Amphiphilic Diblock Polymer Research Articles

Polyether fluorinated amphiphilic diblock polymer: Preparation, characterization and application as drug delivery agent

Amphiphilic polymers or polymeric surfactants forming nano micelles in water have been considered as suitable candidates for loading poor water solubility drugs as they are often featured as excellent bioavailability, biodegradation and entrapment ability. Therefore, in this paper we prepared a series of polyether MPEG-EPTF fluorinated diblock polymers (copolymer of poly(ethylene glycol) monomethyl ether and fluorinated epichlorohydrin) with different composition and molecular weight through living cationic polymerization. The critical micelle concentration (CMC) of these fluorinated polymers and the effect of structure on surface activity are researched in this paper. The particle sizes of nano micelles determined by transmission electron microscopy (TEM) are less than 100 nm, which can perfectly meet the size requirements of micelles used in human body. Besides, the fluorinated amphiphilic polymer can also be employed to load and carry baicalin so as to enhance its solubility in water, and the drug loading (DL) and entrapment efficiency (EE) of these nano systems are very outstanding, reaching to approximately 77.58% and 38.79% respectively. Cumulative release pattern in vitro tested by UV–vis had shown that little amounts baicalin (about 20%) are released over 60 h in vitro.

Development and validation of RP-HPLC method for quantification of repaglinide in mPEG-PCL polymeric nanoparticles: QbD-driven optimization, force degradation study, and assessment of in vitro release mathematic modeling

Repaglinide (REP) an insulinotropic agent used in the treatment of type-2 diabetes. It belongs to meglitinides, which act by blocking the ATP sensitive potassium channels and stimulates the insulin release. REP is the first insulin secretagogue used to target postprandial hyperglycemia. In this study, a rapid, sensitive, and reproducible RP-HPLC method has been developed and validated using an analytical quality-by-design approach. Initially, the Ishikawa fishbone diagram provides the basis of variation in critical analytical attributes with various inputs. Additionally, Taguchi design was selected to screen the critical method parameters affecting method development. Further, systemic optimization of the RP-HPLC method was determined by using Box-Behnken design. The chromatography separation was achieved by acetonitrile and phosphate buffer (60:40) with isocratic flow system on waters Nova-pack C18 column (3.9 × 150 mm, 4 μm) with 0.8 mL/min flow rate and the developed method was validated as per ICH guidelines. Moreover, the force degradation studies were also performed under different conditions (acidic, basic, oxidation and photolytic) to understand the degradation pathways and products. Furthermore, an amphiphilic di-block biodegradable polymer, i.e., polyethylene glycol-polycaprolactone (mPEG-PCL) was synthesized with different molecular weights to encapsulate REP and understand the release kinetics with mathematical modeling. In addition, the validated RP-HPLC method was effectively utilized to determine percent entrapment efficiency and loading efficiency of REP loaded nanoparticles. The developed method would also be applicable to quantify the REP from the biological matrix.

Polyarginine-Mediated siRNA Delivery: A Mechanistic Study of Intracellular Trafficking of PCL-R15/siRNA Nanoplexes.

As a cell-penetrating peptide, polyarginine is widely used in drug delivery systems based on its membrane permeation ability. Previously, we developed the mPEG-PLA-b-polyarginine(R15) triblock copolymer, which exhibited a high siRNA delivery efficiency both in vitro and in vivo. As a continued effort, here the amphiphilic diblock polymer PCL-R15 was synthesized as a simplified model to further elucidate the structure-activity relationship of arginine-based amphiphilic polymers as siRNA delivery systems, and the cellular trafficking mechanisms of the PCL-R15/siRNA nanoplexes were investigated to understand the interaction patterns between the nanoplexes and cells. Compared to the R15/siRNA complexes, the introduction of PCL moiety was found to result in the stronger interactions with cells and the enhanced transfection efficiency after the formation of condensed nanoplexes. Caveolae-mediated endocytosis and clathrin-mediated endocytosis were major routes for the internalization of PCL-R15/siRNA nanoplexes. The intracellular release of siRNA from nanoplexes was confirmed by fluorescence resonance energy transfer assay. It was also noticed that the internalized PCL-R15/siRNA nanoplexes were transported through digestive routes and trapped in lysosomes, which may be the bottleneck for efficient siRNA delivery of PCL-R15/siRNA nanoplexes. This study investigated the relationship between the polymer structure of PCL-R15 and the cellular interaction patterns, which may render implications on the rational design of polyarginine-based siRNA delivery systems.

