Modular Assembly of Host-Guest Metal-Phenolic Networks Using Macrocyclic Building Blocks.

The manipulation of interfacial properties has broad implications for the development of high-performance coatings. Metal-phenolic networks (MPNs) are an emerging class of responsive, adherent materials. Herein, host-guest chemistry is integrated with MPNs to modulate their surface chemistry and interfacial properties. Macrocyclic cyclodextrins (host) are conjugated to catechol or galloyl groups and subsequently used as components for the assembly of functional MPNs. The assembled cyclodextrin-based MPNs are highly permeable (even to high molecular weight polymers: 250-500 kDa), yet they specifically and noncovalently interact with various functional guests (including small molecules, polymers, and carbon nanomaterials), allowing for modular and reversible control over interfacial properties. Specifically, by using either hydrophobic or hydrophilic guest molecules, the wettability of the MPNs can be readily tuned between superrepellency (>150°) and superwetting (ca. 0°).

A bioreducible supramolecular nanoparticle gene delivery system based on cyclodextrin-conjugated polyaspartamide and adamantyl-terminated polyethylenimine.

This article describes a novel reduction degradable supramolecular nanoparticle gene delivery system via host-guest interaction based on cyclodextrin-conjugated polyaspartamide with disulfide linkage (Pasp-SS-CD) and adamantyl-terminated polyethylenimine (Ad4-PEI). The reduction responsiveness of Pasp-SS-CD and the Pasp-SS-CD/Ad4-PEI/pDNA supramolecular nanoparticles (SNPs) in the presence of dl-dithiothreitol (DTT) was confirmed by SEC-MALLS and DLS analysis, respectively. Compared with the Ad4-PEI/pDNA polyplexes, the bioreducible supramolecular polycation/pDNA polyplexes exhibited smaller particle size, slightly higher zeta potential, lower cytotoxicity and hemolysis ratio, improved cellular internalization and higher gene transfection efficiency. It was found that introducing Pasp-SS-CD to assemble Ad4-PEI could substantially enhance the tolerance of protein adsorption and maintain the gene transfer capacity of polycationic carriers, which might be beneficial for in vivo use. In addition, the cellular uptake pathway of the supramolecular polycation/pDNA polyplexes was investigated using different uptake inhibitors. The present study demonstrates that the proper assembly of cyclodextrin-conjugated polyaspartamide and adamantyl-terminated polyethylenimine is an effective strategy for the production of a new gene delivery system.

Supramolecular host-guest polycationic gene delivery system based on poly(cyclodextrin) and azobenzene-terminated polycations.

This article describes the supramolecular host-guest polycationic gene delivery system based on poly(ß-cyclodextrin) (PCD) and azobenzene-terminated polycations. The azobenzene-terminated linear (Az-LPDM) and branched (Az-BPDM) cationic polymers were synthesized by atom transfer radical polymerization (ATRP) of 2-dimethylamino ethyl methacrylate (DMAEMA). The formation and photosensitive behavior of the supramolecular polycations of azobenzene-terminated polycations Az-LPDM and Az-BPDM with PCD were confirmed by UV-vis and NMR analysis. The supramolecular PCD/Az-BPDM/DNA and PCD/Az-LPDM/DNA polyplexes showed smaller size and were less positive than those of their corresponding polyplexes without PCD. Moreover, the UV irradiation may promote release of DNA from the photosensitive supramolecular polyplexes due to dissociation of supramoelcular polyplexes. In vitro experiments revealed that the photosensitive supramolecular polycationic polyplexes (PCD/Az-LPDM/DNA and PCD/Az-BPDM/DNA) exhibited enhancement of cellular uptake, higher transfection efficiency, and lower cytoxicity compared to the azobenzene-terminated polycation/DNA polyplexes in the absence of PCD. Branched polycationic polyplexes showed higher transfection efficiency than its linear polycationic polyplexes. Furthermore, after UV irradiation, the transfection efficiency of photosensitive supramolecular polyplexes was improved resulting from more DNAs delivered and released inside of the cell nuclei. Thus this photoresponsive supramolecular host-guest system containing azobenzene-terminated branched cationic polymers and PCD is a promising gene vector.

Cell-Targeting Cationic Gene Delivery System Based on a Modular Design Rationale.

