- Li

Host–Guest Supramolecular Nanosystems for Cancer Diagnostics and Therapeutics

Extensive efforts have been devoted to the construction of functional supramolecular nanosystems for applications in catalysis, energy conversion, sensing and biomedicine. The applications of supramolecular nanosystems such as liposomes, micelles, inorganic nanoparticles, carbon materials for cancer diagnostics and therapeutics have been reviewed by other groups. Here, we will focus on the recent momentous advances in the implementation of typical supramolecular hosts (i.e., cyclodextrins, calixarenes, cucurbiturils and metallo-hosts) and their nanosystems in cancer diagnostics and therapeutics. We discuss the evolutive process of supramolecular nanosystems from the structural control and characterization to their diagnostic and therapeutic function exploitation and even the future potentials for clinical translation.

Supramolecular adducts of squaraine and protein for noninvasive tumor imaging and photothermal therapy in vivo

Extensive efforts have been devoted to the development of near-infrared (NIR) dye-based imaging probes and/or photothermal agents for cancer theranostics in vivo. However, the intrinsic chemical instability and self-aggregation properties of NIR dyes in physiological condition limit their widely applications in the pre-clinic study in living animals. Squaraine dyes are among the most promising NIR fluorophores with high absorption coefficiencies, bright fluorescence and photostability. By introducing dicyanovinyl groups into conventional squaraine (SQ) skeleton. These acceptor-substituted SQ dyes not only show superior NIR fluorescence properties (longer wavelength, higher quantum yield) but also exhibit more chemical robustness. In this work, we demonstrated highly stable and biocompatible supramolecular adducts of SQ and the natural carrier protein, i.e., bovine serum albumin (BSA) (SQ⊂BSA) for tumor targeted imaging and photothermal therapy in vivo. SQ was selectively bound to BSA hydrophobic domain via hydrophobic and hydrogen bonding interactions with up to 80-fold enhanced fluorescence intensity. By covalently conjugating target ligands to BSA, the SQ⊂BSA was capable of targeting tumor sites and allowed for monitoring the time-dependent biodistribution of SQ⊂BSA, which consequently determined the protocol of photothermal therapy in vivo. We envision that this supramolecular strategy for selectively binding functional imaging agents and/or drugs into human serum albumin might potentially utilize in the preclinical and even clinic studies in the future.

Pathological‐Condition‐Driven Construction of Supramolecular Nanoassemblies for Bacterial Infection Detection

A pyropheophorbide-α-based building block (Ppa-PLGVRG-Van) can be used to construct self-aggregated superstructures in vivo for highly specific and sensitive diagnosis of bacterial infection by noninvasive photoacoustic tomography. This in vivo supramolecular chemistry approach opens a new avenue for efficient, rapid, and early-stage disease diagnosis with high sensitivity and specificity.

An adaptive biointerface from self-assembled functional peptides for tissue engineering.

A self-assembled peptide-based biointerface is demonstrated with triple functional layers that can significantly improve the tissue self-healing process or prevent biofilm-mediated chronic inflammation. This smart biointerface is composed of three functional moieties (i.e., a cell-adhesive peptide, an infectious environment-responsive peptide, and an antifouling hexaethylene glycol (HEG) layer), and the resulting interface coated onto prosthetic replacements can smartly respond to the surrounding physiological or pathological microenvironment.

Dynamic disordering of liposomal cocktails and the spatio-temporal favorable release of cargoes to circumvent drug resistance

Multidrug resistance (MDR) has been a major impediment to the success of cancer chemotherapy. Extensive efforts have been devoted to the development of drug delivery systems using nanotechnology to reverse MDR in cancer. However, the spontaneous release of drug payloads was always a slow process, which leads to the low intracellular drug concentration resulting in consequent drug insensitivity. To circumvent this limitation, we described a liposomal cocktail (LMDHV) constructed by a pH-responsive molecule (i.e., malachite green carbinol base (MG)) and liposome conjugated with Her-2 antibody for codelivery of doxorubicin (DOX) and verapamil (VER) to suppress drug resistance in Her-2 positive breast cancer. MG inserted in the bilayer as pH responders greatly contributed to the destabilization of the vesicle membrane in low pH, followed by the rapid release of the payloads. LMDHV showed 6-fold reversal efficiency in DOX resistant breast cancer owing to the efficient tumor targeting delivery and rapid burst release of drug intracellularly. Compared to tumor inhibition ratio of treated groups by free DOX (32.4 ± 7.4%), our designed kinetically favorable drug release system exhibited significantly (P < 0.01) enhanced tumor inhibition ratio up to 83.9 ± 12.5%, which is attributed to the remarkably increased drug concentration in cells. The spatio-temporal favorable release of drugs resulted in synergistic inhibition of tumor growth in xenografts. We envision that this new type of liposomal cocktail might be potentially utilized to circumvent drug resistance in the future.

