Polypseudorotaxanes constructed from pillar[5]arenes and polyamides by interfacial polymerization.

Polypseudorotaxanes constructed from pillar[5]arene rings and polyamide chains were successfully synthesized by interfacial polymerization between diamines and dicarbonyl chlorides in the presence of pillar[5]arene. The dicarbonyl chloride length and the assocation constants of dicarbonyl chloride-pillar[5]arene complexes were important factors in producing polypseudorotaxanes with high cover ratio of pillar[5]arene rings.

Polypseudorotaxane and polydopamine linkage-based hyaluronic acid hydrogel network with a single syringe injection for sustained drug delivery.

Polypseudorotaxane structure and polydopamine bond-based crosslinked hyaluronic acid (HA) hydrogels including donepezil-loaded microspheres were developed for subcutaneous injection. Both dopamine and polyethylene glycol (PEG) were covalently bonded to the HA polymer for catechol polymerization and inclusion complexation with alpha-cyclodextrin (α-CD), respectively. A PEG chain of HA-dopamine-PEG (HD-PEG) conjugate was threaded with α-CD to make a polypseudorotaxane structure and its pH was adjusted to 8.5 for dopamine polymerization. Poly(lactic-co-glycolic acid) (PLGA)/donepezil microsphere (PDM) was embedded into the HD-PEG network for its sustained release. The HD-PEG/α-CD/PDM 8.5 hydrogel system exhibited an immediate gelation pattern, injectability through single syringe, self-healing ability, and shear-thinning behavior. Donepezil was released from the HD-PEG/α-CD/PDM 8.5 hydrogel in a sustained pattern. Following subcutaneous injection, the weight of excised HD-PEG/α-CD/PDM 8.5 hydrogel was higher than the other groups on day 14. These findings support the clinical feasibility of the HD-PEG/α-CD/PDM 8.5 hydrogel for subcutaneous injection.

Antibiotic Cross-linked Micelles with Reduced Toxicity for Multidrug-Resistant Bacterial Sepsis Treatment.

One potential approach to address the rising threat of antibiotic resistance is through novel formulations of established drugs. We designed antibiotic cross-linked micelles (ABC-micelles) by cross-linking the Pluronic F127 block copolymers with an antibiotic itself, via a novel one-pot synthesis in aqueous solution. ABC-micelles enhanced antibiotic encapsulation while also reducing systemic toxicity in mice. Using colistin, a hydrophilic, potent ″last-resort" antibiotic, ABC-micelle encapsulation yield was 80%, with good storage stability. ABC-micelles exhibited an improved safety profile, with a maximum tolerated dose of over 100 mg/kg colistin in mice, at least 16 times higher than the free drug. Colistin-induced nephrotoxicity and neurotoxicity were reduced in ABC-micelles by 10-50-fold. Despite reduced toxicity, ABC-micelles preserved bactericidal activity, and the clinically relevant combination of colistin and rifampicin (co-loaded in the micelles) showed a synergistic antimicrobial effect against antibiotic-resistant strains of Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. In a mouse model of sepsis, colistin ABC-micelles showed equivalent efficacy as free colistin but with a substantially higher therapeutic index. Microscopic single-cell imaging of bacteria revealed that ABC-micelles could kill bacteria in a more rapid manner with distinct cell membrane disruption, possibly reflecting a different antimicrobial mechanism from free colistin. This work shows the potential of drug cross-linked micelles as a new class of biomaterials formed from existing antibiotics and represents a new and generalized approach for formulating amine-containing drugs.

Local Riluzole Release from a Thermosensitive Hydrogel Rescues Injured Motoneurons through Nerve Root Stumps in a Brachial Plexus Injury Rat Model.

The C5-C6 nerve roots are usually spared from avulsion after brachial plexus injury (BPI) and can thus be used as donors for nerve repair. A BPI rat model with C5-C6 nerve root stumps has been established in our previous work. The aim of this study was to test whether riluzole loaded into a thermosensitive hydrogel could applied locally in the nerve root stumps of this BPI rat model, thus increasing the reparative effect of the nerve root stumps. Nile red (a hydrophobic dye) was used as a substitute for riluzole since riluzole itself does not emit light. Nile red, loaded into a thermosensitive hydrogel, was added to the nerve root stumps of the BPI rat model. Additionally, eighteen rats, with operation on right brachial plexus, were evenly divided into three groups: control (Con), thermosensitive hydrogel (Gel) and thermosensitive hydrogel loaded with riluzole (Gel + Ri) groups. Direct nerve repair was performed after local riluzole release for two weeks. Functional and electrophysiological evaluations and histological assessments were used to evaluate the reparative effect 8 weeks after nerve repair. Nile red was slowly released from the thermosensitive hydrogel and retrograde transport through the nerve root stumps to the motoneurons, according to immunofluorescence. Discernible functional recovery began earlier in the Gel + Ri group. The compound muscle action potential, ChAT-expressing motoneurons, positivity for neurofilaments and S100, diameter of regenerating axons, myelin sheath thickness and density of myelinated fibers were markedly increased in the Gel + Ri group compared with the Con and Gel groups. Our results indicate that the local administration of riluzole could undergo retrograde transportation through C5-C6 nerve root stumps, thereby promoting neuroprotection and increasing nerve regeneration.

