Hybrid Micelles Research Articles

Novel Delivery Systems of Raloxifene Hydrochloride for Improved Bioavailability and Therapeutic Efficacy: A Review

Raloxifene hydrochloride belongs to the selective estrogen receptor modulator category. Initially, US FDA approved its use for the prevention and treatment of osteoporosis in postmenopausal women. Later, raloxifene hydrochloride was also approved for the prevention of invasive breast carcinoma in post-menopausal women under the high-risk category. Despite its immense and diverse therapeutic potential, the oral bioavailability of raloxifene hydrochloride is only ~ 2%. The factors responsible for the poor bioavailability of raloxifene hydrochloride include its amphiphobic nature, para-glycoprotein pump-mediated efflux in the intestine, and high pre-systemic glucuronidation. In the past two decades, multiple novel delivery systems, viz. lipid-based nanocarriers, polymeric nanoparticles, polymer-lipid hybrid nanoparticles, micelles, and mixed micelles, have been developed to overcome its drawbacks. Moreover, inclusion complex, phospholipid complex, and solid dispersion have also been developed to improve its solubility and dissolution rate. Further, some research groups successfully explored non-peroral routes like nasal and transdermal for augmenting the raloxifene hydrochloride bioavailability and its therapeutic efficacy. Hence, the principal objective of this review paper is to critically analyze all the delivery systems developed for raloxifene hydrochloride with their advantages and limitations. In addition, a detailed discussion of the physicochemical and pharmacokinetic parameters of raloxifene hydrochloride has been included in this paper. An in-depth understanding of these parameters will assist formulation scientists in developing efficient delivery systems in the future. In conclusion, the literature review revealed that the nanoparticulate systems successfully augmented the raloxifene hydrochloride bioavailability and therapeutic efficacy in pre-clinical experiments. However, future clinical trials should be conducted to assess their safety and therapeutic efficacy for rapid preclinical to clinical translation.

Detecting Shape of Hybrid Polymer/Surfactant Micelles: Cryo-Transmission Electron Microscopy, Small-Angle Neutron Scattering and Dynamic Light Scattering Study

In-depth study of shape of hybrid micelles in the micellar solutions of anionic surfactant potassium oleate, containing hydrophobic polymer poly(4-vinylpyridine) (P4VP) was conducted via cryo-transmission electron microscopy (cryo-TEM), small-angle neutron scattering (SANS) and dynamic-light scattering of visible light (DLS). Direct visualization of the solutions with cryo-TEM evidenced the coexistence of polymer-free spherical micelles and branched rodlike hybrid micelles with mean length of 200 nm and radius of 2 nm, governed by contour length of solubilized P4VP and length of hydrophobic “tail” of potassium oleate, respectively. The formation of branches in the hybrid micelles was explained by attaching the thermodynamically unfavorable end-caps of micelles to their polymer-loaded cylindrical fragments. By SANS it was shown that the cylindrical local shape and the radius of the micelles are independent of the concentration of embedded P4VP. Relaxation processes in the solutions were investigated with DLS. Three relaxation modes were observed for hybrid micelles, similar to polymer-free wormlike micelles. Fast and medium relaxation modes were attributed to diffusion of entangled micellar chains and their segments, respectively. The slow mode was related to electrostatic repulsion between similarly charged hybrid micelles.

Magnetic hybrid micelles with controllable structures via interfacial instability-induced confined Co-assembly

Co-assembly of amphiphilic block copolymers (BCPs) and nanoparticles (NPs) is an encouraging route to produce shape-tunable functional hybrid micelles, which can integrate the excellent water stability of BCPs and the versatile functionalities of NPs. In this paper, we present an facile method to prepare magnetic hybrid micelles through confined co-assembly of polystyrene grafted Fe3O4@PS NPs and PS-b-poly(ethylene oxide) (PS-b-PEO) induced by interfacial instability of emulsion droplets. The morphology of hybrid micelles can be regulated by varying the surfactant concentration, weight fraction of Fe3O4 NPs, and block ratio of PS-b-PEO. The distribution of NPs inside the micelles is determined by the ratio (d/L) of the NP diameter (d) to the thickness of PS domain of the micelles (L). When 0.49 ≤ d/L < 0.76, the NPs locate within the cylindrical micelles. When d/L ≥ 0.76, the NPs selectively locate in the spherical micelles. More interestingly, the size-selective loading of NPs in the micelles can be achieved, even mixture of NPs different in size is applied. Moreover, these magnetic hybrid micelles show good biocompatibility and morphology-dependent magnetic resonance responsiveness, which may find potential applications in magnetic resonance imaging.

