Multidentate Polymer Coatings for Compact and Homogeneous Quantum Dots with Efficient Bioconjugation.

Quantum dots are fluorescent nanoparticles used to detect and image proteins and nucleic acids. Compared with organic dyes and fluorescent proteins, these nanocrystals have enhanced brightness, photostability, and wavelength tunability, but their larger size limits their use. Recently, multidentate polymer coatings have yielded stable quantum dots with small hydrodynamic dimensions (≤10 nm) due to high-affinity, compact wrapping around the nanocrystal. However, this coating technology has not been widely adopted because the resulting particles are frequently heterogeneous and clustered, and conjugation to biological molecules is difficult to control. In this article we develop new polymeric ligands and optimize coating and bioconjugation methodologies for core/shell CdSe/Cd(x)Zn(1-x)S quantum dots to generate homogeneous and compact products. We demonstrate that "ligand stripping" to rapidly displace nonpolar ligands with hydroxide ions allows homogeneous assembly with multidentate polymers at high temperature. The resulting aqueous nanocrystals are 7-12 nm in hydrodynamic diameter, have quantum yields similar to those in organic solvents, and strongly resist nonspecific interactions due to short oligoethylene glycol surfaces. Compared with a host of other methods, this technique is superior for eliminating small aggregates identified through chromatographic and single-molecule analysis. We also demonstrate high-efficiency bioconjugation through azide-alkyne click chemistry and self-assembly with hexa-histidine-tagged proteins that eliminate the need for product purification. The conjugates retain specificity of the attached biomolecules and are exceptional probes for immunofluorescence and single-molecule dynamic imaging. These results are expected to enable broad utilization of compact, biofunctional quantum dots for studying crowded macromolecular environments such as the neuronal synapse and cellular cytoplasm.

Smart chemistry in polymeric nanomedicine.

This review provides an overview of smart chemistry developed and utilized in the last 5-10 years in polymer-based drug delivery nanomedicine. Smart chemistry not only facilitates the controlled drug loading in a highly specific manner, but also potentially controls the drug release kinetics at the targeted tissues. This review highlights the emergence of new chemistry or unique utilization of conventional chemistry in drug delivery, which is believed to play an important role in developing next generation nanomedicine.

Redox-responsive, core-cross-linked micelles capable of on-demand, concurrent drug release and structure disassembly.

We developed camptothecin (CPT)-conjugated, core-cross-linked (CCL) micelles that are subject to redox-responsive cleavage of the built-in disulfide bonds, resulting in disruption of the micellar structure and rapid release of CPT. CCL micelles were prepared via coprecipitation of disulfide-containing CPT-poly(tyrosine(alkynyl)-OCA) conjugate and monomethoxy poly(ethylene glycol)-b-poly(tyrosine(alkynyl)-OCA), followed by cross-linking of the micellar core via azide-alkyne click chemistry. CCL micelles exhibited excellent stability under physiological conditions, while they underwent rapid dissociation in reduction circumstance, resulting in burst release of CPT. These redox-responsive CCL micelles showed enhanced cytotoxicity against human breast cancer cells in vitro.

Alendronate-conjugated amphiphilic hyperbranched polymer based on Boltorn H40 and poly(ethylene glycol) for bone-targeted drug delivery.

A novel type of alendronate(ALE)-conjugated amphiphilic hyperbranched copolymer based on a hydrophobic hyperbranched Boltorn H40 (H40) core with ALE targeting moiety and many hydrophilic poly(ethylene glycol) (PEG) arms was synthesized as a carrier for bone-targeted drug delivery. The star copolymer H40-star-PEG/ALE was characterized using nuclear magnetic resonance (NMR), Fourier transformed infrared spectroscopy (FTIR), and gel permeation chromatography (GPC) analysis. Benefiting from its highly branched structure, H40-star-PEG/ALE could form micelles in aqueous solution, which was confirmed by transmission electron microscopy (TEM) and dynamic light scattering (DLS) techniques. The cytotoxicity and hemolysis of the H40-star-PEG/ALE micelles were evaluated via methylthiazoletetrazolium (MTT) assay against NIH/3T3 normal cells and red blood cell (RBC) lysis assay, respectively. As a model anticancer drug, doxorubicin (DOX) was encapsulated into the H40-star-PEG/ALE micelles. The anticancer activity of DOX-loaded micelles was evaluated by MTT assay against an HN-6 human head and neck carcinoma cell line. The strong affinity of H40-star-PEG/ALE micelles to bone was confirmed by the hydroxyapatite (HA) binding assay. These results indicate that the H40-star-PEG/ALE micelles are highly promising bone-targeted drug carriers for skeletal metastases.