Mechanistic understanding of salt-induced drug encapsulation in nanosuspension via acid-base neutralization as a nanonization platform technology to enhance dissolution rate of pH-dependent poorly water-soluble drugs.

An acid-base neutralization technique has generated interest for the ability to achieve an enhanced dissolution of pH-dependent weakly basic or acidic poorly water-soluble drugs. However, the underlying nanonization mechanism, following acid-base neutralization, requires further elucidation. We hypothesized that the nanosuspensions (NSPs) via nanonization of drug particles could be attributed to the "salt-induced effect" and surfactant-driven micellization after acid-base neutralization. Rebamipide (RBM) and valsartan (VAL) were chosen as model drugs owing to poor water solubility and pH-dependent aqueous solubility. The drug NSP was rapidly obtained via salt formation (NaCl) after neutralization of the drug in basic NaOH solution and poloxamer 407 (POX 407) in acidic HCl solution. The NSP surrounded by NaCl salt was further stabilized by POX 407. The resulting NaCl salt modulated the critical micelle aggregation of POX 407, stabilizing the drug-loaded NSP in a cage of salt and micellar surfactant. In non-assisted homogenization, size analysis indicated the relationship between salt concentration and size reduction. Fourier transform infrared (FTIR) spectra revealed that the existence of hydrogen bonding between the drug and surfactant after neutralization, attributed to NSP size reduction. Changes in drug crystallinity to the nano-amorphous state were confirmed by powder X-ray diffraction (PXRD). Overall, the salt-induced drug NSP synergistically enhanced the dissolution rate, narrowing a gap between drug dissolution profiles in different pH environments.

Long-Chain Alkyl Epoxides and Glycidyl Ethers: An Underrated Class of Monomers.

Long-chain epoxides and specifically alkyl glycidyl ethers represent a class of highly hydrophobic monomers for anionic ring-opening polymerization (AROP), resulting in apolar aliphatic polyethers. In contrast, poly(ethylene glycol) is known for its high solubility in water. The combination of hydrophobic and hydrophilic monomers in block and statistical copolymerization reactions enables the synthesis of amphiphilic polyethers for a wide range of purposes, utilizing micellar interactions in aqueous solutions, e.g., viscosity enhancement of aqueous solutions, formation of supramolecular hydrogels, or for polymeric surfactants. Controlled polymerization of these highly hydrophobic long-chain epoxide monomers via different synthesis strategies, AROP, monomer-activated anionic ring-opening polymerization, catalytic polymerization, or via postmodification, enables precise control of the hydrophilic/lipophilic balance. This renders amphiphilic polymers highly interesting candidates for specialized applications, e.g., as co-surfactants in microemulsion systems. Amphiphilic polyethers based on propylene oxide and ethylene oxide, such as poloxamers are already utilized in many established applications due to the high biocompatibility of the polyether backbone. Long alkyl chain epoxides add an interesting perspective to this area and permit structural tailoring. This review gives an overview of the recent developments regarding the synthesis of amphiphilic polyethers bearing long alkyl chains and their applications.

Performance and toxicity of different absorption enhancers used in the preparation of Poloxamer thermosensitive in situ gels for ketamine nasal administration.