Hybrid copper-polyelectrolyte nanoaggregates obtained with smart block copolymers based on 4-[(hydroxyimino)aldehyde]butyl methacrylate (HIABMA) in water and acetonitrile

The AB multi-stimuli-responsive block copolymer pTEGMA-b-pHIABMA (TEGMA: tetra(ethyleneglycol) methyl ether methacrylate; HIABMA: 4-[(hydroxyimino)aldehyde]butyl methacrylate) comprises a hydrophilic and thermoresponsive PTEGMA block linked to the hydrophobic PHIABMA chain. The latter is endowed with slightly acidic oxime groups that potentially form complexes with metal ions. Here we investigate the formation of hybrid Cu(II)-polymer nanoaggregates both in water and in acetonitrile. Cu(II) ions are quantitatively and rapidly incorporated, in the presence of a base, into pre-formed polymeric core-shell micelles (30 nm diameter by DLS) in water up to 1:2 metal-to-ligand stoichiometry. The pKa of the polymer is decreased from ≅11.2 to 4.65 due to interaction with Cu(II) and the complex is shown to involve oximate ions. The thermoresponsivity of the polymeric micelles remains unchanged with Cu(II) complexation and allows an easy separation by flocculation of the hybrid complex. Moreover, nanoaggregates (D = 20 nm) form in acetonitrile from the fully solubilized copolymer interacting with Cu(OAc)2. The 1:2 Cu(II)/ligand stoichiometry is confirmed with the Job graphical method. Characterization of the hybrid micelles was carried out by UV–Vis spectrometry, DLS, TEM, STEM and SAXS. Quantitative release of Cu(II) in acidic conditions is demonstrated both in water and in acetonitrile. Full recovery of the free metal ions and of intact polymeric micelles is achieved through centrifugal filtration of the aqueous preparation, as a proof-of-concept for a recyclable system for metal uptake and release. Furthermore, Cu0 nanoparticles of 5–10 nm are obtained through reduction of Cu(II) within the micelles with ascorbic acid in aqueous solution.

Efficient Strategy to Synthesize Tunable pH-Responsive Hybrid Micelles Based on Iron Oxide and Gold Nanoparticles.

The preparation of multifunctional nanomaterials based on inorganic nanoparticles with organic materials has emerged as a promising strategy for the development of new nanomedicines for in vitro and in vivo biomedical applications. Here, we synthesized pH-responsive hybrid inorganic micelles by combining a novel pH-responsive amphiphilic molecule with hydrophobic payloads. This amphiphile was synthesized in a one-pot reaction and self-assembled readily into micelles under acidic pH conditions. In the presence of hydrophobic NP payloads such as AuNPs or IONPs, the amphiphile self-organized around them through hydrophobic interactions, resulting in the formation of colloidally stable hybrid micelles. The size of the hydrophobic NPs determined the pH-response of the inorganic hybrid micelles, which is tuned from pH 7 to 11 for our pH-responsive amphiphilic molecule. This achievement represents a novel approach for the synthesis of tunable pH-responsive hybrid micelles based on inorganic NPs for biomedical imaging, hyperthermia treatment, and also drug delivery nanosystems.

