Supramolecular Micelles Research Articles

Assembly of 2′,3′-Cyclic guanosine Monophosphate-Adenosine monophosphate and their spontaneous intracellular disassembly for enhanced antitumor immunity via natural STING pathway activation

The stimulator of interferon genes (STING) pathway plays an important role in remodeling the immunosuppressive tumor microenvironment (TME). Cyclic dinucleotides (CDNs), the natural ligands of STING, activate innate immunity to enhance tumor immunogenicity. However, the anionic properties of CDNs result in poor membrane permeability, while their rapid metabolism by enzymes hinders the efficient targeting and activation of STING in vitro and in vivo. To improve the bioavailability and antitumor immunity of CDNs, we designed a hydrogen-bonding-based supramolecular approach for 2′,3′-cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP). Leveraging the synthetic molecules cytosine-uracil-hexane (CUH), we formulated supramolecular micelles of cGAMP via specific hydrogen bonds in aqueous solutions. Micelles comprising the CUH-cGAMP complex enhanced the biological efficacy of cGAMP by increasing its stability, thereby prolonging the activation of STING-mediated innate and adaptive immunity. We demonstrated that CUH-cGAMP stands as a promising candidate for immunotherapy, exhibiting significant inhibition of tumor growth in a CT26 syngeneic mouse model.

Dynamic Micelle-Hydrogels for 3D-Architected Transition Metal Sulfides.

Additive manufacturing of transition metal sulfides (TMS) enables the creation of complex 3D structures, significantly expanding their applications. However, preparing 3D-structured TMS remains challenging due to difficulties in developing suitable inks. In this study, a supramolecular micelle hydrogel as the ink to fabricate 3D-structured TMS is utilized. Initially, the hydrogels are printed and infused with metal salt solutions to stabilize the structures, which are then calcined to convert into miniaturized 3D-TMS replicas. The micellar hydrogels crosslink via hydrophobic interactions, with sodium dodecyl sulfonate (SDS) micelles providing both a hydrophobic environment and sulfur sources. During calcination, the decomposed sulfur precursors coordinate with metal ions to form various TMS, including FeS2, Cu2S, Ni3S2, and Co9S8, along with several metal sulfides like PbS and SnS. Additionally, the method also allows for the preparation of transition metal dichalcogenides such as MoS2 and WS2. The formation mechanism is demonstrated using Ni3S2 as an example which exhibits notable catalytic activity in oxygen evolution reactions (OER) and hydrogen evolution reactions (HER). Given its simplicity and versatility, this dynamic micellar hydrogel-derived strategy offers a promising pathway for creating advanced TMS materials.

Reactive oxygen species-responsive supramolecular deucravacitinib self-assembly polymer micelles alleviate psoriatic skin inflammation by reducing mitochondrial oxidative stress.

The new topical formula is urgent needed to meet clinical needs for majority mild patients with psoriasis. Deucravacitinib exerts outstanding anti-psoriatic capacity as an oral TYK2 inhibitor; however, single therapy is insufficient to target the complicated psoriatic skin, including excessive reactive oxygen species (ROS) and persistent inflammation. To address this need, engineered smart nano-therapeutics hold potential for the topical delivery of deucravacitinib. hydrophobic Deucravacitinib was loaded into polyethylene glycol block-polypropylene sulphide (PEG-b-PPS) for transdermal delivery in the treatment of psoriasis. The oxidative stress model of HaCaT psoriasis was established by TNF-α and IL-17A in vitro. JC-1 assay, DCFH-DA staining and mtDNA copy number were utilized to assess mitochondrial function. 0.75% Carbopol®934 was incorporated into SPMs to produce hydrogels and Rhb was labeled to monitor penetration by Immunofluorescence. In vivo, we established IMQ-induced psoriatic model to evaluate therapeutic effect of Car@Deu@PEPS. Deu@PEPS exerted anti-psoriatic effects by restoring mitochondrial DNA copy number and mitochondrial membrane potential in HaCaT. In vivo, Car@Deu@PEPS supramolecular micelle hydrogels had longer retention time in the dermis in the IMQ-induced ROS microenvironment. Topical application of Car@Deu@PEPS significantly restored the normal epidermal architecture of psoriatic skin with abrogation of splenomegaly in the IMQ-induced psoriatic dermatitis model. Car@Deu@PEPS inhibited STAT3 signaling cascade with a corresponding decrease in the levels of the differentiation and proliferative markers Keratin 17 and Cyclin D1, respectively. Meanwhile, Car@Deu@PEPS alleviated IMQ-induced ROS generation and subsequent NLRP3 inflammasome-mediated pyroptosis. Deu@PEPS exerts prominent anti-inflammatory and anti-oxidative effects, which may offers a more patient-acceptable therapy with fewer adverse effects compared with oral deucravacitinib.

