Vitamin E (α-tocopherol; TPGS) micelle is a robust nanocarrier in delivering hydrophobic active pharmaceutical ingredients, but it is suffering from poor stability that is essential in terms of pharmaceutical and biomedical applications. Taking advantage of the chirality of vitamin E, this work reports the stereoselective stabilization of polymer-vitamin E conjugate micelles. Vitamin E was covalently linked to multivalent methoxy poly(ethylene glycol)-co-poly(glutamic acid), generating amphiphilic conjugates that could self-assemble into micelles. Eight types of micelles were produced via tailored combination of polymer backbone and side chain with different chirality. The particle size and critical micelle concentration analysis demonstrated a correlation between conjugate chirality and micelle stability. The most stable micelles were obtained when poly(glutamic acid) and vitamin E both are dextrorotatory, because of the high degree of α-helix revealed by both circular dichroism spectroscopy and molecular dynamics simulation. This phenomenon was further verified by the fluorescence resonance energy transfer (FRET) analysis in HepG2 cells. The current work not only provides a method to enhance the stability of vitamin E micelles, but also adds an additional facile tool in regulating the stability of polymer conjugate micelles without changing the conjugate composition.

It is often challenging to precisely manipulate the release behavior of hydrophilic drugs that is believed to be crucial for a satisfactory therapeutic outcome. The aim of this work was to regulate the dissolution of hydrophilic drug from hot-melt extruded solid dispersion via rational screening of the pore-forming agents. Venlafaxine hydrochloride and Compritol® 888 ATO was selected as the model drug and carrier excipient, respectively. Hydrophilic polyethylene glycol (PEG 6000) and polyvinylpyrolidone (PVP K30) were chosen as the transient pore-forming agents. The X-ray diffraction and thermal analysis showed that both drug and carrier existed in the crystalline form. Both types of polymers could generate pores upon dissolution test and the drug release rate was proportionally correlated to the pore-forming agent content. The mathematical modelling showed that the Ritger-Peppas model gave the best fit to the release curves, which demonstrates a diffusion-dominant release mechanism. The scanning electron microscopy and mercury intrusion porosimetry analysis proved that PVP K30 could generate large pores with low porosity, but PEG 6000 produced smaller pores with relatively high porosity. The in vivo pharmacokinetics study in rat revealed that solid dispersions containing either PEG 6000 or PVP K30 (both at 2.5%, w/w) exhibited an elevated bioavailability compared to the commercial product, Effexor® XR. The current work implied that rational screening of transient pore-forming polymer in solid dispersion could be a robust approach for controlling hydrophilic drug release.Download high-res image (110KB)Download full-size image

Photodynamic therapy (PDT) efficacy is limited by the very short half-life and limited diffusion radius of singlet oxygen (1O2). We report a 1O2-responsive micellar nanoplatform subject to considerable size-expansion upon light triggering to facilitate on-demand release of photosensitizers. Imidazole, a well-known 1O2 scavenger, was incorporated in the hydrophobic core of amphiphilic copolymer micelles, and was used to coordinate with biocompatible Zn2 + and encapsulate the photosensitizer chlorin e6 (Ce6). The micelles are highly sensitive to light irradiation: 1O2 triggering induced dramatic particle size expansion due to the conversion of imidazole to hydrophilic urea, resulting in instantaneous release of Ce6 and rapid intracellular distribution. This 1O2-responsive, size-expandable nanosystem delivered substantially more Ce6 to tumor sites as compared to free Ce6, and exhibited improved anti-tumor efficacy in vivo in 4T1 tumor-bearing mice. This work opens new avenues of particle expansion-induced PDT enhancement by controlled imidazole chemistry.Download high-res image (159KB)Download full-size image

Both reactive oxygen species (ROS) and mitochondria are involved in many physiological and pathological processes. Herein, we employed curved corannulene with a large dipole moment for controlled ROS production and mitochondria targeting. Corannulene was solubilized in water via complexation with gamma-cyclodextrin (1 : 2). The complex could produce type I ROS in water in a dose- and irradiation time-dependent manner. The curvature-induced dipole moment aids electron transfer and hence enables ROS generation. As a consequence of electron delocalization, which facilitates mitochondrial uptake due to the large negative membrane potential of mitochondria, mitochondrial accumulation of corannulene was demonstrated. However, this is not valid for the flat perylene control. This discovery not only presents a new tool for controlled ROS production as well as mitochondria targeting in basic biomedical research, but also opens an avenue for the potential application of curved carbon materials as therapeutic agents.

