Supramolecular Polymer Micelles Research Articles

Chiral-Selective Antigen-Presentation by Supramolecular Chiral Polymer Micelles.

Chirality is ubiquitous in biological systems, which is closely related to biological functions, life processes, and even the pathogenesis of diseases. However, the interface between the chirality of synthetic materials and organisms, particularly the immune system, remains poorly understood. Here, supramolecular chiral polymer micelles (SCPMs) are prepared by complexing antigenic proteins with chiral amino acid-modified polyethyleneimine. The introduction of chirality not only reduces the toxicity of cationic polymer, but also benefits cell uptake and antigen presentation. Especially, D-chirality presents the lowest cytotoxicity, while promoting the highest expression level of costimulatory molecules on dendritic cells compared to L-chirality and achirality. The superiority of D-chirality to stimulate dendritic cell maturation is supported by immunization with D-SCPMs, which achieves significant antigen-specific proliferation of T cells in the spleen, lymph nodes, and tumor of mice. Chirality-mediated antigen processing and presentation are demonstrated by D-SCPMs self-assembled from chiral alkaline histidine or neutral phenylalanine modified polyethyleneimine and tumor associated ovalbumin or severe acute respiratory syndrome coronavirus 2 spike 1 antigenic protein. Immunoactivation enabled by D-chirality opens a window to prepare potent nanotherapeutics for disease prevention and treatment.

Hydrogen Bond-Mediated Supramolecular Polymeric Nanomedicine with pH/Light-Responsive Methotrexate Release and Synergistic Chemo-/Photothermal Therapy.

Complete cancer cure and healing are still difficult, owing to its complexity and heterogeneity. Integration of supramolecular forces, for example, hydrogen bonds (H-bonds), to anti-cancer nanomedicine affords new scaffolds for biomedical material decoration, featuring the advantages of dynamic property and easier processability. Here, we target the construction of H-bond-mediated supramolecular polymer micelles, loaded with a chemotherapeutic drug along with a photothermal agent for synergistic chemo-/photothermal therapies (CT/PTT). To do so, we design and synthesize an amphiphilic ABA-type triblock copolymer, bearing H-bonding moiety (barbiturate, Ba) within the middle hydrophobic B block. The presence of pendant Ba moieties within the hydrophobic core promotes the loading capability of methotrexate (MTX) and transportation stability, benefitting from the formation of specific Ba/MTX H-bonding interactions. IR780, a photothermal agent, concomitantly encapsulated via hydrophobic interactions, facilitates the development of a synergistic CT/PTT modalities, where MTX can be released on demand owing to the dissociation of Ba/MTX H-bonding interactions induced by elevated temperature. Such H-bonding nanomedicine possesses enhanced drug loading capacity and transport performance and can also trigger stimuli-responsive drug release in the tumor zone. We believe that H-bonded nanomedicines provide a fine toolbox that is conducive to attaining biomedical requirements with remarkable values in theranostics that are highly promising in clinical applications.

Hydrogen-bonded supramolecular polymer micelles with pH/photothermal-responsive carmofur release and combined chemo-photothermal therapy

This work targets the construction of hydrogen-bonded (H-bonded) supramolecular polymeric micelles loaded with chemotherapy drugs (carmofur) and photothermal agents (IR780) for combined chemo-photothermal therapies (CT/PTT).

Biodegradable supramolecular micelles via host-guest interaction of cyclodextrin-terminated polypeptides and adamantane-terminated polycaprolactones.

Biodegradable supramolecular micelles were prepared exploiting the host-guest interaction of cyclodextrin and adamantane. Cyclodextrin-initiated polypeptides acted as the hydrophilic corona, whereas adamantane-terminated polycaprolactones served as the hydrophobic core.

Bio-Guided Isolation of Acetogenins from Annona cherimola Deciduous Leaves: Production of Nanocarriers to Boost the Bioavailability Properties.

