Supramolecular Drug Research Articles

An Activatable Host-Guest Conjugate as a Nanocarrier for Effective Drug Release through Self-Inclusion.

There is a challenge in supramolecular chemotherapy for constructing a system equipped with both sufficient protection and high-efficiency release of drugs. To this end, a new strategy of an activatable host-guest conjugate with self-inclusion property is proposed. Based on the binding affinity gain of intramolecular host-guest self-inclusion, an activatable host-guest conjugate was designed, bearing cucurbit[7]uril as the host, an alkyl ammonium moiety as the guest, and the redox-responsive disulfide linkage. Oxaliplatin, a clinical antitumor drug, could be firmly encapsulated by the activatable host-guest conjugate to form the supramolecular drug with high stability. Moreover, oxaliplatin loaded in the activatable host-guest conjugate could be almost completely released by self-inclusion triggered by glutathione in a tumor microenvironment, thus exhibiting comparable antitumor bioactivity with naked oxaliplatin through in vitro cell experiments. It is highly anticipated that this line of research may open new horizons for programmable and on-demand supramolecular chemotherapy with high antitumor efficiency.

Biomimetic Supramolecular Drug Delivery Hydrogels for Accelerated Skin Tissue Regeneration.

Skin tissue is regenerated by the combinational function of skin cells, extracellular matrix (ECM), and bioactive molecules. As an artificial ECM, supramolecular hydrogels exhibited outstanding capability to mimic the physical properties of ECM. However, the lack of biochemical function in supramolecular hydrogels has limited further tissue engineering applications. Here, we developed self-assembling supramolecular drug delivery hydrogels to mimic the skin tissue regeneration process. The supramolecular hydrogels were prepared to encapsulate fibroblasts by the host-guest interaction of cyclodextrin-modified gelatin (GE-CD) and adamantane-modified hyaluronate (Ad-HA) in conjugation with human growth hormone (hGH) for accelerated skin tissue regeneration. In vitro, GE-CD/Ad-HA-hGH hydrogels showed highly facilitated cell growth by the controlled hGH delivery. After a subcutaneous injection into the back of mice, IVIS imaging of bioengineered fibroblasts to express red fluorescence protein (RFP) revealed prolonged cell survival and proliferation in the supramolecular hydrogels for more than 21 days. We could also observe the improved skin tissue regeneration by the facilitated fibroblast proliferation with angiogenesis. Taken together, we could confirm the feasibility of biomimetic supramolecular drug delivery GE-CD/Ad-HA-hGH hydrogels for various tissue engineering applications.

Supramolecular micelles as multifunctional theranostic agents for synergistic photodynamic therapy and hypoxia-activated chemotherapy

