Jixi Zhang

Modulation of the structural properties of mesoporous silica nanoparticles to enhance the T1-weighted MR imaging capability

In this study, we have investigated the contrast enhancement of Gd(iii) incorporated nanoparticle-based contrast agents (CA) by the modulation of the synthesis and structural parameters of the mesoporous silica nanoparticle (MSN) matrix. In the optimisation process, the structure of the MSN matrix, post-synthesis treatment protocols, as well as the source and incorporation routes of paramagnetic gadolinium centers were considered, with the aim to shorten the T1 weighted relaxation time. After preliminary evaluation of the prepared MSNs as nanoparticulate T1/positive contrast agents based on relaxivity, the structure of the MSN matrix was affirmed as the most decisive property to enhance the r1 relaxivity value, alongside the incorporation route of paramagnetic Gd(iii) centers. Based on these findings, the most promising Gd(iii) incorporated MSN-based CA candidate was further evaluated for its cytocompatibility and intensity enhancement by in vitro phantom MR-imaging of labeled cells. Furthermore, pre-labeled tumors grown on a chick embryo chorioallantoic membrane (CAM) were imaged as an in vivo model on a 3T clinical MRI scanner. Our findings show that the optimized MSN-based CA design enables proper access of water to Gd-centers in the selected MSN matrices, and simultaneously decreases the required amount of Gd(iii) content per mass when evaluated against the other MSNs. Consequently, the required Gd amount on a per-dose basis is significantly decreased with regard to clinically used Gd-based CAs for T1-weighted MR imaging.

NIR light-activated dual-modality cancer therapy mediated by photochemical internalization of porous nanocarriers with tethered lipid bilayers

To overcome endo/lysosomal restriction as well as to increase the clinical availability of nanomedicine, we report on a NIR stimuli-responsive nanoplatform based on mesoporous silica nanoparticles tethered with lipid bilayers (MSN@tLB) for chemotherapy and photodynamic dual-modality therapy. In this nanosystem, a hydrophilic drug molecule zoledronic acid (ZOL) was first incorporated into the MSN core with modifications of hyperbranched polyethylenimine (PEI). To prevent the leakage of the payload, the LB shell was covalently tethered onto the MSN core via the PEI cushion which can greatly enhance the stability of the LB. Meanwhile, a hydrophobic photosensitizer IR-780 iodide was introduced into the hydrophobic compartment to endow the system with photo-activation properties. The as-prepared MSN-ZOL@tLB-IR780 possesses high dispersion stability stemming from the LB, as well as negligible cytotoxicity. After cellular internalization and endo/lysosomal capture of the nanoparticles, photochemical internalization (PCI) mediated simultaneous cargo release and endo/lysosomal escape were achieved by local ROS production upon 808 nm irradiation, thus leading to highly efficient chemo-photodynamic therapy on cancer cells in vitro. Such a system presents a sophisticated platform that integrates biocompatibility, spatiotemporal control, NIR-responsiveness, and synergistic therapies to promote cancer therapy.

Integration of polymers in the pore space of mesoporous nanocarriers for drug delivery

In the past decade, controlled integration of polymers in pore space regions (framework walls, pore surface, pore interior) of mesoporous nanocarriers with large surface areas and pore volumes has attracted considerable attention in drug delivery. The system constitutes great advances in multivalent specific interactions which increase the host-guest affinity or avidity in the confined pore space. Herein, we present and discuss the recent advances in the covalent and noncovalent incorporation of polymers into mesopores for drug-oriented delivery systems. The present challenges and new approaches towards functional drug-polymer-inorganic mesostructured hybrids are reviewed for a deeper understanding of the synergy of functions.

Hybrid Mesoporous–Microporous Nanocarriers for Overcoming Multidrug Resistance by Sequential Drug Delivery