Ordered mesoporous nanofibers mimicking vascular bundles for lithium metal batteries.

Hierarchical self-assembly with long-range order above centimeters widely exists in nature. Mimicking similar structures to promote reaction kinetics of electrochemical energy devices is of immense interest, yet remains challenging. Here, we report a bottom-up self-assembly approach to constructing ordered mesoporous nanofibers with a structure resembling vascular bundles via electrospinning. The synthesis involves self-assembling polystyrene (PS) homopolymer, amphiphilic diblock copolymer, and precursors into supramolecular micelles. Elongational dynamics of viscoelastic micelle solution together with fast solvent evaporation during electrospinning cause simultaneous close packing and uniaxial stretching of micelles, consequently producing polymer nanofibers consisting of oriented micelles. The method is versatile for the fabrication of large-scale ordered mesoporous nanofibers with adjustable pore diameter and various compositions such as carbon, SiO2, TiO2 and WO3. The aligned longitudinal mesopores connected side-by-side by tiny pores offer highly exposed active sites and expedite electron/ion transport. The assembled electrodes deliver outstanding performance for lithium metal batteries.

β-cyclodextrin-based supramolecular micelles of diosgenin conjugated with anti-CD64 antibody for rheumatoid arthritis

Supramolecular polymeric micelles from β-CD offer superior targeted-nano-delivery for efficacious therapy with optimal size, shape, encapsulation efficiency with evasion of RES, enzymatic degradation and high blood circulation time. Rheumatoid arthritis is an autoimmune disease characterized by inflammation of the synovium joint causing restriction in the movement of the joint along with swelling, pain, progressively leading to disability, and early death. This encompasses the fabrication of supramolecular polymeric micelles loaded with diosgenin and conjugated to anti-CD64 antibody for targeted action to the inflamed synovium in arthritis. The diosgenin-loaded supramolecular micelles exhibited particle size of 318.7±27.36 nm, good micellar stability with a zeta potential of -13.1±6.94 mV and encapsulation efficiency of 92.45% with controlled release of 86.58±1.51% drug for 24 h. The anti-arthritic activity was confirmed via pharmacodynamic study using Wistar rats, wherein significant reduction in paw diameter following 14-day treatment was observed from 6.47 mm to 4.59 mm. Furthermore, interleukin IL-15(6.88 pg/mL) and tumor necrosis factor-α (10.81 pg/mL) levels in rat serum were analyzed using ELISA and found to be near the normal range. Thus, DSMs propose to be superior effective alternative treatment carrier for arthritis management with high specificity, upregulation of COX-2, downregulation of ILs, NO, TNF- α and various inflammatory markers.

Validation of an MD simulation approach for electrical field responsive micelles and their application in drug delivery

In the current work, a new type of micelle is designed that has active connectivity in respond to exterior stimulus and the desired water solubility. Two end-ornamented homopolymers, polystyrene-beta-cyclodextrin (PS-β-CD) and polyethylene oxide-ferrocene (PE-FE), can aggregate as a supramolecular micelle (PS-β-CD/PE-FE) by the guest–host interactions. Our results showed that the Lennard–Jones and hydrophobic interactions are the main powerful forces for the micelle formation process. It was found that the electrical field plays a role as a driving force in the reversible assembly-disassembly of the micellar system. Moreover, for the first time, we examined the PS-β-CD/PE-FE micelle interaction as a drug delivery system with anastrozole (ANS) and mitomycin C (MIC) anti-cancer drugs. The investigation of the total energy between PS-β-CD/PE-FE micelle and drugs predicts the drug adsorption process as favorable (Etotal = − 638.67 and − 259.80 kJ/mol for the Micelle@ANS and Micelle@MIC complexes, respectively). Our results offer a deep understanding of the micelle formation process, the electrical field-respond, and drug adsorption behaviors of the micelle. This simulation study has been accomplished by employing classical molecular dynamics calculation.

Novel biotin-linked amphiphilic calix[4]arene-based supramolecular micelles as doxorubicin carriers for boosted anticancer activity.