Annonaceous acetogenins (ACGs) are lipophilic polyketides isolated exclusively from Annonaceae. They are considered to be amongst the most potent antitumor compounds. Nevertheless, their applications are limited by their poor solubility. The isolation of ACGs from Annona cherimola leaves, an agricultural waste, has not been reported to date. Molvizarin (1) cherimolin-1 (2), motrilin (3), annonacin (4) and annonisin (5) are isolated for the first time from A. cherimola deciduous leaves. Annonacin was found to be four- and two-times more potent in tumoral cells (HeLa, 23.6% live cells; IGROV-1, 40.8% live cells for 24 h) than in HEK-293 at 50 µM (24 h, 87.2% live cells). Supramolecular polymer micelles (SMPMs) were synthesized to encapsulate the major ACG isolated, annonacin, in order to improve its solubility in aqueous media. The bioavailability of this compound was increased by a factor of 13 in a simulated human digestive system when compared with free annonacin and an encapsulation efficiency of 35% was achieved. In addition, the cytotoxic activity of SMPMs that hosted annonacin (100 µM, 24 h, 5.8% live cells) was increased compared with free annonacin in water (100 µM, 24 h, 92% live cells). These results highlight the use of by-products of A. cherimola, and their pure compounds, as a promising source of anticancer agents. The use of SMPMs as nanocarriers of ACGs could be an alternative for their application in food field as nutraceutical to enhance the administration and efficacy.

Provitamin supramolecular polymer micelle with pH responsiveness to control release, bioavailability enhancement and potentiation of cytotoxic efficacy.

Encapsulation techniques to generate core/shell systems provide a method that improves physicochemical properties, which are very important in biological applications. β-carotene is a common carotenoid that has shown preventive effects in skin diseases and vitamin A deficiency but this compound has limited water solubility and bioavailability, which hinder its broad application. The use of polyrotaxane compounds formed from cyclodextrins has allowed supramolecular polymer micelles (SMPMs) to be synthesized to encapsulate β-carotene. The polymeric compound Pluronic F127® was also used to create core/shell nanoparticles (NPs) that contain β-carotene. Bioactive compound encapsulation was fully confirmed by nuclear magnetic resonance spectroscopy and by scanning and transmission electron microscopy. The method based on cyclodextrin and lecithin allow to release slowly when the systems were exposed to an aqueous medium by pH control, with an increase of 16 times of bioavailability comparing with free carotenoid. This allowed to potentiate the cytotoxic activity on a melanoma cell line by enhancing the water solubility to more than 28 mg/L, and present promising applications of SMPMs to provitamins.

Supramolecular Amphiphilic Polymer-Based Micelles with Seven-Armed Polyoxazoline Coating for Drug Delivery

Supramolecular polymer micelles composed of seven-armed poly(2-methy-2-oxazoline) as the coating and linear poly(dl-lactide) as the core were prepared through synthesizing β-cyclodextrin-terminated poly(2-methy-2-oxazoline) and adamantine-terminated linear poly(dl-lactide), followed by host-guest interaction between β-cyclodextrin and adamantine groups in two polymers and self-assembly in aqueous solution. Dynamic light-scattering measurement showed that the micelles based on supramolecular amphiphilic polymers have the size of 119 nm and were highly stable in salt solution. When the micelles were used as the carrier of cabazitaxel, an antitumor agent for drug-resistant cancers, satisfactory drug loading content and encapsulation efficacy were obtained. In vitro cellular cytotoxicity assays found that cabazitaxel-loaded micelles presented obvious cytotoxicity against taxane-sensitive and -resistant cancer cells. Further in vivo antitumor activity evaluation showed that cabazitaxel-loaded micelles have significantly superior efficacy in inhibiting tumor growth and prolonging survival in tumor-bearing mice compared to that of free paclitaxel and free cabazitaxel.