A self-amplified ROS-responsive chemodrug-inhibitor conjugate for multi-drug resistance tumor therapy.

P-glycoprotein (P-gp) induced multidrug resistance (MDR) is the main reason for the failure of cancer chemotherapy. The combined delivery of chemodrug and P-gp inhibitor is a promising pathway to reverse MDR. However, the intrinsic stimuli in the tumor microenvironment could not realize a complete drug release, which would induce poor cancer therapeutic efficacy. Herein, we conjugated tamoxifen (TAM) with D-α-tocopherol polyethylene glycol1000 succinate (TPGS) based on a reactive oxygen species (ROS)-responsive aryl boronic ester bond to construct a self-amplified ROS-responsive chemodrug-inhibitor (TPGS-TAM) co-delivery system. Due to its amphiphilic property, the TPGS-TAM conjugates could self-assemble into uniform spherical nanoparticles (NPs). After effective endocytosis by cancer cells, the intracellular ROS cleaved the aryl boronic ester bond and initiated the release of TAM and α-tocopherol succinate (α-TOS) from the NPs. Subsequently, the released α-TOS further generated ROS to facilitate the release of TAM. Moreover, α-TOS also consumed adenosine triphosphate (ATP) to impair ATP-dependent P-gp mediated drug efflux to reverse the tumor's drug resistance. As a result, the TPGS-TAM NPs enhanced the antitumor effect with a tumor inhibition rate (TIR) high up to 74.6 ± 6.1% in an MCF-7/ADR tumor model. Based on systematic in vitro and in vivo assessments, this self-amplified ROS-responsive carrier-free conjugate of chemodrug/P-gp inhibitor may shed light on the potential application for the MDR cancer therapy.

Correction: A mesoporous polydopamine nanoparticle enables highly efficient manganese encapsulation for enhanced MRI-guided photothermal therapy.

Correction for 'A mesoporous polydopamine nanoparticle enables highly efficient manganese encapsulation for enhanced MRI-guided photothermal therapy' by Yan Wu et al., Nanoscale, 2021, 13, 6439-6446, DOI: D1NR00957E.

Supramolecular copolymer micelles based on the complementary multiple hydrogen bonds of nucleobases for drug delivery.

Novel supramolecular copolymer micelles with stimuli-responsive abilities were successfully prepared through the complementary multiple hydrogen bonds of nucleobases and then applied for rapid intracellular release of drugs. First, both adenine-terminated poly(ε-caprolactone) (PCL-A) and uracil-terminated poly(ethylene glycol) (PEG-U) were synthesized. The supramolecular amphiphilic block copolymers (PCL-A:U-PEG) were formed based on multiple hydrogen bonding interactions between PCL-A and PEG-U. The micelles self-assembled from PCL-A:U-PEG were sufficiently stable in water but prone to fast aggregation in acidic condition due to the dynamic and sensitive nature of noncovalent interactions. The low cytotoxicity of supramolecular copolymer micelles was confirmed by MTT assay against NIH/3T3 normal cells. As a hydrophobic anticancer model drug, doxorubicin (DOX) was encapsulated into these supramolecular copolymer micelles. In vitro release studies demonstrated that the release of DOX from micelles was significantly faster at mildly acid pH of 5.0 compared to physiological pH. MTT assay against HeLa cancer cells showed DOX-loaded micelles had high anticancer efficacy. Hence, these supramolecular copolymer micelles based on the complementary multiple hydrogen bonds of nucleobases are very promising candidates for rapid controlled release of drugs.

A Smart Core-Crosslinked Supramolecular Drug Delivery System (SDDS) Enabled by Pendant Cyclodextrins Encapsulation of Drug Dimers via Host-Guest Interaction.