Supramolecular carrier-mediated chemotherapy is a highly attractive strategy for targeted drug delivery. In this study, four novel biotin-linked calix[4]arenes BPCA1-BPCA4 have been rationally designed to construct nano-complex with doxorubicin. The in vitro and in vivo assessments reveal that BPCA4-DOX with excellent stability are capable of affording significantly superior anti-tumor activity and lower side effects.

Functional supramolecular micelles driven by the amphiphilic complex of biotin-acyclic cucurbituril and cannabidiol for cell-targeted drug delivery

Precise delivery of hydrophobic drugs has always been a great challenge for drug delivery systems. To overcome this problem, we designed and synthesized a novel supramolecular host biotin-acyclic cucurbituril (ACBB) at the first time, and we have developed a host–guest amphiphilic complex based on ACBB and amantadine-conjugated cannabinoids (AD-CBD) that self-assembles to form functionalized supramolecular micelles (FSMs) for cell-targeted drug delivery. The 1:1 stoichiometric ratio of the amphiphilic complex and its possible host–guest inclusion behaviors are obtained by fluorescence titration, nuclear magnetic resonance (NMR), Fourier transform-infrared spectroscopy (FT-IR) and thermal analysis (TGA and DSC). Using transmission electron microscope (TEM) and dynamic light scattering (DLS), we have observed that the shape of FSMs was spherical and size was 137–192 nm. In addition, MTT test results show that FSMs have good antitumor activity, taking MCF-7 as an example, the in vitro half-maximal inhibitory concentration (IC50) values of FSMs were 1.53 μM and 5.02 μM, which were better than 30.83 μM of cisplatin. Confocal laser scanning microscopy (CLSM) results showed that FSMs loaded with Rhodamine B can specifically aggregate on the surface of tumor cells and the targeting ability has been directly verified. Flow cytometry results showed that FSMs could promote tumor cell apoptosis. All results indicated that FSMs had high bioavailability, stability, accurate targeting and excellent delivery efficiency, which had great application potential in the field of drug delivery.

Tunable Size of Hierarchically Porous Alumina Ceramics Based on DIW 3D Printing Supramolecular Gel.

A new three-dimensional (3D) printing gel is developed to construct hierarchically porous ceramics with adjustable millimeter-, micrometer-, and nanometer-scale size for application in thermal management. Not only does the gel based on supramolecular micelles exhibit excellent DIW 3D printability but also the supramolecular micelles act as templates that can precisely control the structure of micrometer-scale pores. The effect of millimeter- and μmicrometer-scale size on properties of porous ceramics is investigated in detail. The 3D-printed ceramic foam with millimeter-scale pores and smaller micrometer-scale pores shows better thermal insulation and lower compressive strength. For the thermal insulation, the local temperature of a chip exposed to contact heat is only 34.2 °C in the presence of a printed foam cap with a pore size of 41.5 μm, while the local temperature is 54.8 °C in the absence of the printed foam cap. The study provides a new method to construct hierarchically porous alumina ceramics with precisely tunable size, avoiding the issues of subtractive manufacturing and opening up new applications in portable devices or consumer electronics.

Verteporfin-loaded supramolecular micelles for enhanced cisplatin-based chemotherapy via autophagy inhibition.

Cisplatin (CDDP) is one of the most successful chemotherapeutic agents for cancer therapy. However, CDDP can activate pro-survival autophagy, which inhibits the therapeutic efficacy of CDDP. Herein, autophagy inhibitor verteporfin (VTPF) is integrated into CDDP-conjugated micelles to address this issue. The CDDP-conjugated micelles are prepared by host-guest interaction of zwitterionic poly(2-(methacryloyloxy)ethyl phosphorylcholine)-co-poly(2-(methacryloyloxy)ethyl adamantane-1-carboxylate) (P(MPC-co-MAd)) and CDDP conjugated β-cyclodextrin (CD-CDDP). VTPF is then physically encapsulated into the supramolecular micelles by hydrophobic interaction. Due to the zwitterionic corona of the supramolecular micelles, the micelles are stable in different media. CDDP and VTPF could be released in a reductive environment. CDDP-activated autophagy could be inhibited by VTPF, which is fully characterized by western blot, fluorescence imaging, and transmission electron microscopy (TEM). Moreover, the outstanding therapeutic efficacy of CDDP and VTPF co-loaded micelles is validated both in vitro and in vivo. This research not only provides a new strategy to fabricate CDDP delivery systems by supramolecular self-assembly, but also presents an innovative way to enhance cisplatin-based chemotherapy via autophagy inhibition.