Supramolecular polymer micelles as universal tools for constructing high-performance fluorescent nanoparticles

This study is the first attempt to encapsulate fluorescent rhodamine 6G (R6G) into supramolecular micelles as a means of manipulating the fluorescence color and quantum efficiency of R6G, and provides a quick and simple route towards the fabrication of high-efficiency fluorescent nanoparticles for next-generation lighting devices and biomedical image applications. We demonstrate that these R6G-loaded micelles exhibit a uniform size distribution, tunable R6G loading capacity and a rapid R6G release rate, in combination with excellent thermal sensitivity due to dissociation of the dynamic hydrogen bonds at environmental temperatures above the lower critical solution temperature. Importantly, R6G-loaded micelles act as an effective chromophore to greatly improve the fluorescence-color stability of R6G in aqueous solution and provide a maximum quantum yield of 0.75, which is more than two times higher than that of the equivalent concentration of free R6G; these features are highly desirable yet extremely rare in conventional polymer carriers and low-molecular-weight surfactant systems.

Synthesis of 6‐O‐Poly(ϵ‐caprolactone)‐L‐ascorbic Acid and its Controlled Release from Supramolecular Polymer Micelles

Lipophilic 6-O-poly (ϵ-caprolactone)-L-ascorbic acid (AA-6-PCL) is synthesized through ROP of ϵ-caprolactone (CL). The number of repeating CL units in the polymer chain varies from 6 to 19. AA-6-PCL loaded supramolecular polymer micelles (SMPMs) are constructed with β-cyclodextrin (β-CD) and PCL as blocks. Transmission electron microscopy images show a nanospheric morphology of the micelles with a size range of 43.3 ± 5.0 nm. The drug loading contents are 22.53-39.23% for AA-6-PCL. AA-6-PCL exhibits high radical scavenging capacity (93.96-96.73%) and efficient scavenging potency, and a cytotoxicity study proves the excellent cytocompatibility of AA-6-PCL loaded β-CD/PCL SMPMs, which altogether herald their potential application in the study of the induced pluripotent stem cells.

Host–guest chemistry of cyclodextrin carbamates and cellulose derivatives in aqueous solution

Supramolecular polymer micelles were prepared on basis of the inclusion complexation between cyclodextrin carbamates and cellulose derivatives in aqueous media. Cyclodextrin carbamates were synthesized by microwave-assisted method from cyclodextrin and urea. The urea modified cyclodextrin shows the higher yield than the physical mixture of urea/cyclodextrin in the micellization with cellulose derivatives. The supramolecular structure of the core–shell micelles was demonstrated by 1H NMR spectra, TEM images, and fluorescence spectra. The drug release behavior of the supramolecular polymer micelles was evaluated using prednisone acetate as a model drug. The drug loaded micelles showed steady and long time drug release behavior. With these properties, the supramolecular polymer micelles are attractive as drug carriers for pharmaceutical applications.

Biopolymer-based supramolecular micelles from β-cyclodextrin and methylcellulose

Supramolecular polymer micelles (SMPMs) were constructed from natural and natural-derived polymers: β-cyclodextrin (β-CD)/maleic anhydride modified β-cyclodextrin (MAh-β-CD) and methylcellulose (MC) in aqueous solution by one-pot self-assembly procedure, in which, β-CD and MAh-β-CD inclusion complexes were used as the hydrophilic shell and the free MC as the core. The shapes of the SMPMs were regular spheres with diameters of 25±5nm. The critical micelle concentrations, calculated from steady-state fluorescence emission spectra, were around 15.13 and 20.89mg/L for MC/β-CD and MC/MAh-β-CD SMPMs, respectively. The in vitro drug release behaviors of the micelles were studied using prednisone acetate as a model drug, and the results showed that the MC/MAh-β-CD micelle had a drug-enrichment core and excellent drug released behaviors with a sustaining release time of 700h.