En route to target cells, a gene carrier faces multiple extra- and intracellular hurdles that would affect delivery efficacy. Although diverse strategies have been proposed to functionalize gene carriers for individually overcoming these barriers, it is challenging to generate a single multifunctional gene carrier capable of surmounting all these barriers. Aiming at this challenge, we have developed a supramolecular modular approach to fabricate a multifunctional cationic gene delivery system. It consists of two prefunctionalized modules: (1) a host module: a polymer (PCD-SS-PDMAEMA) composed of poly(ß-cyclodextrin) backbone and disulfide-linked PDMAEMA arms, expectedly acting to compact DNA and release DNA upon cleavage of disulfide linkers in reductive microenvironment; and (2) a guest module: adamantyl and folate terminated PEG (Ad-PEG-FA), expectedly functioning to reduce nonspecific interactions, improve biocompatibility, and provide folate-mediated cellular targeting specificity. Through the host-guest interaction between ß-cyclodextrin units of the "host" module and adamantyl groups of the "guest" module, the PCD-SS-PDMAEMA-1 (host) and Ad-PEG-FA (guest) self-assemble forming a supramolecular pseudocopolymer (PCD-SS-PDMAEMA-1/PEG-FA). Our comprehensive analyses demonstrate that the functions preassigned to the two building modules are well realized. The gene carrier effectively compacts DNA into stable nanosized polyplexes resistant to enzymatic digestion, triggers DNA release in reducing environment, possesses significantly improved hemocompatibility, and specifically targets folate-receptor positive cells. Most importantly, endowed with these predesigned functions, the PCD-SS-PDMAEMA-1/PEG-FA supramolecular gene carrier exhibits excellent transfection efficacy for both pDNA and siRNA. Thus, this work represents a proof-of-concept example showing the efficiency and convenience of an adaptable, modular approach for conferring multiple functions to a single supramolecular gene carrier toward effective in vivo delivery of therapeutic nucleic acids.

Sericin/Dextran Injectable Hydrogel as an Optically Trackable Drug Delivery System for Malignant Melanoma Treatment.

Severe side effects of cancer chemotherapy prompt developing better drug delivery systems. Injectable hydrogels are an effective site-target system. For most of injectable hydrogels, once delivered in vivo, some properties including drug release and degradation, which are critical to chemotherapeutic effects and safety, are challenging to monitor. Developing a drug delivery system for effective cancer therapy with in vivo real-time noninvasive trackability is highly desired. Although fluorescence dyes are used for imaging hydrogels, the cytotoxicity limits their applications. By using sericin, a natural photoluminescent protein from silk, we successfully synthesized a hydrazone cross-linked sericin/dextran injectable hydrogel. This hydrogel is biodegradable and biocompatible. It achieves efficient drug loading and controlled release of both macromolecular and small molecular drugs. Notably, sericin's photoluminescence from this hydrogel is directly and stably correlated with its degradation, enabling long-term in vivo imaging and real-time monitoring of the remaining drug. The hydrogel loaded with Doxorubicin significantly suppresses tumor growth. Together, the work demonstrates the efficacy of this drug delivery system, and the in vivo effectiveness of this sericin-based optical monitoring strategy, providing a potential approach for improving hydrogel design toward optimal efficiency and safety of chemotherapies, which may be widely applicable to other drug delivery systems.

A light and reduction dual sensitive supramolecular self-assembly gene delivery system based on poly(cyclodextrin) and disulfide-containing azobenzene-terminated branched polycations.

Novel reduction degradable and photosensitive disulfide-containing azobenzene-terminated branched poly(2-(dimethylamino)ethyl methacrylate)s (Az-ss-BPDMs) and supramolecular host-guest self-assembly systems with poly(cyclodextrin) (PCD) were prepared and evaluated as non-viral gene delivery vectors. The reduction and light dual sensitive properties of the supramolecular polycations PCD/Az-ss-BPDMs and their polyplexes PCD/Az-ss-BPDMs/DNA were confirmed by UV-Vis, SEC, DLS and zeta potential analyses, respectively. It was shown that the inclusion of PCD, introduction of disulfide bonds into branched polycations, increase of the branching degree of the branched Az-ss-BPDMs and use of UV irradiation could enhance the gene transfection efficiency and cellular internalization of the supramolecular disulfide-containing azobenzene-terminated branched polycationic polyplexes (PCD/Az-ss-BPDM/DNA). Importantly, the transfection efficiency of the light and reduction dual-sensitive supramolecular PCD/Az-ss-BPDM/DNA polyplexes achieved almost 10 times higher value than that of 25 kDa PEI control; whereas the cytotoxicity of the supramolecular polyplexes was lower than that of PEI control. Thus this light and reduction dual responsive supramolecular host-guest system containing azobenzene-terminated branched cationic polymers with disulfide bonds and PCD is a promising gene vector.