One-Pot Synthesis of Oxidation-Sensitive Supramolecular Gels and Vesicles.

Polypeptide-based nanoparticles offer unique advantages from a nanomedicine perspective such as biocompatibility, biodegradability, and stimuli-responsive properties to (patho)physiological conditions. Conventionally, self-assembled polypeptide nanostructures are prepared by first synthesizing their constituent amphiphilic polypeptides followed by postpolymerization self-assembly. Herein, we describe the one-pot synthesis of oxidation-sensitive supramolecular micelles and vesicles. This was achieved by polymerization-induced self-assembly (PISA) of the N-carboxyanhydride (NCA) precursor of methionine using poly(ethylene oxide) as a stabilizing and hydrophilic block in dimethyl sulfoxide (DMSO). By adjusting the hydrophobic block length and concentration, we obtained a range of morphologies from spherical to wormlike micelles, to vesicles. Remarkably, the secondary structure of polypeptides greatly influenced the final morphology of the assemblies. Surprisingly, wormlike micellar morphologies were obtained for a wide range of methionine block lengths and solid contents, with spherical micelles restricted to very short hydrophobic lengths. Wormlike micelles further assembled into oxidation-sensitive, self-standing gels in the reaction pot. Both vesicles and wormlike micelles obtained using this method demonstrated to degrade under controlled oxidant conditions, which would expand their biomedical applications such as in sustained drug release or as cellular scaffolds in tissue engineering.

A Smart Core-Crosslinked Supramolecular Drug Delivery System (SDDS) Enabled by Pendant Cyclodextrins Encapsulation of Drug Dimers via Host-Guest Interaction.

Owing to poor aqueous solubility and low delivery efficiency, most of anti-cancer chemodrugs depend on various smart drug delivery platforms to enhance the treatment efficacy. Herein, a stimuli-responsive supramolecular drug delivery system (SDDS) is developed based on polymeric cyclodextrins (PCD) which crosslinked by stimuli-cleavable drug dimers via host-guest interaction. PEGylated PCD was precisely controlled synthesized by ring-opening polymerization and azide-alkyne click chemistry, and two doxorubicins (DOX) were linked with a disulfide bond to form a drug dimer (ss-DOX). They then co-assembled into supramolecular micelles. Drug dimers were utilized as cross-linkers to stabilize the micelles. The drug loading efficiency was very high that could be up to 98%. The size and morphology were measured by DLS and TEM. Owing to the disulfide bonds of drug dimers, these supramolecular micelles were dissociated by treating with dithiothreitol (DTT). In the meanwhile, the free DOXs were recovered and released from cavities of cyclodextrins because of dynamic equilibrium and hydrophilicity changes. The release profile was studied under mimic physiological conditions. Furthermore, in vitro cytotoxicity study showed excellent anti-cancer efficacy of reduced-responsive supramolecular polymeric micelles. Therefore, it can be served as a safe and stimuli-responsive SDDS for cancer therapy.

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.

Mercury-containing supramolecular micelles with highly sensitive pH-responsiveness for selective cancer therapy

Construction and manipulation of metal-based supramolecular polymers—which are based on a combination of nucleobase hydrogen bonding interactions and functional metal ions—to obtain the desired physicochemical properties and achieve the efficacy and safety required for biomedical applications remain extremely challenging. We successfully designed and synthesized a new mercury-based supramolecular polymer, Hg-BU-PPG, containing an oligomeric polypropylene glycol backbone and pH-sensitive uracil-mercury-uracil (U-Hg-U) linkages. This multifunctional metallo-supramolecular material spontaneously self-organizes into nanosized spherical micelles in aqueous solution. The micelles possess several attractive properties, including desired long-term structural stability in serum-rich conditions, unique fluorescence behavior and highly sensitive, well-controlled pH-responsiveness. Interestingly, Hg-BU-PPG micelles exhibited strong, selective cytotoxic effects towards cancer cells in vitro, without harming normal cells. The highly selective cytotoxicity can be attributed to rapid dissociation of the U-Hg-U complexes within the micelles in the mildly acidic intracellular pH of cancer cells, followed by release of inherently toxic mercury ions. Importantly, fluorescence microscopy and flow cytometry clearly demonstrated that Hg-BU-PPG selectively entered the cancer cells via endocytosis and rapidly promoted massive apoptotic cell death. In contrast, internalization of Hg-BU-PPG by normal cells was limited, resulting in high biocompatibility and no cytotoxic effects. Thus, this newly discovered ‘cytotoxicity-concealing’ supramolecular system could represent a viable route to enhance the safety and efficacy of cancer therapy and bioimaging via a strategy that does not require incorporation of anticancer drugs and fluorescent probes. Statement of significanceWe report a significant breakthrough in the construction of mercury-containing supramolecular polymers, namely the creation of multifunctional micelles with unique chemical and physical properties conferred by pH-sensitive uracil-mercury-uracil (U-Hg-U) linkages and tunable structural and dynamical features due to the presence of hydrogen-bonded uracil moieties. Importantly, in vitro experiments clearly demonstrated that introduction of the U-Hg-U complexes into the micelles not only improved the efficiency of selective uptake via endocytosis into cancer cells, but also accelerated the induction of massive apoptotic cell death. Thus, this work provides crucial new insight for the development of metallo-supramolecular polymeric micelles that may substantially enhance the safety and efficacy of cancer therapy and bioimaging without requiring incorporation of anticancer drugs or fluorescent probes.