Photodynamic therapy (PDT), where a photosensitizer (under light irradiation) converts molecular oxygen to singlet oxygen to elicit programmed cell death, is a promising cancer treatment modality with a high temporal and spatial resolution. However, only limited cancer treatment efficacy has been achieved in clinical PDT due to the hypoxic conditions of solid tumor microenvironment that limits the generation of singlet oxygen, and PDT process often leads to even more hypoxic microenvironment due to the consumption of oxygens during therapy. Herein, we designed novel supramolecular micelles to co-deliver photosensitizer and hypoxia-responsive prodrug to improve the overall therapeutic efficacy. The supramolecular micelles (CPC) were derived from a polyethylene glycol (PEG) system dually tagged with hydrophilic cucurbit[7]uril (CB[7]) and hydrophobic Chlorin e6 (Ce6), respectively on each end, for synergistic antitumor therapy via PDT of Ce6 and chemotherapy of a hypoxia-responsive prodrug, banoxantrone (AQ4N), loaded into the cavity of CB[7]. In addition, CPC was further modularly functionalized by folate (FA) via strong host-guest interaction between folate-amantadine (FA-ADA) and CB[7] to produce a novel nanoplatform, AQ4N@CPC-FA, for targeted delivery. AQ4N@CPC-FA exhibited enhanced cellular uptake, negligible cytotoxicity and good biocompatibility, and improved intracellular reactive oxygen species (ROS) generation efficiency. More importantly, in vivo evaluation of AQ4N@CPC-FA revealed a synergistic antitumor efficacy between PDT of Ce6 and hypoxia-activated chemotherapy of AQ4N (that can be converted to chemotherapeutic AQ4 for tumor chemotherapy in response to the strengthened hypoxic tumor microenvironment during PDT treatment). This study not only provides a new nanoplatform for synergistic photodynamic-chemotherapeutic treatment, but also offers important new insights to design and development of multifunctional supramolecular drug delivery system. Statement of significancePhotodynamic therapy (PDT) has exhibited a variety of advantages for cancer phototherapy as compared to traditional chemotherapy. However, the unsatisfactory therapeutic efficacy by PDT alone as a result of the enhanced tumor hypoxia during PDT has limited its clinical application. Herein, we designed multifunctional supramolecular micelles to co-deliver photosensitizer and hypoxia-responsive prodrug to improve the overall therapeutic efficacy. The supramolecular micelles are biocompatible and possess strong red absorption, controlled drug release profile, and ultimately enhanced therapeutic outcome via PDT-chemotherapy. This study not only provides a new nanoplatform for synergistic photodynamic-chemotherapeutic treatment of cancer, but also offers important new insights to design and development of multifunctional supramolecular drug delivery tool for multi-modality cancer therapy.

Structure and energetics of intermolecular association in two lurasidone co-amorphous drug systems

The use of amorphous phases has been proposed as one of the alternatives for drug formulations of low solubility active pharmaceutical ingredients (API). To overcome stability problems of these metastable phases, co-amorphous mixtures of API with safe small molecule co-formers are being investigated. Therefore, it is of great importance to study the factors that control the supramolecular association of drug substance with the co-formers, despite lack of long-range order in these systems creating some experimental and computational challenges. This work aims to apply various computational chemistry methods to the study of co-amorphous drug systems, namely the local structural and intermolecular interactions responsible for the intimate drug–co-former association that prevents relaxation to the crystalline state. The subjects of this study are two co-amorphous systems, recently proposed and studied experimentally, that include the drug lurasidone with two different co-formers, saccharin and cysteine. First, the conformational landscape of lurasidone is explored by random search molecular mechanics to provide a varied set of initial conformations. Then, these conformations and those extracted from the available X-ray diffraction crystal structures of the three component substances are subject to geometry optimization by a DFT method (B3LYP/def2-SVP), including corrections for dispersion. The same optimization procedure is applied to homodimers extracted from the crystal structures, and to heterodimers built using the evidence for the manner of aggregation provided by the published experimental studies. The intermolecular association is further explored with Natural Bond Orbital (NBO) and Non-Covalent Interaction (NCI) analyses of the dimers, to better understand the electronic structure of the supramolecular drug–co-former entities and compare how they interact. It is concluded that faster, more approximate, methods were useful to deal with large and conformationally flexible drug molecules that are typical amorphous phase formers, and that the more rigorous quantum mechanical methods are necessary to rationalize and evaluate the molecular interactions in co-amorphous systems. The NBO analysis indicated that lurasidone has stronger hydrogen bonding with cysteine than with saccharin.

SUPRAMOLECULAR DRUG CARRIERS IN CANCER THERAPEUTICS

Cancer has a significant effect on society worldwide. Statistics on cancer explain what happens in a large set of people and give a real picture of the burden on society. A number of cancer treatments are accessible nowadays and enormous numbers are in the pipeline, but society still faces several lacks in full therapy cure. The objective is to determine, parallel to the kinds and uses of supramolecular drug carriers, and the incidence and incidences of cancer with various medical systems concentrated primarily on targeted structures. Rational drug delivery designs have shown important interest in enhancing therapeutics in latest years with regard to leveraging supramolecular chemistry that is ‘‘chemistry beyond molecules.'' Particular tunable and dynamic non-covalent interaction of engineering can be used for drug delivery. Advantages of this include molecular composition control, improved drug integration and targeting pathways, and new delivery devices which respond to a various physiological indicators. One of the largely recognizable motivations for supramolecular drug delivery is macrocyclic hosts-guest complexes. The scope of this review is to give a clear picture that how supramolecular drugs carrier plays an effective role in cancer treatment.