The purpose of this study was to investigate the nasal absorption rate and nasal mucosal toxicity of thermosensitive ketamine in situ gels containing various absorption enhancers. The optimal composition ratio for the gel matrix was determined to be 17.2% Poloxamer 407 and 2% Poloxamer 188, as this combination resulted in solutions with a gelation point within the range found in the nasal cavity. Ketamine gels containing the tested enhancers, namely, ethylenediaminetetraacetic acid disodium salt, hydroxypropyl-ß-cyclodextrin, propylene glycol, or Tween-80, were compared with enhancer-free counterparts to determine the absorption of the drug, in vivo by measuring its plasma levels in rats and in vitro using a Franz diffusion cell. Moreover, the toxicity of each gel type was assessed by microscopic observation of the morphology of rat nasal mucosa as well as by determining the mobility of the mucosal cilia using an established toad model. The results showed that gels containing hydroxypropyl-ß-cyclodextrin could promote the absorption of ketamine without added toxicity compared to enhancer-free gels. Thus, we consider hydroxypropyl-ß-cyclodextrin as the most promising absorption enhancer for the nasal administration of ketamine using in situ gels.

Porphyrin-terminated nanoscale fluorescent polyrotaxane as a biodegradable drug carrier for anticancer research.

Drug delivery carriers hold tremendous promise for improving cancer treatment, and polyrotaxane (PR) has shown excellent drug-carrying properties. However, there have been some reports that, when used as a drug carrier, water-soluble PR is not easily labeled with organic fluorescent dyes. Herein, we synthesized a drug-loaded fluorescent porphyrin-terminated PR (PR-COOH) which can be used as a tracer material in drug and gene delivery. The structure, morphology and zeta potential of PR-COOH were characterized by nuclear magnetic resonance, high-resolution transmission electron microscopy and zeta potentiometry. In this research, cisplatin (CDDP) is used as a model drug. The zeta potential, drug encapsulation efficiency and drug release of CDDP-loaded PR (PR-COOH-Pt) were studied. Confocal laser scanning microscopy showed that PR-COOH could be internalized by HeLa and CT26 cells. The antitumor efficacy of PR-COOH-Pt was investigated in vitro by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and in vivo by a xenograft tumor model. The results showed that PR-COOH-Pt could significantly inhibit tumor growth; thus PR-COOH-Pt has a promising role in cancer therapy.

Mobility Tuning of Polyrotaxane Surfaces to Stimulate Myocyte Differentiation.

Polyrotaxanes, consisting of poly(ethylene glycol) and α-cyclodextrins, are mechanically interlocked supermolecules. The structure allows α-cyclodextrins to move along the polymer, referred to as molecular mobility. Here, polyrotaxane-based triblock copolymers, composed of polyrotaxanes with different degrees of methylation and poly(benzyl methacrylate) at both terminals, are coated on culture surfaces to fabricate dynamic biointerfaces for myocyte differentiation. The molecular mobility increases with the degree of methylation and the contact angle hysteresis of water droplets and air bubbles. When the mouse myoblast cell line C2C12 is cultured on methylated polyrotaxane surfaces, the expression levels of myogenesis-related genes, myogenin (Myog) and myosin heavy chain (Myhc) are altered by the degree of methylation. Polyrotaxane surfaces with intermediate degrees of methylation promote the highest expression levels among all the surfaces. The polyrotaxane surface provides an appropriate environment for myocyte differentiation by accurately adjusting the degrees of methylation.

Tumor- and mitochondria-targeted nanoparticles eradicate drug resistant lung cancer through mitochondrial pathway of apoptosis.

Chemotherapeutic drugs frequently encounter multidrug resistance. ATP from mitochondria helps overexpression of drug efflux pumps to induce multidrug resistance, so mitochondrial delivery as a means of "repurposing'' chemotherapeutic drugs currently used in the clinic appears to be a worthwhile strategy to pursue for the development of new anti-drug-resistant cancer agents. TPP-Pluronic F127-hyaluronic acid (HA) (TPH), with a mitochondria-targeting triphenylphosphine (TPP) head group, was first synthesized through ester bond formation. Paclitaxel (PTX)-loaded TPH (TPH/PTX) nanomicelles exhibited excellent physical properties and significantly inhibited A549/ADR cells. After TPH/PTX nanomicelles entered acidic lysosomes through macropinocytosis, the positively charged TP/PTX nanomicelles that resulted from degradation of HA by hyaluronidase (HAase) in acidic lysosomes were exposed and completed lysosomal escape at 12 h, finally localizing to mitochondria over a period of 24 h in A549/ADR cells. Subsequently, TPH/PTX caused mitochondrial outer membrane permeabilization (MOMP) by inhibiting antiapoptotic Bcl-2, leading to cytochrome C release and activation of caspase-3 and caspase-9. In an A549/ADR xenograft tumor model and a drug-resistant breast cancer-bearing mouse model with lung metastasis, TPH/PTX nanomicelles exhibited obvious tumor targeting and significant antitumor efficacy. This work presents the potential of a single, nontoxic nanoparticle (NP) platform for mitochondria-targeted delivery of therapeutics for diverse drug-resistant cancers.