Owing to poor aqueous solubility and low delivery efficiency, most of anti-cancer chemodrugs depend on various smart drug delivery platforms to enhance the treatment efficacy. Herein, a stimuli-responsive supramolecular drug delivery system (SDDS) is developed based on polymeric cyclodextrins (PCD) which crosslinked by stimuli-cleavable drug dimers via host-guest interaction. PEGylated PCD was precisely controlled synthesized by ring-opening polymerization and azide-alkyne click chemistry, and two doxorubicins (DOX) were linked with a disulfide bond to form a drug dimer (ss-DOX). They then co-assembled into supramolecular micelles. Drug dimers were utilized as cross-linkers to stabilize the micelles. The drug loading efficiency was very high that could be up to 98%. The size and morphology were measured by DLS and TEM. Owing to the disulfide bonds of drug dimers, these supramolecular micelles were dissociated by treating with dithiothreitol (DTT). In the meanwhile, the free DOXs were recovered and released from cavities of cyclodextrins because of dynamic equilibrium and hydrophilicity changes. The release profile was studied under mimic physiological conditions. Furthermore, in vitro cytotoxicity study showed excellent anti-cancer efficacy of reduced-responsive supramolecular polymeric micelles. Therefore, it can be served as a safe and stimuli-responsive SDDS for cancer therapy.

A mesoporous polydopamine nanoparticle enables highly efficient manganese encapsulation for enhanced MRI-guided photothermal therapy.

Theranostic agents based on magnetic resonance imaging (MRI) and photothermal therapy (PTT) play an important role in tumor therapy. However, the available theranostic agents are facing great challenges such as biocompatibility, MRI contrast effect and photothermal conversion efficiency (η). In this work, mesoporous polydopamine nanoparticles (MPDAPs/Mn) were prepared on MRI and PTT combined theranostic nanoplatforms, of which the high loading manganese ions and specific surface areas enable good MRI contrast and excellent photothermal conversion efficiency, respectively. The MPDAPs/Mn have uniform morphology, good stability and biocompatibility. Meanwhile, in vitro and in vivo studies have confirmed their superior T1-weighted MRI effect and photothermal conversion efficiency. Furthermore, MPDAPs/Mn have excellent antitumor efficacy in HeLa tumor-bearing mice. Therefore, this developed MPDAPs/Mn theranostic nanoplatform could be a promising candidate for MRI-guided photothermal cancer therapy.

Control of the optical properties of a star copolymer with a hyperbranched conjugated polymer core and poly(ethylene glycol) arms by self-assembly.

A self-assembly approach to tuning the optical properties of a star copolymer is reported herein. The star copolymer HCP-star-PEG with a hyperbranched conjugated polymer (HCP) core and many linear poly(ethylene glycol) (PEG) arms has been prepared successfully. The HCP core was synthesized by Wittig coupling of N-(n-hexyl)-3,6-diformylcarbazole and 1,3,5-bis[(triphenylphosphonio)methyl]benzene tribromide. Subsequently, the linear PEG arms were grafted onto the HCP core by acylhydrazone connection. It was found that the optical properties of HCP-star-PEG in chloroform solution changed on addition of acid. Both (1)H NMR and UV/Vis spectroscopic investigations confirmed that the variation of the optical properties was related to the complexation of the acid and the imine bond in the acylhydrazone group. HCP-star-PEG self-assembled into core-shell micelles in the mixed solvent of chloroform and acetonitrile, which affected the protonation of the imine bond. Therefore the optical properties of HCP-star-PEG can be readily controlled by self-assembly.

Construction and application of a pH-sensitive nanoreactor via a double-hydrophilic multiarm hyperbranched polymer.

A double-hydrophilic multiarm hyperbranched polymer with a hyperbranched poly(amidoamine) (HPAMAM) core and many poly(ethylene glycol) monomethyl ether (MPEG) arms connected by pH-sensitive acylhydrazone bonds (HPAMAM-g-MPEG) was successfully prepared. Benefiting from the cationic dendritic core and PEGylation shell, the double-hydrophilic multiarm hyperbranched polymer was used as a nanoreactor for CdS quantum dots (CdS QDs) synthesis in aqueous solution. The obtained HPAMAM-g-MPEG and CdS/HPAMAM-g-MPEG nanocomposites were carefully characterized by (1)H NMR, (13)C NMR, Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible absorption spectroscopy (UV-vis), fluorescence spectroscopy (FL), dynamic light scattering (DLS), transmission electron microscopy (TEM), selected area electron diffraction (SAED), and electronic dispersive X-ray spectroscopy (EDS) analysis. Both (1)H NMR and fluorescence spectroscopy investigations confirmed that the acylhydrazone linkage between the dendritic core and linear arms was readily broken under acidic condition (pH <5.5). When MPEG arms departed from the HPAMAM core, the fluorescence intensity of CdS/HPAMAM-g-MPEG nanocomposites greatly increased. Such pH-responsive behavior of CdS/HPAMAM-g-MPEG nanocomposites was utilized as an exploration of a novel fluorescence probe in an acidic lysosome exemplified by COS-7 cells.