ICG-Conjugated and 125 I-Labeled Polymeric Micelles with High Biosafety for Multimodality Imaging-Guided Photothermal Therapy of Tumors.

Noninvasive multimodality imaging-guided precision photothermal therapy (PTT) is proven to be an effective strategy for tumor theranostics by integrating diagnostics and therapeutics in one nanoplatform. In this study, indocyanine green (ICG)-conjugated and radionuclide iodine-125 (125 I)-labeled polymeric micelles (PEG-PTyr(125 I)-ICG PMs) are strategically prepared by the self-assembly of the ICG-decorated amphiphilic diblock polymer poly(ethylene glycol)-poly(l-tyrosine-125 I)-(indocyanine green) (PEG-PTyr(125 I)-ICG). The as-prepared polymeric micelles exhibit favorable biocompatibility, excellent size/photo/radiolabel stability, a high-photothermal conversion efficiency, a passive tumor-targeting ability, and a fluorescence (FL)/photoacoustic (PA)/single photon emission computed tomography (SPECT) imaging property. After tail intravenous injection, the polymeric micelles can efficiently accumulate at the tumor site and present comprehensive FL/PA/SPECT images with a high sensitivity, excellent spatial resolution, and unlimited tissue penetration under near-infrared (NIR) irradiation. Upon 808 nm laser irradiation, the subsequent precision PTT of tumors can be achieved with minimal cumulative side effects. Thus, this capable multifunctional nanoplatform with simple components and preparation procedures for FL/PA/SPECT multimodality imaging-guided PTT can be a potential candidate for clinical tumor theranostics.

Multistimuli-Responsive Emulsifiers Based on Two-Way Amphiphilic Diblock Polymers.

Diblock copolymers of poly(tert-butyl methacrylate) (PtBuMA) and poly(2-dimethylaminoethyl methacrylate) (PDMAEMA) of four different block lengths were prepared by sequential two-step reversible addition–fragmentation chain transfer radical polymerization, followed by hydrolysis of the PtBuMA blocks to obtain poly(methacrylic acid)-b-PDMAEMA (PMAA-b-PDMAEMA). The effect of the PDMAEMA block length on the multistimuli-responsive amphiphilic features of both types of diblock copolymers was investigated as CO2-switchable emulsifiers for emulsification/demulsification of n-octane (an oil) in water in response to CO2/N2 bubbling. The amphiphilicity of PtBuMA-b-PDMAEMA was switched on, and the amphiphilicity of PMAA-b-PDMAEMA was switched off by CO2 bubbling at pH 12 and 25 °C to achieve emulsification/demulsification. A longer PDMAEMA block length in PMAA-b-PDMAEMA conferred more sensitive CO2-responsive amphiphilicity but reduced the extent of recovery of emulsification ability on N2 bubbling. This newly developed diblock copolymer system could potentially serve as a “multifunctional surfactant” for CO2-switchable emulsification/demulsification of oil-in-water and water-in-oil mixtures.