One-pot fabrication of dual-redox sensitive, stabilized supramolecular nanocontainers for potential programmable drug release using a multifunctional cyclodextrin unit

Facile engineering of β-cyclodextrin (β-CD)-based supramolecular nanocontainers with simultaneous enhanced extracellular stability and efficient intracellular biosignals-triggered destabilization generally suffers from multistep synthesis and tedious purification process, thus remains a significant challenge for the scale-up production and clinical translation of β-CD-based supramolecular nanomedicine. To address these issues, we reported in this study a one-pot preparation of dual-redox sensitive, stabilized supramolecular nanocontainers for potential programmable drug release by self-crosslinking of a multifunctional β-CD unit that integrates a host cavity for oxidation-mediated reversible complexation with ferrocence (Fc) guest molecule and lipoic acids (LAs)-decorated primary and secondary faces for reversible in-situ crosslinking by the reducible disulfide links. The resulting doxorubicin (DOX)-loaded nanoparticles showed, on one hand, enhanced colloidal stability and high DOX loading capacity with a drug loading content (DLC) of approximately 11.3% due to the crosslinked structure, and on the other hand, a programmable destruction of the supramolecular micelles triggered by a simultaneous adoption of intracellular glutathione (GSH) and reactive oxygen species (ROS) toward a complete structural destruction for promoted drug release with enhanced therapeutic efficiency. Notably, an optimized DOX-loaded micelle formation, DOX@CL P1 showed greater cytotoxicity with an IC50 of 2.94 ± 0.25 μg/mL than free DOX (6.00 ± 0.56 μg/mL) in Bel-7402 cancer liver cells, but a significantly reduced side effect relative to free DOX in L02 normal liver cells. In vivo animal study in Bel-7402 tumor-bearing BALB/c mice further confirmed prolonger elimination half-life time, efficient tumor accumulation, enhanced therapeutic efficiency and compromised systemic toxicity of this micelle construct. Therefore the multifunctional CD unit developed in this study offers an extremely straightforward and robust strategy with respect to dual-redox responsive, stabilized supramolecular nanocontainers with potential programmable controlled release properties for clinical translations.

Photo-Responsive Supramolecular Micelles for Controlled Drug Release and Improved Chemotherapy.

Development of stimuli-responsive supramolecular micelles that enable high levels of well-controlled drug release in cancer cells remains a grand challenge. Here, we encapsulated the antitumor drug doxorubicin (DOX) and pro-photosensitizer 5-aminolevulinic acid (5-ALA) within adenine-functionalized supramolecular micelles (A-PPG), in order to achieve effective drug delivery combined with photo-chemotherapy. The resulting DOX/5-ALA-loaded micelles exhibited excellent light and pH-responsive behavior in aqueous solution and high drug-entrapment stability in serum-rich media. A short duration (1–2 min) of laser irradiation with visible light induced the dissociation of the DOX/5-ALA complexes within the micelles, which disrupted micellular stability and resulted in rapid, immediate release of the physically entrapped drug from the micelles. In addition, in vitro assays of cellular reactive oxygen species generation and cellular internalization confirmed the drug-loaded micelles exhibited significantly enhanced cellular uptake after visible light irradiation, and that the light-triggered disassembly of micellar structures rapidly increased the production of reactive oxygen species within the cells. Importantly, flow cytometric analysis demonstrated that laser irradiation of cancer cells incubated with DOX/5-ALA-loaded A-PPG micelles effectively induced apoptotic cell death via endocytosis. Thus, this newly developed supramolecular system may offer a potential route towards improving the efficacy of synergistic chemotherapeutic approaches for cancer.