Platinum-Containing Supramolecular Drug Self-Delivery Nanomicelles for Efficient Synergistic Combination Chemotherapy.

Supramolecular drug self-delivery systems (SDSDSs) involving active drugs as building blocks linked by supramolecular interactions have been well defined as an advanced chemotherapy strategy. However, the lack of detecting release of drugs from SDSDSs at specific tumor sites inevitably leads to unsatisfactory therapeutic effects, owing to the lack of information regarding the administration of these drugs. In this work, predesigned platinum-containing supramolecular drug self-delivery nanomicelles (SDSDNMs) were employed to synchronously realize drug monitoring by computed tomography imaging, immediately reflecting the evolution of drug release and real-time treatment at the tumor site. The appropriate administration dosage (1.2 mg mL-1,100 μL) and the injection interval (once every 3 days) needed to guide the antitumor activity of SDSDNMs were then defined, thereby attaining the aim of efficient synergistic combination chemotherapy. In vivo tumor inhibition and histological analyses showed that SDSDNMs exhibited a strong tumor inhibition effect and good safety with respect to normal organs. Such a supramolecular drug self-delivery strategy with monitored functions may offer new potential opportunities for application in the field of synergistic combination chemotherapy.

A pH-Responsive Supramolecular Drug Delivery System Constructed by Cationic Pillar[5]arene for Enhancing Antitumor Activity.

Drug delivery systems have good biocompatibiliy and low side effects for cancer treatment, but overcoming high efficiency of drug-loading and the drug-targeting controlled release still remains challenging. In this work, supramolecular vesicles, with pH-triggering effect, have been successfully constructed for drug delivery, which are fabricated by the complexation between a cationic pillar[5]arene (DAWP5) and a sodium dodecyl sulfonate (SDS) in aqueous solution. Drug-loading and releasing results demonstrated that anticancer drug doxorubicin (DOX) could be loaded efficiently by such cationic vesicles in neutral condition, and the drug release could be controlled in the simulated weak acid environment of tumor cells. Moreover, the vesicles had low cytotoxicity to normal human cell (L02), while the DOX-loaded vesicles could significantly enhance the cytotoxicity of free DOX for normal cell L02 and four tested tumor cells (Hela, HepG2, MGC-803 and T24). Especially for HepG2, after 24 h incubation time, IC50 of DOX-loaded vesicles was only 0.79 μM, about 23% of that of DOX (3.43 μM). These results suggested that such novel vesicles have promising potential to construct nano-drug delivery systems for various biomedical applications.

Supramolecular PEGylation of camptothecin for cancer therapy

PEGylated drugs and their self-assembled nanoparticles have been used as a first-line technology in nanomedicines. However, premature disassembly before reaching the lesions under dilute conditions limits their bioavailability. This challenge can be overcome by covalent crosslinking. However, undefined molecular structures of the prodrugs are introduced, which hinder large-scale production and clinical translation. Herein, a supramolecular PEGylated camptothecin nanodrug with a crosslinked architecture and defined molecular drug structure was developed. PEGylated mono-tetraethylenepentamine β-cyclodextrin (mPEG-TEPA-CD) and adamantane modified camptothecin (AD-SS-CPT) were first synthesized. The host-guest coupling of β-cyclodextrin (β-CD) and adamantine (AD) moieties between mPEG-TEPA-CD and AD-SS-CPT induced the formation of supramolecular PEGylated camptothecin, which could self-assemble into micelles in the aqueous medium. They were further stabilized by the addition of a diacrylate crosslinker for reaction with the amine groups on mPEG-TEPA-CD, maintaining the unaltered AD-SS-CPT. The nanodrugs can internalize into tumor cells quickly and release free camptothecin in response to glutathione. They also have prolonged blood circulation time and can accumulate efficiently at tumor sites, thus showing effective antitumor activity. This supramolecular drug delivery system provides a new strategy for the design of nanodrugs.