Suspending Polyrotaxane Dissociation via Photo-Reversible Capping of Terminals.

Reversible covalent bonds yield polymeric materials with functional characteristics such as self-healing, shape memory, stress relaxation, and stimuli-responsiveness. Here, photo-reversibly cappable polyrotaxanes are designed and the on-off controlled dissociation of their supramolecular architectures is demonstrated. The polyrotaxanes are synthesized by capping dithiobenzoates at both terminals of polyethylene glycol threaded through multiple α-cyclodextrins. Since dethreading of the α-cyclodextrins is prevented by the dithiobenzoate stoppers, the supramolecular dissociation is induced by their photo-cleavage. Subsequently, the cleaved dithiobenzoates spontaneously re-cap the polyrotaxane terminals in darkness. Thus, the supramolecular dissociation can be modulated by photo-reversible capping of the dithiobenzoate stoppers. These polyrotaxanes with dithiobenzoate stoppers are promising functional materials for photo-controlling physical properties and structures.

Quality-by-Design Approach for Biological API Encapsulation into Polymersomes Using "Off-the-Shelf" Materials: a Study on L-Asparaginase.

Polymersomes are versatile nanostructures for protein delivery with hydrophilic core suitable for large biomolecule encapsulation and protective stable corona. Nonetheless, pharmaceutical products based on polymersomes are not available in the market, yet. Here, using commercially available copolymers, we investigated the encapsulation of the active pharmaceutical ingredient (API) L-asparaginase, an enzyme used to treat acute lymphoblastic leukemia, in polymersomes through a quality-by-design (QbD) approach. This allows for streamlining of processes required for improved bioavailability and pharmaceutical activity. Polymersomes were prepared by bottom-up (temperature switch) and top-down (film hydration) methods employing the diblock copolymers poly(ethylene oxide)-poly(lactic acid) (PEG45-PLA69, PEG114-PLA153, and PEG114-PLA180) and the triblock Pluronic® L-121 (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), PEG5-PPO68-PEG5). Quality Target Product Profile (QTPP), Critical Quality Attributes (CQAs), Critical Process Parameters (CPPs), and the risk assessment were discussed for the early phase of polymersome development. An Ishikawa diagram was elaborated focusing on analytical methods, raw materials, and processes for polymersome preparation and L-asparaginase encapsulation. PEG-PLA resulted in diluted polymersomes systems. Nonetheless, a much higher yield of Pluronic® L-121 polymersomes of 200 nm were produced by temperature switch, reaching 5% encapsulation efficiency. Based on these results, a risk estimation matrix was created for an initial risk assessment, which can help in the future development of other polymersome systems with biological APIs nanoencapsulated.

Safety and biocompatibility of injectable vaccine adjuvants composed of thermogelling block copolymer gels.

Injectable thermogelling polymers have been recently investigated as novel adjuvants and delivery systems for next generation vaccines. As research into natural and synthetic biocompatible polymers progresses, the safety and biocompatibility of these compounds is of paramount importance. We have developed cationic pentablock copolymer (PBC) vaccine adjuvants based on Pluronic F127, a thermogelling triblock copolymer that has been approved by the FDA for multiple applications, and methacrylated poly(diethyl amino)ethyl methacrylate outer blocks. These novel materials have been demonstrated to effectively create an antigen depot, minimally impact antigen stability, and enhance the immune response to antigens (i.e., adjuvanticity) in mice. In this work, we investigated the safety and biocompatibility of the parent triblock Pluronic gels and the cationic PBC gels in mice. Histological analysis showed no injection site reactions and no damage to the liver or kidneys was observed upon administering the block copolymer formulations. However, the subcutaneous injection of a thermogelling Pluronic solution induced increased levels of lipids in the blood, with no further deleterious effects observed from the addition of the cationic outer blocks. This hyperlipidemia resolved within 30 days after the administration of the Pluronic formulation. To mitigate this adverse effect, the vaccine adjuvant formulations were modified by adding poly(vinyl alcohol), which allowed gelation, while reducing the amount of Pluronic in the formulation. This modified formulation abrogated the observed hyperlipidemia and no adverse effects were observed in the serum through biomarker analysis or at the injection site (i.e., inflammation) in comparison to the responses induced by administration of saline or incomplete Freund's adjuvant. These studies provide a foundation to developing these gels as adjuvants for next generation vaccines. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1754-1762, 2019.