The topology of hydrophobic moieties can affect the stability of self-assembled micelles. Curved corannulene and flat perylene were selected as model hydrophobic molecules with poly(ethylene glycol) as the hydrophilic segment. The curvature can enhance the intermolecular π–π interaction, and hence the driving force of micelle formation.

Curved corannulene (Cor) can produce reactive oxygen species (ROS) in a controlled manner due to the large dipole moment. However, the poor aqueous solubility of Cor necessitates the employment of solubilization vehicles. This work revealed that PEGylation was less efficient than the cyclodextrin complexation regarding ROS production.

Catechol-Fe3+ coordinated micelles show the potential for achieving on-demand drug delivery and magnetic resonance imaging in a single nanoplatform. Herein, we developed bioinspired coordination-cross-linked amphiphilic polymeric micelles loaded with a model anticancer agent, doxorubicin (Dox). The nanoscale micelles could tolerate substantial dilution to a condition below the critical micelle concentration (9.4 ± 0.3 μg/mL) without sacrificing the nanocarrier integrity due to the catechol-Fe3+ coordinated core cross-linking. Under acidic conditions (pH 5.0), the release rate of Dox was significantly faster compared to that at pH 7.4 as a consequence of coordination collapse and particle de-cross-linking. The cell viability study in 4T1 cells showed no toxicity regarding placebo cross-linked micelles. The micelles with improved stability showed a dramatically increased Dox accumulation in tumors and hence the enhanced suppression of tumor growth in a 4T1 tumor-bearing mouse model. The presence of Fe3+ endowed the micelles T1-weighted MRI capability both in vitro and in vivo without the incorporation of traditional toxic paramagnetic contrast agents. The current work presented a simple “three birds with one stone” approach to engineer the robust theranostic nanomedicine platform.Keywords: drug delivery; magnetic resonance imaging; micelle; stability; stimuli-responsive;

Co-delivery of multiple anti-cancer drugs in a single nanoplatform has shown great promise in enhancing therapeutic efficacy and reducing adverse effects. However, the ratiometric dose control is pivotal, but often challenging in combinational nanomedicine. Here, we report the employment of cyclodextrin-bearing amphiphilic polymer conjugate micelles for ratiometric, non-covalent loading of three hydrophobic model drugs, curcumin (CUR), camptothecin (CPT), and doxorubicin (DOX) in one single nanocarrier. Each drug was physically encapsulated in the cyclodextrin-bearing polymer conjugate via guest-host complexation. All three drugs displayed a 1:1 complexation behavior with the cyclodextrin, which corresponded to a drug loading of 6.0 ± 0.1% (CUR), 7.5 ± 0.1% (CPT), and 9.0 ± 0.1% (DOX) (w/w). The apparent association constant between the conjugate and drug was 2803.7 ± 87.0 (CUR), 3699.4 ± 123.3 (CPT), and 6760.9 ± 176.3 (DOX), respectively. Ratiometric co-assembly of three types of drug-loaded conjugates produced mixed micelles in a dose- and ratio-controlled manner. The hydrodynamic diameter of co-assembled spherical micelles was ca. 150 nm that was similar to the single-drug loaded micelles. The ratiometric co-delivery of three drugs via mixed micelles was demonstrated both in HepG2 cells in vitro and in a mice model in vivo compared to a mixture of free drugs, as evidenced by co-localization analysis. This work provides a facile way to realize ratiometric co-administration of multiple drugs.Download high-res image (114KB)Download full-size image