Surface charge-conversion polymeric nanoparticles for photodynamic treatment of urinary tract bacterial infections

Urinary tract infections are typical bacterial infections which result in a number of economic burdens. With increasing antibiotic resistance, it is urgent that new approaches are explored that can eliminate pathogenic bacteria without inducing drug resistance. Antimicrobial photodynamic therapy (PDT) is a new promising tactic. It is a gentle in situ photochemical reaction in which a photosensitizer (PS) generates reactive oxygen species (ROS) under laser irradiation. In this work, we have demonstrated Chlorin e6 (Ce6) encapsulated charge-conversion polymeric nanoparticles (NPs) for efficiently targeting and killing pathogenic bacteria in a weakly acidic urinary tract infection environment. Owing to the surface charge conversion of NPs in an acidic environment, the NPs exhibited enhanced recognition for Gram-positive (ex. S. aureus) and Gram-negative (ex. E. coli) bacteria due to the charge interaction. Also, those NPs showed significant antibacterial efficacy in vitro with low cytotoxicity. The MIC value of NPs to E. coli is 17.91 μg ml(-1), compared with the free Ce6 value of 29.85 μg ml(-1). Finally, a mouse acute cystitis model was used to assess the photodynamic therapy effects in urinary tract infections. A significant decline (P < 0.05) in bacterial cells between NPs and free Ce6 occurred in urine after photodynamic therapy treatment. And the plated counting results revealed a remarkable bacterial cells drop (P < 0.05) in the sacrificed bladder tissue. Above all, this nanotechnology strategy opens a new door for the treatment of urinary tract infections with minimal side effects.

Intracellular construction of topology-controlled polypeptide nanostructures with diverse biological functions

Topological structures of bio-architectonics and bio-interfaces play major roles in maintaining the normal functions of organs, tissues, extracellular matrix, and cells. In-depth understanding of natural self-assembly mechanisms and mimicking functional structures provide us opportunities to artificially control the natural assemblies and their biofunctions. Here, we report an intracellular enzyme-catalyzed polymerization approach for efficient synthesis of polypeptides and in situ construction of topology-controlled nanostructures. We reveal that the phase behavior and topological structure of polypeptides are encoded in monomeric peptide sequences. Next, we elucidate the relationship between polymerization dynamics and their temperature-dependent topological transition in biological conditions. Importantly, the linearly grown elastin-like polypeptides are biocompatible and aggregate into nanoparticles that exhibit significant molecular accumulation and retention effects. However, 3D gel-like structures with thermo-induced multi-directional traction interfere with cellular fates. These findings allow us to exploit new nanomaterials in living subjects for biomedical applications.The intracellular topology of a nanostructure plays a major role in its interactions with the cell and accordingly, its biological applications. Here, the authors design peptides that intracellularly polymerize into elastin-like polypeptides and assemble into various topologies, each of which exhibits a distinct set of biological functions.

Quantitative Analysis of Caspase-1 Activity in Living Cells Through Dynamic Equilibrium of Chlorophyll-Based Nano-assembly Modulated Photoacoustic Signals

In situ construction of self-assemblies with unique property in living systems is a promising direction in the biomedical field. The noninvasive methods for significant enzyme activity in living cells or living subjects are imperative and meantime challenge tasks. The dynamic process of self-assembly of chlorophyll-based molecules in complex biological systems can be monitored by photoacoustic signals, which supports a noninvasive way to understand and quantitatively measure the activity of caspase-1. Furthermore, the activity of caspase-1 enables reflection of the bacterial infection in the early stage. Here, we present a biocompatible self-assembly from chlorophyll-peptide derivatives and first correlate the dynamic equilibrium with ratiometric photoacoustic signals. The intracellular equilibrium was managed by a bacterial infection precaution protein, i.e., caspase-1. This system offers a trial of noninvasive method to quantitative detection and real-time monitoring of bacterial infection in the early stage.

A non-contact strategy for controlled enrichment, manipulation, and separation of carbon nanotubes by surface acoustic waves

We report a flexible method to manipulate carbon nanotubes (CNTs) in a microfluidic device employing surface acoustic waves (SAWs). First, CNTs in suspension were enriched to the surface of the piezoelectric substrate by SAW; standing SAWs (SSAWs) could orchestrate controllable alignment and movement of the CNTs in a microfluidic channel. In the two-dimensional (2D) case, moreover, the enriched and aligned CNTs could be precisely rotated to all directions via adjusting the coupling of the 2D SSAWs. Finally, we demonstrated the SAW technique as a promising candidate for purifying metallic single-walled carbon nanotubes from the mixture species in a non-contact manner.

General Approach of Stimuli-Induced Aggregation for Monitoring Tumor Therapy

Intracellular construction of nanoaggregates from synthetic molecules to mimic natural ordered superstructures has gained increasing attention recently. Here, we develop an endogenous stimuli-induced aggregation (eSIA) approach to construct functional nanoaggregates for sensing and monitoring cellular physiological processes in situ. We design a series of thermosensitive polymer-peptide conjugates (PPCs), which are capable of constructing nanoaggregates in cells based on their isothermal phase transition property. The PPCs are composed of three moieties (i.e., a thermoresponsive polymer backbone, a grafted peptide, and a signal-molecule label). The bioenvironment-associated phase transition behavior of PPCs are carefully studied by consideration of various crucial parameters such as chain length, hydrophilicity, ratio of grafted peptides, and concentration. Intriguingly, under the specific intracellular stimulus, the PPCs are tailored and simultaneously form nanoaggregates exhibiting long-term retention effect, which enables specific identification and quantification of endogenous factors. This general approach is expected for high-performance in situ sensing and dynamic monitoring of disease progression in living subjects.