Design and Biological Evaluation of Lipoprotein-Based Donepezil Nanocarrier for Enhanced Brain Uptake through Oral Delivery.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with memory and cognitive impairment. Donepezil is an acetylcholinesterase inhibitor used for the symptomatic treatment of AD. However, high dose of donepezil is prescribed to achieve effective concentration in the brain, which leads to significant side effects, gastrointestinal alterations, and hepatotoxicity. In the present study, ApoE3 conjugated polymeric nanoparticles derived from diblock copolymer methoxy poly(ethylene glycol)-polycaprolactone (mPEG-PCL) have been used to boost the delivery of donepezil to the brain. mPEG-PCL is an amphiphilic diblock polymer with a tendency to avoid nanoparticle uptake by phagocytic cells in the liver and can significantly reduce the gastric mucosal irritations. Moreover, ApoE3-based nanocarriers showed a promising ability to enhance brain uptake, binding to amyloid beta with high affinity and accelerating its clearance. Donepezil-loaded polymeric nanoparticles were performed by using a nanoprecipitation method and further surface modified with polysorbate 80 and ApoE3 to increase the brain bioavailability and reduce the dose. Optimization of various process parameters were performed using quality by design approach. ApoE3 polymeric nanoparticles were found to be stable in simulated gastric fluids and exhibited a sustained drug release pattern. Cellular uptake studies confirmed better neuronal uptake of the developed formulation, which is further corroborated with pharmacokinetic and biodistribution studies. Orally administered ApoE3 polymeric nanoparticles resulted in significantly higher brain donepezil levels after 24 h (84.97 ± 11.54 ng/mg tissue) as compared to the pure drug (not detected), suggesting a significant role of surface coating. Together, these findings are promising and offer preclinical evidence for better brain availability of donepezil by oral administration.

Diblock Polymer Brush (PHEAA- b-PFMA): Microphase Separation Behavior and Anti-Protein Adsorption Performance.

In this paper, a series of amphiphilic diblock polymers of poly(hydroxyethylacrylamide)- b-poly(1H,1H-pentafluoropropyl methacrylate) (PHEAA- b-PFMA) were grafted from silicon wafer via surface-initiated atom transfer radical polymerization (SI-ATRP). Surface wettability and chemical compositions of the modified surfaces were characterized by contact angle goniometer and X-ray photoelectron spectroscopy (XPS) respectively. Molecular weight and polydispersity of each block were measured using gel permeation chromatography (GPC). The topography and the microphase separation behavior of PHEAA- b-PFMA surfaces were investigated by atomic force microscope (AFM). The results show that only when the grafting density (σ) and thickness of PHEAA brush were in the range of 0.9-1.3 (chain/nm2) and 6.6-15.1 nm, respectively, and the ratio of PFMA/PHEAA varied from 89/42 to 89/94, could the diblock copolymer phase separate into nanostructures. Further, the antiprotein adsorption performance of the modified surfaces against BSA, fibrinogen, and lysozyme was studied. The results indicated the modified surfaces could reduce the protein adsorption compared to the pristine silicon wafer. For Fibrinogen, the antiadsorption effect of PHEAA- b-PFMA-modified surfaces with microphase segregation was better than that of corresponding PHEAA modified surfaces. The results provide further evidence that surface composition and microphase segregation of fluorinated moieties of block copolymer brushes significantly impact protein adsorption behaviors.

Tilianin-loaded Reactive Oxygen Species-Scavenging Nano-Micelles Protect H9c2 Cardiomyocyte Against Hypoxia/Reoxygenation-Induced Injury.

Previous studies have shown that tilianin alleviates ischemia-reperfusion-induced cardiomyocyte injury. However, its clinical translation has been hampered because of its insolubility in water. Tilianin-based nano-micelles that may overcome this critical issue are presented. A polyethylene glycol compound was covalently attached to propylene sulfide-formed amphiphilic diblock polymers. In the aqueous solution, tilianin is encapsulated in a hydrophobic shell to form nano-micelles. The Ph-PPS-PEG self-assembled into nanoscale micelles with a size of approximately 70 nm, termed "tilianin-loaded micelles" (TLMs). TLMs are highly efficient hydrogen peroxide scavengers and the activity of caspase-3 inhibition, thereby protecting cells from H/R-induced cytotoxicity. In addition, TLMs decreased levels of MDA, IL-1 and tumor necrosis factor (TNF-α), inhibited apoptosis, TLR4 and nuclear transcription factor (NF-κB p65) protein expression in hypoxia-reoxygenation (H/R) model. Taken together, the study suggests that TLMs may be of clinical value for the protective effects of cardiomyocytes by inhibiting Inflammation and oxidative stress during myocardial ischemia-reperfusion injury.