Controlling the Optical Properties of Hyperbranched Conjugated Polyazomethines through Terminal-Backbone Interactions.

A simple approach to tune the optical properties of the hyperbranched conjugated polymers by only adjusting the terminal-backbone interactions has been reported in this article. Hyperbranched conjugated polyazomethines have been successfully prepared by the reaction of tetramine and dialdehyde. Not only varying the monomer feed ratio to change the quantity of terminal amino groups, but also adopting protonation or complexion with proper dopants (SnCl(2) and ß-cyclodextrin), can alter the interactions between amino terminals and imine bonds in the backbone. Correspondingly, the optical properties of the resulting hyperbranched polymers are controlled.

Compact Quantum Dots for Quantitative Cytology.

In this chapter, we describe the preparation of fluorescent quantum dots for imaging and measuring protein expression in cells. Quantum dots are nanocrystals that have numerous advantages for biomolecular detection compared with organic dyes and fluorescent proteins, but their large size has been a limiting factor. We describe the synthesis of nanoparticles smaller than 10 nm (smaller than an antibody), their attachment to monoclonal antibodies through click chemistry, characterization of the conjugates, and use for labeling of cellular antigens. We further discuss the unique advantages and challenges associated with this approach compared with conventional immunofluorescence techniques.

Tetramodal Imaging and Synergistic Cancer Radio-Chemotherapy Enabled by Multiple Component-Encapsulated Zeolitic Imidazolate Frameworks.

The abundant species of functional nanomaterials have attracted tremendous interests as components to construct multifunctional composites for cancer theranostics. However, their distinct chemical properties substantially require a specific strategy to integrate them in harmony. Here, we report the preparation of a distinctive multifunctional composite by encapsulating small-sized semiconducting copper bismuth sulfide (CBS) nanoparticles and rare-earth down-conversion (DC) nanoparticles in larger-sized zeolitic imidazolate framework-8 (ZIF8) nanoparticles, followed by loading an anticancer drug, doxorubicin (DOX). Such composites can be used for tetramodal imaging, including traditional computed tomography and magnetic resonance imaging and, recently, for photoacoustic imaging and fluorescence imaging. With a pH-responsive release of the encapsulated components, synergistic radio-chemotherapy with a high (87.6%) tumor inhibition efficiency is achieved at moderate doses of the CBS&DC-ZIF8@DOX composite with X-ray irradiation. This promising strategy highlights the extending capacity of zeolitic imidazolate frameworks to encapsulate multiple distinct components for enhanced cancer imaging and therapy.

Hybrid polymerization of vinyl and hetero-ring groups of glycidyl methacrylate resulting in thermoresponsive hyperbranched polymers displaying a wide range of lower critical solution temperatures.

Hybrid polymerization of glycidyl methacrylate (GMA) with potassium hydride (KH) and various oligo(ethylene glycol)s as the initiating system, in which both vinyl polymerization and ring-opening polymerization occur simultaneously, generates hyperbranched poly(ether-ester)s. The reaction process has been followed by an in situ nuclear magnetic resonance technique. The experimental results indicate that both the vinyl and epoxy groups of GMA undergo polymerization, with the reactivity of the latter being much higher than that of the former. Interestingly, the resulting hyperbranched polymers exhibit a sharp phase transition in water at the lower critical solution temperature (LCST). Significantly, the LCST values can be accurately controlled from 0 to 100 degrees C by changing the hydrophilic/hydrophobic balance of GMA and various oligo(ethylene glycol)s or by modification of the precursor polymer through acetylation. This novel stimuli-responsive hyperbranched polymer is a promising candidate for a new generation of commercially viable thermoresponsive polymers following on from the widely used poly(N-isopropylacrylamide) (PNIPAM).

Role of branching architecture on the glass transition of hyperbranched polyethers.