Umbrella‐Shaped Amphiphiles: Internal Alkylation of an Aromatic Micelle and Its Impact on Cavity Features

AbstractTo develop new hybrid micelles with alkyl/polyaromatic core–shell structures, we synthesized umbrella‐shaped amphiphiles bearing a bent anthracene dimer with a linear alkyl chain (i.e., octyl and hexadecyl groups). The amphiphiles quantitatively assemble into spherical micelles (~2–3 nm in core diameter), possessing an alkylated cavity surrounded by a polyaromatic framework, in water. The alkylation significantly enhances the stability of the micellar structures against dilution (up to 9 μM) and heat (up to &gt;120 °C). The highly condensed hexadecyl core of the hybrid micelle, as indicated by solvatochromic guest probes, displays increased uptake ability toward large alkylated metallodyes. Interestingly, efficient uptake of aromatic macrocycles (i.e., [n]cycloparaphenylenes) by the present micelle provides pseudorotaxane‐shaped host–guest composites with high emissivity (ΦF=up to 35 %). Internal multi‐alkylation of an aromatic micelle can thus successfully enhance its assembly stability/guest uptake functions.

Umbrella-Shaped Amphiphiles: Internal Alkylation of an Aromatic Micelle and Its Impact on Cavity Features.

To develop new hybrid micelles with alkyl/polyaromatic core-shell structures, we synthesized umbrella-shaped amphiphiles bearing a bent anthracene dimer with a linear alkyl chain (i.e., octyl and hexadecyl groups). The amphiphiles quantitatively assemble into spherical micelles (~2-3 nm in core diameter), possessing an alkylated cavity surrounded by a polyaromatic framework, in water. The alkylation significantly enhances the stability of the micellar structures against dilution (up to 9 μM) and heat (up to >120 °C). The highly condensed hexadecyl core of the hybrid micelle, as indicated by solvatochromic guest probes, displays increased uptake ability toward large alkylated metallodyes. Interestingly, efficient uptake of aromatic macrocycles (i.e., [n]cycloparaphenylenes) by the present micelle provides pseudorotaxane-shaped host-guest composites with high emissivity (ΦF=up to 35 %). Internal multi-alkylation of an aromatic micelle can thus successfully enhance its assembly stability/guest uptake functions.

Order–disorder–order mesophase transitions in self-assembled mesoporous alumina for enhanced CO2 adsorption

The addition of a hydrophobic micelle pore expander to self-assembling mesostructured hybrid materials enables access to new combinations with differently ordered mesophases and enhanced structural properties. Here we detail our investigations into the influence of 1,3,5-trimethylbenzene (TMB) on the self-assembly behaviors of an F127 Pluronic triblock copolymer with an aluminum oxide sol additive. By varying the chemical mixing sequence, the TMB-to-F127 mass ratio and the acid-to-metal molar ratio, we observe that TMB exhibits dual roles, functioning both as a hydrophobic swelling agent and as a low dielectric co-solvent. This induces a mesophase transition from an ordered p6mm lattice to a disordered state and subsequently back to the ordered p6mm phase. We propose a structure formation mechanism based on the DLVO theory to describe the thermodynamics and kinetic mobility of the hybrid micelles during the order-disorder and ensuing disorder-order mesophase transitions. The resulting ordered mesoporous alumina structures, with considerable pore sizes (up to 12 nm), high surface areas (up to 314 m2/g) and pore volumes (up to 0.74 cm3/g), organized pore geometry and variable inorganic wall thicknesses, have shown excellent CO2 adsorption capacities and are appealing for various applications, including stable high temperature catalyst supports, separation and sensing.

Harnessing the potential of fatty Acid-Surfactant-Based micellar gel for enhanced topical delivery of Apremilast in psoriasis treatment

Apremilast (APR) is a potent anti-psoriatic agent that inhibits the phosphodiesterase 4 enzyme. Due to the poor oral bioavailability and associated systemic side effects the clinical applicability of APR has been constrained. Nanotechnology-based carrier system presents a novel option to increase the efficacy of the topical treatment of APR. The current investigation deals with the development of fatty acid-surfactant conjugate-based hybrid mixed micellar gel (HMMG) for the topical delivery of APR. The developed micelles exhibited an average size of 83.59 ± 4.46 nm, PDI of 0.239 ± 0.047, % entrapment efficiency of ∼ 94.78 ± 3.98 %, with % practical drug loading of ∼11.37 ± 3.14 %. TEM analysis revealed the spherical shape of micelles. The hybrid micelles were further loaded in a carbopol®934P gel base for ease of application. Ex vivo permeation study revealed enhanced permeation and ∼ 38-fold higher retention in deeper layers of skin from a hybrid micellar gel. In vivo, assessment demonstrated augmented efficacy of APR-HMMG as compared to 0.1 % betamethasone valerate. Also, APR-HMMG showed no sign of irritation, suggesting superior safety as a topical application. Thus, the proposed formulation strategy represents a viable avenue for enhancing the therapeutic efficacy of various anti-psoriatic moieties.