Targeting structural features of viral genomes with a nano-sized supramolecular drug.

RNA targeting is an exciting frontier for drug design. Intriguing targets include functional RNA structures in structurally-conserved untranslated regions (UTRs) of many lethal viruses. However, computational docking screens, valuable in protein structure targeting, fail for inherently flexible RNA. Herein we harness MD simulations with Markov state modeling to enable nanosize metallo-supramolecular cylinders to explore the dynamic RNA conformational landscape of HIV-1 TAR untranslated region RNA (representative for many viruses) replicating experimental observations. These cylinders are exciting as they have unprecedented nucleic acid binding and are the first supramolecular helicates shown to have anti-viral activity in cellulo: the approach developed in this study provides additional new insight about how such viral UTR structures might be targeted with the cylinder binding into the heart of an RNA-bulge cavity, how that reduces the conformational flexibility of the RNA and molecular details of the insertion mechanism. The approach and understanding developed represents a new roadmap for design of supramolecular drugs to target RNA structural motifs across biology and nucleic acid nanoscience.

Real-Time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-Chip.

The performance of supramolecular nanocarriers as drug delivery systems depends on their stability in the complex and dynamic biological media. After administration, nanocarriers are challenged by physiological barriers such as shear stress and proteins present in blood, endothelial wall, extracellular matrix, and eventually cancer cell membrane. While early disassembly will result in a premature drug release, extreme stability of the nanocarriers can lead to poor drug release and low efficiency. Therefore, comprehensive understanding of the stability and assembly state of supramolecular carriers in each stage of delivery is the key factor for the rational design of these systems. One of the main challenges is that current 2D in vitro models do not provide exhaustive information, as they fail to recapitulate the 3D tumor microenvironment. This deficiency in the 2D model complexity is the main reason for the differences observed in vivo when testing the performance of supramolecular nanocarriers. Herein, we present a real-time monitoring study of self-assembled micelles stability and extravasation, combining spectral confocal microscopy and a microfluidic cancer-on-a-chip. The combination of advanced imaging and a reliable 3D model allows tracking of micelle disassembly by following the spectral properties of the amphiphiles in space and time during the crucial steps of drug delivery. The spectrally active micelles were introduced under flow and their position and conformation continuously followed by spectral imaging during the crossing of barriers, revealing the interplay between carrier structure, micellar stability, and extravasation. Integrating the ability of the micelles to change their fluorescent properties when disassembled, spectral confocal imaging and 3D microfluidic tumor blood vessel-on-a-chip resulted in the establishment of a robust testing platform suitable for real-time imaging and evaluation of supramolecular drug delivery carrier’s stability.

Self-assembly supramolecular drug delivery system for combination of photodynamic therapy and chemotherapy

Aims To construct a self-assembly supramolecular drug delivery system (DDS) to co-deliver chlorin e6 (Ce6) and tripeptide tyroseroleutide (YSL) and evaluate the anti-tumour effects. Methods A supramolecular DDS was constructed via self-assembly of Ce6 and YSL based on π-π stacking and hydrogen-bond interaction. The size, morphology, stability, in vitro drug release, cellular uptake, cytotoxicity, pharmacokinetics analysis and pharmacodynamics analysis were respectively studied. Results Ce6-YSL nanoparticles with a uniform size of 75 ± 3.5 nm (PDI = 0.128) and monodispersed spherical morphology were constructed. The nanoparticles exhibited good stability with zeta potential −21.2 ± 1.73 mV. Under the weak acidic conditions, the accumulative drug release was 82.8% (w/w) (pH = 6.0) and 91.5% (w/w) (pH = 5.0), respectively, indicating that nanoparticles performed smart responsive properties and achieved controlled release characteristics in acidic tumour microenvironment. In addition, nanoparticles could easily enter the tumour cells and induce ROS production and inhibit cell proliferation in SMMCC-7721 cells with IC50 value 3.4 ± 0.023 μg/mL under laser irradiation. Furthermore, the nanoparticles could retain a much higher blood concentration in vivo and displayed excellent antitumor effect in tumour-bearing mice, showing no influence on body weight. Conclusions This self-assembly supramolecular DDS can be used for combination of photodynamic therapy and chemotherapy in future research.