Supramolecular polymer micelles self-assembled from α-cyclodextrin and PLLA–PCL based copolymers

Accumulation of macrophages and neutrophil granulocytes in the lung are key events in the inflammatory response to inhaled particles. The present study aims at the time course of chemotaxis in vitro in response to the challenge of various biopersistent particles and its functional relation to the transcription of inflammatory mediators.NR8383 rat alveolar macrophages were challenged with particles of coarse quartz, barium sulfate, and nanosized silica for one, four, and 16 h and with coarse and nanosized titanium dioxide particles (rutile and anatase) for 16 h only. The cell supernatants were used to investigate the chemotaxis of unexposed NR8383 macrophages. The transcription of inflammatory mediators in cells exposed to quartz, silica, and barium sulfate was analyzed by quantitative real-time PCR.Challenge with quartz, silica, and rutile particles induced significant chemotaxis of unexposed NR8383 macrophages. Chemotaxis caused by quartz and silica was accompanied by an elevated transcription of CCL3, CCL4, CXCL1, CXCL3, and TNFα. Quartz exposure showed an earlier onset of both effects compared to the nanosized silica. The strength of this response roughly paralleled the cytotoxic effects. Barium sulfate and anatase did not induce chemotaxis and barium sulfate as well caused no elevated transcription.In conclusion, NR8383 macrophages respond to the challenge with inflammatory particles with the release of chemotactic compounds that act on unexposed macrophages. The kinetics of the response differs between the various particles.

Highly Efficient Drug Delivery Nanosystem via L‐Phenylalanine Triggering Based on Supramolecular Polymer Micelles

An intelligent drug delivery nanosystem has been developed based on biodegradable supramolecular polymer micelles (SMPMs). The drug release can be triggered from SMPMs responsively by a bioactive agent, L-phenylalanine in a controlled fashion. The SMPMs are constructed from ethylcellulose-graft-poly(ε-caprolactone) (EC-g-PCL) and α-cyclodextrin (α-CD) derivate via host-guest and hydrophobic interactions. It has been found that these SMPMs have disassembled rapidly in response to an additional L-phenylalanine, due to great affinity discrepancy to α-CD between L-phenylalanine and PCL. Experiments have been carried out on trigger-controlled in vitro drug release of the SMPMs loaded with a model porphyrin based photosensitizer THPP. The result shows that the SMPMs released over 85% THPP in 6 h, which is two orders magnitudes faster than that of control. Also investigated is the photodynamic therapy (PDT) of THPP-loaded SMPMs with and without L-phenylalanine on MCF-7 carcinoma cell line. An effective trigger-concentration dependent lethal effect has been found showing promise in clinical photodynamic therapy.

Supramolecular polymer micelles prepared by steric effect tuned self-assembly: a new strategy for self-assembly

Low molecular weight poly(e-caprolactone) (PCL) and α-cyclodextrin (α-CD) favor forming crystallized peseudopolyrotaxanes in most of solvents, which impedes their biomedical application. This work provides an example of site-specific polymer functionalization of PCL to control the hierachical assembly with CDs to form novel supramolecular polymer micelles (SMPMs). The unique design of functional PCL includes the introduction of anticancer drug doxorubicin (Dox) with a larger molecular volume as the steric group into the backbone of PCL to realize the partial inclusion complex of PCL with α-CD. This inclusion complex can then self assemble into SMPMs with an average size of around 20 nm in aqueous solution due to the hydrophobic–hydrophilic interaction. The structure and morphology of the SMPMs were investigated and revealed by comprehensive characterizations including 1HNMR, XRD and TEM, TGAetc., their controlled drug release and cell internalization behavior were also explored. The above proof of concept paves the way for a new strategy for self-assembly and overcomes the dispersion of pseudopolyrotaxanes, also, the micelles formed show great promise in biomedical applications, especially in controlled drug release.

A Facile One‐Pot Construction of Supramolecular Polymer Micelles from α‐Cyclodextrin and Poly(ε‐caprolactone)

A matter of control: A method has been developed for the construction of supramolecular polymer micelles (SMPMs) from α-cyclodextrin (α-CD) and poly(ε-caprolactone) (PCL) by controlling the intermolecular hydrogen bonds between CDs (see scheme). These micelles show great potential for use as drug carriers, templates for the synthesis of inorganic nanoparticles, and nanoreactors.