐responsive block copolymer mPEG‐b‐poly(Tyr)‐g‐NB was prepared by introduction of o‐nitrobenzyl ester group into the side chain of amphiphilic poly(ethylene glycol)‐b‐poly(α‐hydroxy acids) (mPEG‐b‐poly(Tyr)) containing pendent alkynyl group via copper‐catalyzed azide‐alkyne cycloaddition reaction. The amphiphilic mPEG‐b‐poly(Tyr) was synthesized via the ring‐opening polymerization of O‐carboxyanhydrides, with monomethoxy poly(ethylene glycol) (mPEG) as macroinitiator. The molecular structure, self‐assembly, and photo‐controlled release of the obtained mPEG‐b‐poly(Tyr)‐g‐NB were thoroughly investigated. mPEG‐b‐poly(Tyr)‐g‐NB could self‐assemble into spherical micelles in water and showed disassembly under UV light irradiation, which was demonstrated by means of UV‐vis spectroscopy, scan electron microscopes, and dynamic light scattering measurement. Fluorescence emission measurements demonstrated that Nile red, encapsulated by micelles, can be released upon UV irradiation. This study provides a convenient way to construct smart poly(α‐hydroxy acids)‐based nanocarriers for controlled release of hydrophobic drugs. Copyright © 2015 John Wiley & Sons, Ltd.     

Tuning nanoscopic self‐assembly of diblock copolymer blends on a two‐dimensional interface

Spreading amphiphilic diblock copolymers on a two‐dimensional liquid interface has been observed to produce nanoscale features via self‐assembly. Here, we develop a model that incorporates the effects of polymer entanglement and surface diffusion in polymer blends to quantitatively predict the size of experimentally observed structures. Simulations show that different polymers in the blend cooperate to self‐assemble into nanoscale features of varying sizes. Characteristic nanoscopic dimensions can be tuned by adjusting two easily controllable macroscopic quantities: the blend composition and the initial surface concentration. Theoretical predictions are in agreement with experimentally measured feature dimensions. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2011