A polymeric micelle is a versatile nanoscale platform for sustained release of short-lived nitric oxide (NO). The aim of this work was to better understand the correlation between polymer architecture and NO release kinetics. Stable nitrate was selected as the NO donor and co-conjugated to a multivalent polymer backbone together with amphiphilic methoxy poly(ethylene glycol) and poly(lactic acid) (mPEG–PLA), or D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). Both graft polymers could self-assemble into micellar nanocarriers with a size less than 100 nm. The weight-based NO loading was 4.92% (w/w) and 6.05% (w/w) for mPEG–PLA- and TPGS-modified micelles, respectively. The former is less stable than the latter with a corresponding critical micelle concentration of 23.9 ± 2.0 nM and 9.8 ± 0.5 nM. Using the standard Griess assay, it was shown that both micelles could achieve sustained NO release in vitro. However, the TPGS-modified nanocarrier exhibited a delayed onset, but faster steady-state release of NO in comparison to its counterpart. This was primarily due to folded PEG conformation and its high packing surface density. These results illustrate the potential utility of polymer architecture engineering to precisely tune the NO release behavior for ultimately optimum therapeutic outcome.

We report that the polymer residue of hydrazone-containing pH-responsive polymeric conjugate micelles could induce considerable cytotoxicity in a model cell line (HeLa). However, there was no significant difference between the cytotoxicity of the residue of the model drug (curcumin) and its parent form post hydrolysis. The results demonstrated that both the polymer residue and active drug could be beneficial for cancer treatment, whereas such a synergistic role of an amine-containing polymer residue was often neglected.

Multifunctional thermosensitive dendrimeric nanocarriers were generated via tailored surface modification. Such design not only facilitated the rapid endosomal escape of dendrimers, but also achieved tunable surface hydrophobicity, which could be employed to achieve on-demand cargo release. These smart dendrimers are promising for enhancing intracellular drug delivery.

A novel type of superparamagnetic iron oxide nanoparticles (SPIONs) with dual coatings was reported to address the problem of poor loading capability of traditional SPIONs. It was found that the loading of a model drug, paclitaxel, in such SPIONs increased up to ca. 190 times.

The acne skin is characteristic of a relatively lower pH microenvironment compared to the healthy skin. The aim of this work was to utilize such pH discrepancy as a site-specific trigger for on-demand topical adapalene delivery.The anti-acne agent, adapalene, was encapsulated in acid-responsive polymer (Eudragit® EPO) nanocarriers via nanoprecipitation. The nanocarriers were characterized in terms of particle size, surface morphology, drug-carrier interaction, drug release and permeation.Adapalene experienced a rapid release at pH 4.0 in contrast to that at pH 5.0 and 6.0. The permeation study using silicone membrane revealed a significant higher drug flux from the nanocarrier (6.5 ± 0.6 μg.cm−2.h−1) in comparison to that (3.9 ± 0.4 μg.cm−2.h−1) in the control vehicle (Transcutol®). The in vitro pig skin tape stripping study showed that at 24 h post dose-application the nanocarrier delivered the same amount of drug to the stratum corneum as the positive control vehicle did.The acid-responsive nanocarriers hold promise for efficient adapalene delivery and thus improved acne therapy.

Nanoparticle drug delivery to tumors via the enhanced permeability and retention (EPR) effect is usually limited by the step of blood circulation and extravasation. Only less than 10% of the administered dose would eventually reach the tumor tissue. To enhance the drug delivery efficiency, we report the approach of magnetic plus molecular dual targeting nanoparticles to combine tumor targeting, drug delivery, and in situ imaging together. The surface of superparamagnetic iron oxide nanoparticles (SPIONs) was coated with biocompatible poly(ethylene glycol)–poly(lactic acid) and then anchored with folic acid (FA). Despite the presence of FA, the hydrodynamic size of SPIONs was less than 100 nm. Increasing the surface FA density sacrificed the aqueous stability of SPIONs, but 20% FA did not induce noticeable particle aggregation. The existence of 20% FA maintained the superparamagnetic property of SPIONs with a saturation magnetization level at ca. 30 emu g−1. The drug release profile was not significantly different between SPIONs with (20%) and without FA. However, the presence of FA dramatically increased the intracellular uptake of SPIONs when using the MCF-7 breast cancer cell line. These results highlighted the role of surface ligand optimization in the design of desired magnetic-molecular dual tumor-targeting nanoparticles.