β-Cyclodextrin modified Pt(II) metallacycle-based supramolecular hyperbranched polymer assemblies for DOX delivery to liver cancer cells

Despite the widespread clinical application of chemotherapeutic anticancer drugs, their adverse side effects and inefficient performances remain ongoing issues. A drug delivery system (DDS) designed for a specific cancer may therefore overcome the drawbacks of single chemotherapeutic drugs and provide precise and synergistical cancer treatment by introducing exclusive stimulus responsiveness and combined chemotherapy properties. Herein, we report the design and synthesis of a supramolecular drug delivery assembly 1 constructed by orthogonal self-assembly technique in aqueous media specifically for application in liver cancer therapy. Complex 1 incorporates the β-cyclodextrin host molecule-functionalized organoplatinum(II) metallacycle 2 with two specific stimulus-responsive motifs to the signaling molecule nitric oxide (NO), in addition to the three-armed polyethylene glycol (PEG) functionalized ferrocene 3 with redox responsiveness. With this molecular design, the particularly low critical aggregation concentration (CAC) of assembly 1 allowed encapsulation of the commercial anticancer drug doxorubicin (DOX). Controlled drug release was also achieved by morphological transfer via a sensitive response to the endogenous redox and NO stimuli, which are specifically related to the microenvironment of liver tumor cells. Upon combination of these properties with the anticancer ability from the platinum acceptor, in vitro studies demonstrated that DOX-loaded 1 is able to codeliver anticancer drugs and exhibit therapeutic effectiveness to liver tumor sites via a synergistic effect, thereby revealing a potential DDS platform for precise liver cancer therapeutics.

Targeting structural features of viral RNA genomes with a nano-sized supramolecular drug.

Targeting structural features of viral RNA genomes with a nano-sized supramolecular drug.

Polysaccharide-based supramolecular drug delivery systems mediated via host-guest interactions of cucurbiturils

With excellent biocompatibility and biodegradability, natural polysaccharides and their derivatives have exhibited great potential in constructing drug delivery vehicles for tissue engineering and therapeutics. Cucurbit[n]uril (CB[n])-mediated reversible crosslinking of polysaccharides possess intrinsic stimuli-responsiveness towards competitive guests and have been extensively investigated to fabricate various particles and hydrogels for multiple stimuli-responsive drug release by incorporation with other stimuli including photo, redox, and enzyme. Through host-guest interactions between CB[6] and aliphatic diamines, functional tags covalently connected with CB[6] can be readily anchored into polysaccharide-based hydrogels, realizing multiple functionalization. The rheological property and drug release profile of polysaccharide-based supramolecular hydrogels can be facilely tuned through CB[8]-mediated dynamic homo or hetero crosslinking of polysaccharides and/or other polymers. In this review, we introduce and summarize recent progress regarding polysaccharide-based supramolecular drug delivery systems mediated via host-guest interactions of CB[6] and CB[8], covering both bulk hydrogels and particular systems. At the end, possible utilization of CB[7]-based host-guest interactions in constructing polysaccharide-based drug delivery systems and future perspectives of this research direction are also discussed.