Combination chemotherapy with a modulator and a chemotherapeutic drug has become one of the most promising strategies for the treatment of multidrug resistance (MDR) in cancer therapy. However, the development of nanocarriers with a high payload and sequential release of therapeutic agents poses a significant challenge. In this work, we report a type of hybrid nanocarriers prepared by polydopamine (PDA) mediated integration of the mesoporous MSN core and the microporous zeolite imidazolate frameworks-8 (ZIF-8) shell. The nanocarriers exploit storage capacities for drugs based on the high porosity and molecular sieving capabilities of ZIF-8 for sequential drug release. Particularly, large amounts of an anticancer drug (DOX, 607 μg mg-1) and a MDR inhibitor curcumin (CUR, 778 μg mg-1) were sequentially loaded in the mesoporous core via π-π stacking interactions mediated by PDA and in the microporous shell via the encapsulation during ZIF-8 growth. The sustained release of DOX was observed to follow earlier and faster release of CUR by acid-sensitive dissolution of the ZIF-8 shell. Furthermore, the nanoparticles showed good biocompatibility and effective cellular uptake in in vitro evaluations using drug-resistant MCF-7/ADR cancer cells. More importantly, the preferentially released CUR inhibited the drug efflux function of the membrane P-glycoprotein (P-gp), which subsequently facilitated the nuclear transportation of DOX released from the PDA-MSN core, and, in turn, the synergistic effects on killing MDR cancer cells. The hybrid mesoporous-microporous nanocarrier holds great promise for combination chemotherapy applications on the basis of sequential drug release.

Interfacially active polydopamine for nanoparticle stabilized nanocapsules in a one-pot assembly strategy toward efficient drug delivery

Nanoscale colloidal capsules are promising drug delivery carriers currently while the demand for multiple-step syntheses and the difficulties in achieving high capsule stability are key obstacles that have greatly restricted their development. Herein, we report a polydopamine (PDA) nanoparticle stabilized nanocapsule as a drug delivery system based on the combination of nanoparticle formation and capsule assembly/stabilization in one pot. In this system, an arginine modified linoleic acid nanoemulsion was employed as the template for the in situ generation/assembly of interfacially active PDA nanoparticles, while directional interaction pairs of carboxylate-guanidine and amino-PDA linked by arginine are involved in the assembly process. The nanocapsules possess an average size of 100 nm, high stability in biological media, and efficient lipophilic transfer of the loaded lipophilic cargo. Notably, the high biocompatibility of the nanocapsules and the non-endocytotic delivery to the cytosol of cancer cells were demonstrated in vitro. Furthermore, the efficient delivery of paclitaxel, as well as paclitaxel/doxorubicin dual cargo, was realized, resulting in the high inhibition of cancer cells. Altogether, the PDA nanoparticle stabilized nanocapsules open new opportunities for the development of promising nanocapsule platforms for biomedical delivery.

Stable photoluminescence of lanthanide complexes in aqueous media through Metal-Organic Frameworks Nanoparticles with plugged surface

The photoluminescence stability of lanthanide complex in aqueous media is a prerequisite for diagnostics probes. The combination of building blocks working in concert to facilitate host-guest structures is now considered state of the art in surpassing this roadblock, yet there still remains a tremendous challenge. Here, a stable, highly-luminescent system was developed through trapping anionic complexes sensitized by tridentate pyridine-tetrazolate (pytz) ligands within the rigid framework of ZIF-8 (zeolitic imidazolate framework-8) particles (∼60 nm in size). The key to maintaining the stable luminescence of lanthanide complexes inside ZIF-8 frameworks is a stopcock design, i.e. stopper molecules (an imidazolium based ionic liquid) selectively plugged on the pore entrances located at the exterior surface of the ZIF-8 host, which protect both the host and the guests from deteriorations by surrounding ions/water molecules. Remarkably, the obtained Ln complex encapsulated ZIF-8 particles (Ln = terbium, europium) particles possessed high quantum yields (23.2% and 8.5%), large absorption cross-section (∼10-12 cm2), and long luminescence lifetimes (1.9 and 3.0 ms) in PBS buffer. In addition, the system can realize single/multi-color encoding by altering the loading amounts and the weight ratios of complexes emitting at different wavelengths.

Terbium complexes encapsulated in hierarchically organized hybrid MOF particles toward stable luminescence in aqueous media

Hierarchically organized hybrid MOF particles were developed to meet the stable luminescence requirements of lanthanide complexes for applications in biological media. Anionic terbium (Tb) complexes sensitized by tridentate pyridine-tetrazolate (pytz) ligands (i.e. Tb(pytz)3) were encapsulated in zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (∼150 nm). TIF-1Zn (Zn(DMBIM)2) frameworks were then hybridized with ZIF-8 by the mediation of a hydrophobic ligand, i.e. DMBIM (5,6-dimethylbenzimidazole). A bio-inspired polymer, i.e. polydopamine, was utilized for imparting the particles with hydrophilicity and functionalization ability. An unprecedentedly high quantum yield (82.0%) and luminescence stability in PBS buffer were realized by the hierarchical structure.