Adenine‐Functionalized Supramolecular Micelles for Selective Cancer Chemotherapy

Adenine‐Functionalized Supramolecular Micelles for Selective Cancer Chemotherapy

Synthesis of cyclodextrin-derived star poly(N-vinylpyrrolidone)/poly(lactic-co-glycolide) supramolecular micelles via host-guest interaction for delivery of doxorubicin

Supramolecular micelles are of particular interest in cancer therapy, owing to their capability to enable the on-demand drug release in tumor microenvironments. Nano platforms of supramolecular micelles can be facilely achieved from β-cyclodextrin (β-CD) based polymers. Herein, we developed novel supramolecular micelles of β-CD-(PNVP)4-AD-PLGA produced from β-CD-grafted star poly(N-vinylpyrrolidone) (β-CD-(PNVP)4) and adamantine-terminated linear-poly(lactic-co-glycolide) (AD-PLGA) by host-guest interaction between β-cyclodextrin and adamantine groups. A model anticancer drug, doxorubicin (DOX) was loaded into the supramolecular micelles during self-assembly in aqueous solution. The dissociation of the supramolecular micelles was triggered by acidic environments, which led to the release of DOX more in pH 6.4 compared to pH 7.4. The in vitro toxicity of the drug loaded micelles revealed 87% of cytotoxicity after 72 h against glioblastoma (C6 cells) while β-CD-(PNVP)4-AD-PLGA was biocompatible to HEK 293 cells (non-cancerous). Furthermore, β-CD-(PNVP)4-AD-PLGA and β-CD-(PNVP)4-AD-PLGA/DOX were found to be hemocompatible and more suitable for Intravenous administration. Our results suggest that the developed micelle system can provide a promising robust and sustained anticancer drug delivery system for the future cancer treatment.

Adenine-Functionalized Supramolecular Micelles for Selective Cancer Chemotherapy.

Functional supramolecular micelles containing self-complementary multiple hydrogen bonding adenine groups (A-PPG) can spontaneously self-assemble into stable nanosized micelles in aqueous solution. These micelles can be used to selectively deliver anticancer drugs to cancer cells and effectively promote tumor cell death via apoptosis, without harming normal cells. The drug-loaded micelles exhibit tunable drug-loading capacity and rapid pH-triggered drug release under acidic conditions, as well as a high drug-entrapment stability in serum-rich media due to the reversible hydrogen-bonded adenine-adenine interactions within the micellar interior; these properties are critical to achieving effective chemotherapeutic drug delivery and controlled drug release. In vitro assays show that the drug-loaded micelles exert significant cytotoxic effects on cancer cells, with minimal effects on normal cells under physiological conditions. Cytotoxicity assays using A-PPG micelles loaded with different anticancer drugs confirm these effects. Importantly, cellular internalization and flow cytometric analyses demonstrate that the adenine moieties within A-PPG micelles significantly increase selective endocytic uptake of the supramolecular micelles by cancer cells, which in turn induce apoptotic cell death and substantially enhance the response to chemotherapy. Thus, A-PPG micelles can improve the safety and efficacy of cancer chemotherapy.

Photosensitive Supramolecular Micelle-Mediated Cellular Uptake of Anticancer Drugs Enhances the Efficiency of Chemotherapy.

The development of stimuli-responsive supramolecular micelles with high drug-loading contents that specifically induce significant levels of apoptosis in cancer cells remains challenging. Herein, we report photosensitive uracil-functionalized supramolecular micelles that spontaneously form via self-assembly in aqueous solution, exhibit sensitive photo-responsive behavior, and effectively encapsulate anticancer drugs at high drug-loading contents. Cellular uptake analysis and double-staining flow cytometric assays confirmed the presence of photo-dimerized uracil groups within the irradiated micelles remarkably enhanced endocytic uptake of the micelles by cancer cells and subsequently led to higher levels of apoptotic cell death, and thus improved the therapeutic effect in vitro. Thus, photo-dimerized uracil-functionalized supramolecular micelles may potentially represent an intelligent nanovehicle to improve the safety, efficacy, and applicability of cancer chemotherapy, and could also enable the development of nucleobase-based supramolecular micelles for multifunctional biomaterials and novel biomedical applications.