Hybrid Polymer-Surfactant Wormlike Micelles for Concurrent Use for Oil Recovery and Drag Reduction.

We report on the effect of a hydrocarbon (n-dodecane) on the rheological properties and shapes of the hybrid wormlike micelles (WLMs) of a surfactant potassium oleate with an embedded polymer poly(4-vinylpyridine). With and without hydrocarbon solutions, the hybrid micelles exhibit the same values of viscosity at shear rates typical for hydraulic fracturing (HF) tests, as solutions of polymer-free WLMs. Therefore, similar to WLMs of surfactants, they could be applied as thickeners in HF fluids without breakers. At the same time, in the presence of n-dodecane, the hybrid micelles have much higher drag-reducing efficiency compared to microemulsions formed in polymer-free systems since they form "beads-on-string" structures according to results obtained using cryo-transmission electron microscopy (cryo-TEM), dynamic-light scattering (DLS), and small-angle X-ray scattering (SAXS). Consequently, they could also act as drag-reducing agents in the pipeline transport of recovered oil. Such a unique multi-functional additive to a fracturing fluid, which permits its concurrent use in oil production and oil transportation, has not been proposed before.

Targeted Delivery of Celastrol via Chondroitin Sulfate Derived Hybrid Micelles for Alleviating Symptoms in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is caused by an accumulation of excess fat in the liver leading to oxidative stress and liver cell injury, as well as overproduction of inflammatory cytokines. CD44 has been identified as a potential therapeutic target in the development of NAFLD to nonalcoholic steatohepatitis. Here, chondroitin sulfate (CS) is selected to construct a CD44-targeted delivery system for the treatment of NAFLD. Specifically, two CS-derived amphiphilic materials including CS conjugated with either 4-aminophenylboronic acid pinacol ester (CS-PBE) or phenformin (CS-PFM) were synthesized, respectively. The presence of PBE moieties on CS-PBE rendered the vehicle with enhanced loading capacity and scavenging potential against reactive oxygen species, while the presence of guanidine moieties on CS-PFM enhanced the internalization of vehicles in the differentiated hepatocytes. Next, celastrol (CLT) was encapsulated in the hybrid micelle to afford CS-Hybrid/CLT, which demonstrates sufficient stability, enhanced cellular uptake efficiencies in differentiated HepG2 cells, and therapeutic potential to alleviate lipid accumulation in differentiated HepG2 cells. In a high-fat-diet-induced NAFLD rat model, CS-Hybrid/CLT micelles demonstrated the capacity to dramatically decrease hepatic lipid accumulation and free fatty acid levels with greatly improved pathologic liver histology and downregulated hepatic inflammation levels. These results suggest that CS-based amphiphilic micelles may offer a promising strategy to effectively deliver therapeutic cargos to the liver for the treatment of NAFLD.

Betaine-Based and Polyguanidine-Inserted Zwitterionic Micelle as a Promising Platform to Conquer the Intestinal Mucosal Barrier.