Reprogramming axial ligands facilitates the self-assembly of a platinum(iv) prodrug: overcoming drug resistance and safer in vivo delivery of cisplatin.

We herein reprogrammed axial ligands of platinum(iv) prodrugs, conferring the constructed prodrug entities with the ability to self-assemble in aqueous solution. Further cloaking of the PEG chain with Pluronic surfactant makes this nanoassembly (termed Pt(iv)-NP) suitable for systemic injection. Notably, Pt(iv)-NP significantly alleviated the toxicity of the parent cisplatin drug in vivo while preserving the pharmacological activity.

In situ formation of interpenetrating polymer network using sequential thermal and click crosslinking for enhanced retention of transplanted cells.

Injectable hydrogels, which are used as scaffolds in cell therapy, provide a minimally invasive strategy to enhance cell retention and survival at injection site. However, till now, slow in situ gelation, undesired mechanical properties, and weak cell adhesion characteristics of reported hydrogels, have led to improper results. Here, we developed an injectable fully-interpenetrated polymer network (f-IPN) by integration of Diels-Alder (DA) crosslinked network and thermosensitive injectable hydrogel. The proposed DA hydrogels were formed in a slow manner showing robust mechanical properties. Interpenetration of thermosensitive network into DA hydrogel accelerated in situ gel-formation and masked the slow reaction rate of DA crosslinking while keeping its unique features. Two networks were formed by simple syringe injection without the need of any initiator, catalyst, or double barrel syringe. The DA and f-IPN hydrogels showed comparable viscoelastic properties along with outstanding load-bearing and shape-recovery even under high levels of compression. The subcutaneous administration of cardiomyocytes-laden f-IPN hydrogel into nude mice revealed high cell retention and survival after two weeks. Additionally, the cardiomyocyte's identity of retained cells was confirmed by detection of human and cardiac-related markers. Our results indicate that the thermosensitive-covalent networks can open a new horizon within the injection-based cell therapy applications.

Novel in vitro dynamic metabolic system for predicting the human pharmacokinetics of tolbutamide.

Liver metabolism is commonly considered the major determinant in drug discovery and development. Many in vitro drug metabolic studies have been developed and applied to understand biotransformation. However, these methods have disadvantages, resulting in inconsistencies between in vivo and in vitro experiments. A major factor is that they are static systems that do not consider the transport process in the liver. Here we developed an in vitro dynamic metabolic system (Bio-PK metabolic system) to mimic the human pharmacokinetics of tolbutamide. Human liver microsomes (HLMs) encapsulated in a F127'-Acr-Bis hydrogel (FAB hydrogel) were placed in the incubation system. A microdialysis sampling technique was used to monitor the metabolic behavior of tolbutamide in hydrogels. The measured results in the system were used to fit the in vitro intrinsic clearance of tolbutamide with a mathematical model. Then, a PBPK model that integrated the corresponding in vitro intrinsic clearance was developed to verify the system. Compared to the traditional incubation method, reasonable PK profiles and the in vivo clearance of tolbutamide could be predicted by integrating the intrinsic clearance of tolbutamide obtained from the Bio-PK metabolic system into the PBPK model. The predicted maximum concentration (Cmax), area under the concentration-time curve (AUC), time to reach the maximum plasma concentration (Tmax) and in vivo clearance were consistent with the clinically observed data. This novel in vitro dynamic metabolic system can compensate for some limitations of traditional incubation methods; it may provide a new method for screening compounds and predicting pharmacokinetics in the early stages, supporting the development of compounds.

Surface Layer Modification of Poly(d,l-lactic- co-glycolic acid) Nanoparticles with Targeting Peptide: A Convenient Synthetic Route for Pluronic F127-Tuftsin Conjugate.

Nanoparticles consisting of biodegradable poly(d,l-lactic- co-glycolic acid) (PLGA) are promising carriers for drug molecules to improve the treatment of tuberculosis. Surface modifiers, such as Pluronic F127, are essential for biocompatibility and for the protection against particle aggregation. This study demonstrates a successful approach to conjugate Pluronic F127 coated PLGA nanoparticles with Tuftsin, which has been reported as a macrophage-targeting peptide. Transformation of Pluronic F127 hydroxyl groups-which have limited reactivity-into aldehyde groups provide a convenient way to bind aminooxy-peptide derivatives in a one-step reaction. We have also investigated that this change has no effect on the physicochemical properties of the nanoparticles. Our data showed that coating nanoparticles with Pluronic-Tuftsin conjugate markedly increased the internalization rate and the intracellular activity of the encapsulated drug candidate against Mycobacterium tuberculosis. By employing this approach, a large variety of peptide targeted PLGA nanoparticles can be designed for drug delivery.