Supramolecular self-assembled drug delivery system (SADDs) of vancomycin and tocopherol succinate as an antibacterial agent: in vitro, in silico and in vivo evaluations

In this study self-assembled drug delivery system (SADDs) composed of a hydrophobic d-α-tocopherol succinate (TS) and a hydrophilic vancomycin (VCM) were formulated, and its potential for enhancing the antibacterial activity of VCM against Staphylococcus aureus (SA) and Methicillin-resistant Staphylococcus aureus (MRSA) were explored. The SADDs were synthesized via supramolecular complexation, then characterized for in silico, in vitro and in vivo studies. In silico studies confirmed the self-assembly of VCM/TS into NPs. The size, surface charge and drug loading of the SADDs was ˂100 nm, −27 mV and 68%, respectively. The SADDs were non-hemolytic and biosafe. A sustained release of VCM from SADDs was noted, with 52.2% release after 48 hr. The in vitro antibacterial test showed a twofold decrease in Minimum inhibitory concentration (MIC) against SA and MRSA, and a significantly higher reduction in MRSA biofilms compared to bare VCM. Further, in silico studies confirmed strong and stable binding of TS to MRSA efflux pumps. The in vivo study using mice skin infection models showed a 9.5-fold reduction in bacterial load after treatment with SADDs, in comparison with bare VCM. These findings affirmed that VCM/TS NPs as a promising novel nano-delivery for treating bacterial infections.

The Self-Assembly of a Cyclometalated Palladium Photosensitizer into Protein-Stabilized Nanorods Triggers Drug Uptake In Vitro and In Vivo.

Enhanced passive diffusion is usually considered to be the primary cause of the enhanced cellular uptake of cyclometalated drugs because cyclometalation lowers the charge of a metal complex and increases its lipophilicity. However, in this work, monocationic cyclometalated palladium complexes [1]OAc (N^N^C^N) and [2]OAc (N^N^N^C) were found to self-assemble, in aqueous solutions, into soluble supramolecular nanorods, while their tetrapyridyl bicationic analogue [3](OAc)2 (N^N^N^N) dissolved as isolated molecules. These nanorods formed via metallophilic Pd···Pd interaction and π–π stacking and were stabilized in the cell medium by serum proteins, in the absence of which the nanorods precipitated. In cell cultures, these protein-stabilized self-assembled nanorods were responsible for the improved cellular uptake of the cyclometalated compounds, which took place via endocytosis (i.e., an active uptake pathway). In addition to triggering self-assembly, cyclometalation in [1]OAc also led to dramatically enhanced photodynamic properties under blue light irradiation. These combined penetration and photodynamic properties were observed in multicellular tumor spheroids and in a mice tumor xenograft, demonstrating that protein-stabilized nanoaggregation of cyclometalated drugs such as [1]OAc also allows efficient cellular uptake in 3D tumor models. Overall, serum proteins appear to be a major element in drug design because they strongly influence the size and bioavailability of supramolecular drug aggregates and hence their efficacy in vitro and in vivo.

Lipid Bilayer Interactions of Peptidic Supramolecular Polymers and Their Impact on Membrane Permeability and Stability.

The synthesis and physicochemical characterization of supramolecular polymers with tunable assembly profiles offer exciting opportunities, involving the development of new biomedical carriers. Because synthetic nanocarriers aim to transport substances across or toward cellular membranes, we evaluated the interactions of amphiphilic peptide-based supramolecular polymers with lipid bilayers. Here, we focused on nanorod-like supramolecular polymers, obtained from two C3-symmetric dendritic peptide amphiphiles with alternating Phe/His sequences, equipped with a peripheral tetraethylene glycol dendron (C3-PH) or charged ethylenediamine end groups (C3-PH+). Triggered by pH changes, these amphiphiles assemble reversibly. Our results show that the supramolecular polymers have an impact on the lipid order in model membranes. Changes in the lipid order were observed depending on the charge state of the amphiphilic building blocks, as well as the chemical composition and physical properties of the bilayer. Furthermore, we further performed cell viability assays with the C3-PH+ and C3-PH supramolecular polymers. For C3-PH, the cell viability and extent of proliferation were decreased and the membrane permeability was enhanced, indicating a strong interaction of the polymer with cellular membranes. The results have implications for the design of novel pH-switchable supramolecular drug carriers and delivery vehicles that can respond to an altered microenvironment of tumorous or inflamed tissue.