Developing nanocarriers for oral drug delivery is often hampered by the dilemma of balancing mucus permeation and epithelium absorption, since huge differences in surface properties are required for sequentially overcoming these two processes. Inspired by mucus-penetrating viruses that universally possess a dense charge distribution with equal opposite charges on their surfaces, we rationally designed and constructed a poly(carboxybetaine)-based and polyguanidine-inserted cationic micelle platform (hybrid micelle) for oral drug delivery. The optimized hybrid micelle exhibited a great capacity for sequentially overcoming the mucus and villi barriers. It was demonstrated that a longer zwitterionic chain was favorable for mucus diffusion for hybrid micelles but not conducive to cellular uptake. In addition, the significantly enhanced internalization absorption of hybrid micelles was attributed to the synergistic effect of polyguanidine and proton-assisted amine acid transporter 1 (PAT1). Moreover, the retrograde pathway was mainly involved in the intracellular transport of hybrid micelles and transcytosis delivery. Furthermore, the prominent intestinal mucosa absorption in situ and in vivo liver distribution of the oral hybrid micelle were both detected. The results of this study indicated that the hybrid micelles were capable of conquering the intestinal mucosal barrier, having a great potential for oral application of drugs with poor oral bioavailability.

Relaxivity Enhancement of Hybrid Micelles via Modulation of Water Coordination Numbers for Magnetic Resonance Lymphography.

Considerable efforts have been made to develop nanoparticle-based magnetic resonance contrast agents (CAs) with high relaxivity. The prolonged rotational correlation time (τR) induced relaxivity enhancement is commonly recognized, while the effect of the water coordination numbers (q) on the relaxivity of nanoparticle-based CAs gets less attention. Herein, we first investigated the relationship between T1 relaxivity (r1) and q in manganese-based hybrid micellar CAs and proposed a strategy to enhance the relaxivity by increasing q. Hybrid micelles with different ratios of amphiphilic manganese complex (MnL) and DSPE-PEG2000 were prepared, whose q values were evaluated by Oxygen-17-NMR spectroscopy. Micelles with lower manganese doping density exhibit increased q and enhanced relaxivity, corroborating the conception. In vivo sentinel lymph node (SLN) imaging demonstrates that DSPE-PEG/MnL micelles could differentiate metastatic SLN from inflammatory LN. Our strategy makes it feasible for relaxivity enhancement by modulating q, providing new approaches for the structural design of high-performance hybrid micellar CAs.

Calcium phosphate hybrid micelles inhibit orthotopic bone metastasis from triple negative breast cancer by simultaneously killing cancer cells and reprogramming the microenvironment of bone resorption and immunosuppression.

Triple negative breast cancer (TNBC) is prone to develop drug resistance and metastasis. Bone is the most common distant metastasis site of breast cancer cell. Patients with bone metastasis from TNBC suffer from unbearable pain due to the growth of bone metastasis and bone destruction. Simultaneously blocking the growth of bone metastasis and reprogramming the microenvironment of bone resorption and immunosuppression is a promising strategy to treat bone metastasis from TNBC. Herein, we prepared a pH and redox responsive drug delivery system, named DZ@CPH, by encapsulating docetaxel (DTX) with hyaluronic acid-polylactic acid micelle then reinforcing with calcium phosphate and zoledronate for targeting to bone metastasis from TNBC. DZ@CPH reduced the activation of osteoclast and inhibited bone resorption by decreasing the expression of nuclear factor κB receptor ligand and increasing the expression of osteoprotegerin in drug-resistant bone metastasis tissue. At the same time, DZ@CPH inhibited the invasion of bone metastatic TNBC cells by regulating the apoptosis-related and invasion-related protein expression. It also increased the sensitivity of orthotopic drug-resistant bone metastasis to DTX by inhibiting the expression of P-glycoprotein, Bcl-2 and transforming growth factor-β in tissue of drug-resistant bone metastasis. Moreover, the ratio between M1 type macrophage to M2 type macrophage in bone metastasis tissue was increased by DZ@CPH. In a word, DZ@CPH blocked the growth of bone metastasis from drug-resistant TNBC through inducing the apoptosis of drug-resistant TNBC cells and reprogramming the microenvironment of bone resorption and immunosuppression. DZ@CPH has a great potential in clinical application for the treatment of bone metastasis from drug-resistant TNBC. STATEMENT OF SIGNIFICANCE: Triple negative breast cancer (TNBC) is prone to develop bone metastasis. Now bone metastasis is still an intractable disease. In this study, docetaxel and zoledronate co-loaded calcium phosphate hybrid micelles (DZ@CPH) were prepared. DZ@CPH reduced the activation of osteoclasts and inhibited bone resorption. At the same time, DZ@CPH inhibited the invasion of bone metastatic TNBC cells by regulating the expression of apoptosis and invasion related protein in bone metastasis tissue. Moreover, the ratio between M1 type macrophages to M2 type macrophages in bone metastases tissue was increased by DZ@CPH. In a word, DZ@CPH blocked vicious cycle between the growth of bone metastasis and bone resorption, which greatly improved the therapeutic effect on bone metastasis from drug-resistant TNBC.