Poloxamer 407-chitosan grafted thermoresponsive hydrogels achieve synchronous and sustained release of antigen and adjuvant from single-shot vaccines.

Sustained-release vaccine delivery systems may enhance the immunogenicity of subunit vaccines and reduce the need for multiple vaccinations. The aim of this study was to develop a thermoresponsive hydrogel using poloxamer 407-chitosan (CP) grafted copolymer as a delivery system for single-shot sustained-release vaccines. The CP copolymer was synthesized using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and N-hydroxysuccinimide chemistry. The CP copolymer was a free flowing solution at ambient temperature and transformed rapidly into a gel at body temperature. The hydrogels were loaded with vaccine antigen and adjuvants or the vaccine components were encapsulated in poly (lactic-co-glycolic acid) nanoparticles in order to ensure synchronous release. The CP hydrogels were stable for up to 18 days in vitro. Release of both nanoparticles and the individual components was complete, with release of the individual components being modulated by incorporation into nanoparticles. In vivo, a single dose of CP hydrogel vaccine induced strong, long lasting, cellular and humoral responses that could protect against the development of tumors in a murine melanoma model.

Enhancement of oral bioavailability of magnolol by encapsulation in mixed micelles containing pluronic F127 and L61.

OBJECTIVES: We aimed to prepare novel magnolol-loaded mixed micelles (MAG-M) by pluronic F127 and L61 to overcome the challenges of magnolol's poor solubility and then further improve its oral bioavailability. METHODS: Magnolol-loaded mixed micelles containing pluronic F127 and L61 were prepared by an organic solvent evaporation method. Physicochemical, transport experiment across Caco-2 cell monolayers and pharmacokinetic studies were performed to characterize MAG-M and to determine the final improvement of the oral bioavailability. KEY FINDINGS: The MAG-M solution was transparent and colourless with average size, polydispersity index and zeta potential of 228.0 ± 2.1 nm, 0.298 ± 0.012 and -0.89 ± 0.02 mV. The micelle solution has a higher EE% and DL% of 81.57 ± 1.49% and 27.58 ± 0.53%, respectively. TEM result showed that the morphology of MAG-M was homogeneous and spherical shape. The dilution stability of MAG-M was no significant change in particle size and entrapment efficiency. MAG was demonstrated a sustained-release behaviour after encapsulated in micelles. MAG permeability across a Caco-2 cell monolayer was enhanced, and the pharmacokinetics study of MAG-M showed a 2.83-fold increase in relative oral bioavailability compared with raw MAG. CONCLUSIONS: The mixed micelles containing pluronic F127 and L61 as drug delivery system provided a well strategy for resolving the poor solubility and bioavailability problems of MAG.

Redox-responsive F127-folate/F127-disulfide bond-d-α-tocopheryl polyethylene glycol 1000 succinate/P123 mixed micelles loaded with paclitaxel for the reversal of multidrug resistance in tumors.

INTRODUCTION: The development of nanodrug carriers utilizing tumor microenvironment has become a hotspot in reversing multidrug resistance (MDR). MATERIALS AND METHODS: This study synthesized a redox-sensitive copolymer, Pluronic F127-disulfide bond-d-α-tocopheryl polyethylene glycol 1000 succinate (FSST), through the connection of the reduction-sensitive disulfide bond between F127 and d-α-tocopheryl polyethylene glycol 1000 succinate. This polymer could induce the elevation of reactive oxygen species (ROS) levels, ultimately resulting in cytotoxicity. Moreover, the redox-responsive mixed micelles, F127-folate (FA)/FSST/P123 (FFSSTP), based on FSST, Pluronic F127-FA, and Pluronic P123, were prepared to load paclitaxel (PTX). RESULTS: The in vitro release study demonstrated that FFSSTP/PTX accelerated the PTX release through the breakage of disulfide bond in reductive environment. In cellular experiment, FFSSTP/PTX induced significant apoptosis in PTX-resistant MCF-7/PTX cells through inhibiting adenosine triphosphate (ATP)-binding cassette proteins from pumping out PTX by interfering with the mitochondrial function and ATP synthesis. Furthermore, FFSSTP/PTX induced apoptosis through elevating the intracellular levels of ROS. CONCLUSION: FFSSTP could become a potential carrier for the treatment of MDR tumors.