Study progress of supramolecular drug delivery system loading traditional Chinese medicine/natural anti-tumor products

Ingredients with the anti-tumor property from traditional Chinese medicine/natural products have effects in treating tumor by regulating immune function, inhibiting tumor cell growth, inducing apoptosis, and reversing multidrug resistance. However, the potential of clinical application was restricted by the low hydrophilicity, stability and bioavailability and the lack of targeting. The above problems can be solved through research and development of supramolecular chemistry based on the non-covalent interactions between molecules. The supramolecular macrocyclic host molecules are characterized by a special cavity structure, low toxicity, high stability and rich derivatives spot. The anti-tumor supramolecular drug delivery system loading traditional Chinese medicine/natural products were designed to solve the above problems. In this paper, different supramolecular macrocyclic molecules, including crown ethers, cyclodextrin, calixarene, cucurbituril and two new-type supramolecular macrocyclic hosts were introduced. Their inclusion in enhancing drug solubility and stability, targeting drug delivery, synergies, combinative administration and new-type therapies in different applications, as well as such drug load modes as supramolecular polymers, indirect combination drug mode and polyrotaxanes were also reviewed in this paper, in order to provide a new idea for effective drug utilization.

The pH-responsive calix[4]resorcinarene-mPEG conjugates bearing acylhydrazone bonds: Synthesis and study of the potential as supramolecular drug delivery systems

The synthesis of new conjugates of calix[4]resorcinarenes and methoxy-PEG via acylhydrazone bonds and their study in the formation of pH-sensitive low-toxic supramolecular drug delivery systems have described. The syntheses have been performed on the base of two calix[4]resorcinarenes in chair and boat conformations to obtain the dendrimer-like and amphiphilic conjugates, respectively. The structures of the conjugates have been confirmed by 1H, 13C NMR, and FT-IR spectroscopy, Maldi-TOF mass spectroscopy, and SLS method. The self-association of both amphiphilic and dendrimer-like conjugates has been found (NMR FT-PGSE, fluorimetry, DLS and TEM methods). The hydrolysis of the conjugates at pH 5.5 (proved by 1H NMR and FT-IR spectroscopy, DLS method) lead to the improved release of the conjugate-encapsulated Dox. The low hemolytic activity and low cytotoxicity against Chang liver cells of the conjugates and products of their hydrolysis have been demonstrated. Meanwhile, the improved cytotoxicity and photodynamic activity of conjugates-encapsulated drugs (Dox and Methylene Blue, respectively) has been found in vitro. The results have indicated the potential using of the calix[4]resorcinarene-mPEG conjugates bearing acylhydrazone bonds as supramolecular drug delivery systems.

Suger-coated pillararenes for drug delivery applications

Supramolecular drug delivery systems (SDDSs) provide a useful platform for smart and functional drug carriers owing to their high selectivity towards various guest molecules and stimulus-responsive properties. Pillar[n]arenes represent a new generation of macrocyclic hosts with unique structures and chemical properties. In recent times pillar[n]arenes have attracted considerable attention as ideal scaffolds for the construction of SDDSs. Since sugar functionalized pillar[n]arenes have good water solubility and excellent biocompatibility, they have been widely applied in supramolecular systems construction, such as nanoparticles, vesicles, and gels by non-covalent interactions, so as to meet the requirements of their applications in biomedicine. These SDDSs present good responsiveness, not only realizing targeted delivery and controllable release of drugs, but also improving drug solubility and reducing its toxic and side effects. Here, according to the different structure of the assembly, the SDDSs constructed by the sugar functionalized pillar[n]arenes are summarized, and the development prospect of the system is prospected.