Novel pH-responsive E-selectin targeting natural polysaccharides hybrid micelles for diabetic nephropathy

Diabetic nephropathy (DN) is an important complication of diabetes and is the main cause of end-stage renal disease. The pathogenesis of DN is complex, including glucose and lipid metabolism disorder, inflammation, and so on. Novel hybrid micelles loaded Puerarin (Pue) based on Angelica sinensis polysaccharides (ASP) and Astragalus polysaccharide (APS) were fabricated with pH-responsive ASP-hydrazone-ibuprofen (BF) materials (ASP-HZ-BF, SHB) and sialic acid (SA) modified APS-hydrazone-ibuprofen materials (SA/APS-HZ-BF, SPHB) by thin-film dispersion method. The SA in hybrid micelles can specifically bind to the E-selectin receptor which is highly expressed in inflammatory vascular endothelial cells. The loaded Pue could be accurately delivered to the inflammatory site of the kidney in response to the low pH microenvironment. Overall, this study provides a promising strategy for developing hybrid micelles based on natural polysaccharides for the treatment of diabetic nephropathy by inhibiting renal inflammatory reactions, and antioxidant stress.

Diblock versus block-random copolymer architecture effect on physical properties of Gd3+-based hybrid polyionic complexes

HypothesisRandom insertion of vinylphosphonic acid (VPA) units into a of PEG-PAA block copolymer improves the chemical stability and properties of hybrid nanoobjects obtained from the complexation of the copolymer with metal ions. ExperimentsBlock polymers based on poly(acrylic acid) (PAA) and poly(ethylene glycol) (PEG) are modified by random insertion of 0 to 100 % of phosphonic acid functions in PAA block by a RAFT polymerization process. These polymers are then used to form hybrid polyionic complexes (HPICs) by complexation with gadolinium or europium ions. The properties of the obtained assemblies are evaluated by magnetic relaxivity, fluorescence and light scattering measurements. FindingsThe insertion of VPA units within the PAA block increases the chemical stability of the hybrid micelles by maintaining their integrity even at low pH. This insertion also minimizes the exchange of ions between HPICs and the surrounding medium thanks to a strengthening of interactions toward lanthanide ions. When such systems are used as MRI contrast agents or luminescent probe, 50/50 AA/VPA composition appears to be a good compromise to achieve optimal relaxivity or luminescent properties while ensuring a good chemical stability.

Ferroptosis and Pyroptosis Co‐Activated Nanomodulator for “Cold” Tumor Immunotherapy and Lung Metastasis Inhibition

AbstractImmune checkpoint blockade (ICB) therapy is an emerging strategy for cancer immunotherapy; however, the actual effects of ICB therapy are greatly limited by the immunosuppressive tumor microenvironment (TME, i.e., “cold” tumors). Although engineered nanomaterials display significant importance to regulate TME in cancer treatment, most of them focus on “immunosilent” apoptotic processes that cannot elicit sufficient immune responses for further immunotherapy. Herein, a GSH‐responsive nanomodulator is reported that can reverse the immunosuppressive TME for “cold” tumor immunotherapy and lung metastasis inhibition through simultaneous ferroptosis and pyroptosis induction. The nanomodulator is constructed by loading FDA‐approved sulfasalazine (SAS) and doxorubicin (DOX) on disulfide‐doped organosilica hybrid micelles, where SAS and DOX are released through the GSH‐stimulated rupture of micelles to induce ferroptosis and pyroptosis, respectively, promoting dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) elevation through massive tumor‐associated antigen release. In vivo experimental results verify that desirable tumor destruction of the nanomodulator at low concentrations is achieved. More importantly, combination of this nanomodulator and programed death ligand‐1 antibodies significantly inhibits primary tumors and distant lung metastases as a result of elevated mature DCs and CTLs. This strategy to modulate immunosuppressive TME by nanomodulator‐induced non‐apoptotic death provides a new promising paradigm for ICB therapy.