The influence of branching architecture on the glass transition of hyperbranched polyethers has been investigated. For amorphous samples, the glass transition temperature (T(g)) first increases with the degree of branching (DB), passes through a maximum, and then decreases sharply. An attempt is made to explain this by the competition between the junction density and the free volume of terminal units. For the crystalline samples, the crystallization of polymer chains makes the relationship of DB and T(g) more complicated. By the introduction of branching architecture, the crystallization ability of the branched polymer is weakened gradually. When the samples are isothermally crystallized for a long time, the T(g) of polyethers decreases monotonically with DB.

Facile controlled preparation of gold nanoparticles with amphiphilic thiacalix[4]arene as reductant and stabilizer.

A facile controlled synthesis method of gold nanoparticles (AuNPs) under mild conditions has been developed by combining the stabilization ability of amphiphilic thiacalixarene and the reduction ability of phenolic moieties together, and the particle sizes of AuNPs can be readily controlled by only adjusting the feeding ratio of Au/S.

Site-dependent fluorescence enhanced polymers with a self-restricted GFP chromophore for living cell imaging.

The ß-barrel structure of green fluorescent protein (GFP) provides a confined environment to enhance its fluorescence efficiency. Inspired by the unique structure of GFP, we reported a self-restricted GFP chromophore analogue which was rationally grafted onto the middle or the terminal of poly(ethylene glycol)-block-poly(N-isopropyl acrylamide) (PEG-b-PNIPAM) via click chemistry to obtain PEG-GA-PNIPAM and PEG-PNIPAM-GA (GA: MeOBDPI). These structures were characterized through NMR, GPC, and FT-IR. By varying the length of PNIPAM and the location of the GFP chromophore, self-assembly behaviour and fluorescence intensity were correspondingly changed. PEG-GA-PNIPAM and PEG-PNIPAM-GA were assembled into nano-sized spherical micelles above the low critical solution temperature (LCST). The size of the micelles increased with the length of the PNIPAM block. These optical properties were carefully evaluated by UV-Vis and fluorescence spectroscopy. The results indicated that increasing the length of the PNIPAM block enhanced the fluorescence in water, and PEG-PNIPAM74-GA has more remarkable fluorescence intensity than PEG-GA-PNIPAM106 in living cells such as MCF-7 cells. Furthermore, the fluorescence behaviour of PEG-PNIPAM74-GA was studied in MCF-7 cells and L929 cells. The result showed that PEG-PNIPAM74-GA was mostly located in the cytoplasm. Compared with the CellTracker™ Red CMTPX dye, it could enter into MCF-7 cells and L929 cells more easily in DMEM with 10% FBS. Therefore, PEG-PNIPAM74-GA has potential application prospects for living cell imaging.

Construction of polyrotaxanes via reversible chain exchange between acylhydrazone bonds.

By simply heating mixtures of alpha-cyclodextrins and dumbbell-like poly(ethylene glycol) derivatives at 120 degrees C, polyrotaxanes form spontaneously via reversible chain exchange between acylhydrazone bonds, which have been proven by analyses of diffusion-ordered NMR, WAXD, 1H NMR, solid-state 13C CP/MAS NMR, DSC and UV-Vis together.

Supramolecularly engineered phospholipids constructed by nucleobase molecular recognition: upgraded generation of phospholipids for drug delivery.

Despite of great advances of phospholipids and liposomes in clinical therapy, very limited success has been achieved in the preparation of smart phospholipids and controlled-release liposomes for in vivo drug delivery and clinical trials. Here we report a supramolecular approach to synthesize novel supramolecularly engineered phospholipids based on complementary hydrogen bonding of nucleosides, which greatly reduces the need of tedious chemical synthesis, including reducing the strict requirements for multistep chemical reactions, and the purification of the intermediates and the amount of waste generated relative more traditional approaches. These upgraded phospholipids self-assemble into liposome-like bilayer structures in aqueous solution, exhibiting fast stimuli-responsive ability due to the hydrogen bonding connection. In vitro and in vivo evaluations show the resulted supramolecular liposomes from nucleoside phospholipids could effectively transport drug into tumor tissue, rapidly enter tumor cells, and controllably release their payload in response to an intracellular acidic environment, thus resulting in a much higher antitumor activity than conventional liposomes. The present supramolecularly engineered phospholipids represent an important evolution in comparison to conventional covalent-bonded phospholipid systems.