Nanoparticles have been increasingly used as carriers for local and systemic drug delivery via the skin. Dendrimers are emerging as the new generation of nanocarriers in skin drug delivery mainly due to their small size, extreme molecular uniformity, and highly functional surfaces. Despite the abundance of investigations which demonstrate the dendrimer-mediated skin delivery enhancement both in vitro and in vivo, there are still controversies over the mechanisms of their action. Based on the critical analysis of currently available data in this field, it is found that the skin delivery enhancement by dendrimers depends on the drug–dendrimer–skin interactions and three potential mechanisms are proposed. Firstly, for some drugs, dendrimers may act as a drug release modifier and speed up the drug dissolution that is the rate-limiting step of percutaneous drug absorption. Secondly, via particle engineering the properties of dendrimers can be tailored to preferably penetrate the skin via the follicular route. Finally, certain low generation dendrimers may impair the stratum corneum barrier function, particularly in the presence of potent vehicles.

Both reactive oxygen species (ROS) and mitochondria are involved in many physiological and pathological processes. Herein, we employed curved corannulene with a large dipole moment for controlled ROS production and mitochondria targeting. Corannulene was solubilized in water via complexation with gamma-cyclodextrin (1:2). The complex could produce type I ROS in water in a dose- and irradiation time-dependent manner. The curvature-induced dipole moment aids electron transfer and hence enables ROS generation. As a consequence of electron delocalization, which facilitates mitochondrial uptake due to the large negative membrane potential of mitochondria, mitochondrial accumulation of corannulene was demonstrated. However, this is not valid for the flat perylene control. This discovery not only presents a new tool for controlled ROS production as well as mitochondria targeting in basic biomedical research, but also opens an avenue for the potential application of curved carbon materials as therapeutic agents.

The topology of hydrophobic moieties can affect the stability of self-assembled micelles. Curved corannulene and flat perylene were selected as model hydrophobic molecules with poly(ethylene glycol) as the hydrophilic segment. The curvature can enhance the intermolecular π–π interaction, and hence the driving force of micelle formation.

Nanoparticle drug delivery to tumors via the enhanced permeability and retention (EPR) effect is usually limited by the step of blood circulation and extravasation. Only less than 10% of the administered dose would eventually reach the tumor tissue. To enhance the drug delivery efficiency, we report the approach of magnetic plus molecular dual targeting nanoparticles to combine tumor targeting, drug delivery, and in situ imaging together. The surface of superparamagnetic iron oxide nanoparticles (SPIONs) was coated with biocompatible poly(ethylene glycol)–poly(lactic acid) and then anchored with folic acid (FA). Despite the presence of FA, the hydrodynamic size of SPIONs was less than 100 nm. Increasing the surface FA density sacrificed the aqueous stability of SPIONs, but 20% FA did not induce noticeable particle aggregation. The existence of 20% FA maintained the superparamagnetic property of SPIONs with a saturation magnetization level at ca. 30 emu g−1. The drug release profile was not significantly different between SPIONs with (20%) and without FA. However, the presence of FA dramatically increased the intracellular uptake of SPIONs when using the MCF-7 breast cancer cell line. These results highlighted the role of surface ligand optimization in the design of desired magnetic-molecular dual tumor-targeting nanoparticles.

Multifunctional thermosensitive dendrimeric nanocarriers were generated via tailored surface modification. Such design not only facilitated the rapid endosomal escape of dendrimers, but also achieved tunable surface hydrophobicity, which could be employed to achieve on-demand cargo release. These smart dendrimers are promising for enhancing intracellular drug delivery.

Curved corannulene (Cor) can produce reactive oxygen species (ROS) in a controlled manner due to the large dipole moment. However, the poor aqueous solubility of Cor necessitates the employment of solubilization vehicles. This work revealed that PEGylation was less efficient than the cyclodextrin complexation regarding ROS production.