Unveiling the Transformation from Aggregation‐Caused Quenching to Encapsulation‐Induced Emission Enhancement for Improving the Photoluminescence Properties and Detection Performance of Conjugated Polymer Material in Multiple States

AbstractHigh hydrophobicity of π‐extended conjugated polymers (CPs) adversely affects their photoluminescence quantum yield (PLQY) in water and hydrogel/solid state via an unsolicited aggregation‐caused quenching (ACQ) process which ultimately hampers their sensing and imaging performance. Herein, an efficient strategy is presented to suppress and transform such ACQ process into an encapsulation‐induced emission enhancement (EIEE) effect through facile preparation of CP/Pluronic F‐127 fluorescent hybrid micelles and hydrogel. As a proof‐of‐concept, successful encapsulation of polyfluorene derivative PF‐DBT‐Im into F‐127 micelles not only displays an improved PLQY (≈200% increment) in water/hydrogel state but also delivers unique and augmented sensing responses toward the emerging pollutants tetracyclines taken as model analyte, validating the superiority of EIEE‐active hybrid micellar systems over ACQ suffering PF‐DBT‐Im aggregates. The established method not only provides a facile solution to circumvent ACQ problem existing in low water dispersible CPs but also endorses an enhanced, simplified sensing system for visual and on‐site detection of analytes with likely futuristic applications in biomedicine and solid‐state optoelectronics.

Tuning the Endocytosis of Hybrid Micelles through Spatial Regulation of Cationic Groups.

The ability of nanocarriers to enter tumor cells can be enhanced by positive surface charge. Nonetheless, the relationship between the spatial distributions of cationic groups and the endocytosis and tumor penetration of nanocarriers remains largely elusive. Here, using quaternary ammonium salt (QAS) as a model cationic group, a series of hybrid micelles (HMs) bearing QAS with different spatial distributions were prepared from star-shaped polymers with well-defined molecular architectures. The structural characteristics of HM, such as spatial location of QAS and local poly(ethylene glycol) (PEG) density near QAS, were investigated by both experimental techniques and dissipative particle dynamics (DPD) simulation. We show that the drug carriers with QAS extending to the micellar outer space allows QAS to facilitate cell surface binding with minimized hindrance, resulting in greatly enhanced endocytosis compared with nanocarriers with QAS attached onto the micellar surface or shielded by a PEG corona. This study offers cues for future development of tumor-penetrating drug delivery systems.

Hybrid Micelles of Carbon Quantum Dot-Doxorubicin Conjugates as Nanotheranostics for Tumor Therapy and Turn-On Fluorescence Imaging: Impact of Conjugated Structures and On-Off-On Mechanism.

Carbon quantum dots (CDs) have attracted more and more attention in the field of biological imaging, while their applications are restricted due to their nonspecific fluorescence and small particle size. Herein, two pH-responsive carbon quantum dot-doxorubicin (DOX) conjugates were designed with maleic acid (MA, cis-butenedioic acid) and fumaric acid (FA, trans-butenedioic acid) as linker, respectively, which could self-assemble into unique hybrid micelles as tumor-specific carrier-free nanotheranostics. Owing to the acid-labile covalent modification with conjugated groups and the interaction with the surrounding DOX molecules, the fluorescence of CDs was completely quenched, while it could be recovered in the tumor intracellular microenvironment by acid-triggered cleavage of the fluorophore-drug conjugates, showing excellent turn-on fluorescence for effective cellular imaging. Especially, the trans conjugate with FA as linker possessed higher drug content, better drug release behavior and stronger inhibition of tumor cells than the cis one with MA as linker, demonstrating its promising potential as carrier-free nanotheranostics for future tumor treatment.