Amphiphilic poly-n-vinyl-2-pyrrolidone: Synthesis, properties, nanoparticles

Water-soluble amphiphilic polymers based on N-vinyl-2-pyrrolidone (Amph-PVP) have been synthesized. Amphiphilic diblock polymers have been obtained via a single-step technique. For the synthesized amphiphilic polymers, the critical concentrations of mycelium formation (CCM) have been determined. The structure of the polymers obtained was confirmed by IR and NMR spectroscopy. The critical concentration of micelle formation (CCM) for the synthesized polymers has been found to be in the micromolar range. The fluorescent dye 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (Dil) was chosen as a model substance for the synthesis of nanoparticles. Micellar particles were obtained via an ultrasonic technique followed by evaporation of the organic solvent (emulsion method).

Poly(glycerol) Used for Constructing Mixed Polymeric Micelles as T1 MRI Contrast Agent for Tumor-Targeted Imaging.

There was much interest in the development of nanoscale delivery vehicles based on polymeric micelles to realize the diagnostic and therapeutic applications in biomedicine. Here, with the purpose of constructing a micellar magnetic resonance imaging (MRI) contrast agent (CA) with well biocompatibility and targeting specificity, two types of amphiphilic diblock polymers, mPEG-PG(DOTA(Gd))-b-PCL and FA-PEG-b-PCL, were synthesized to form mixed micelles by coassembly. The nanostructure of the resulting micellar system consisted of poly(caprolactone) (PCL) as core and poly(glycerol) (PG) and poly(ethylene glycol) (PEG) as shell, simultaneously modified with DOTA(Gd) chelates and folic acid (FA), which afforded functions of MRI contrast enhancement and tumor targeting. The mixed micelles in aqueous solution presented a hydrodynamic diameter of about 85 nm. Additionally, this mixed micelles exhibited higher r1 relaxivity (14.01 mM-1 S1-) compared with commercial Magnevist (3.95 mM-1 S1-) and showed negligible cytotoxicity estimated by WST assay. In vitro and in vivo MRI experiments revealed excellent targeting specificity to tumor cells and tissue. Furthermore, considerably enhanced signal intensity and prominent positive contrast effect were achieved at tumor region after tumor-bearing mice were intravenously injected with the mixed micelles. These preliminary results indicated the potential of the mixed micelle as T1 MRI CA for tumor-targeted imaging.

Tumor-targeted micelle-forming block copolymers for overcoming of multidrug resistance

New amphiphilic diblock polymer nanotherapeutics serving simultaneously as a drug delivery system and an inhibitor of multidrug resistance were designed, synthesized, and evaluated for their physico-chemical and biological characteristics. The amphiphilic character of the diblock polymer, containing a hydrophilic block based on the N-(2-hydroxypropyl)methacrylamide copolymer and a hydrophobic poly(propylene oxide) block (PPO), caused self-assembly into polymer micelles with an increased hydrodynamic radius (Rh of approximately 15nm) in aqueous solutions. Doxorubicin (Dox), as a cytostatic drug, was bound to the diblock polymer through a pH-sensitive hydrazone bond, enabling prolonged circulation in blood, the delivery of Dox into a solid tumor and the subsequent stimuli-sensitive controlled release within the tumor mass and tumor cells at a decreased pH. The applicability of micellar nanotherapeutics as drug carriers was confirmed by an in vivo evaluation using EL4 lymphoma-bearing C57BL/6 mice. We observed significantly higher accumulation of micellar conjugates in a solid tumor because of the EPR effect compared with similar polymer-drug conjugates that do not form micellar structures or with the parent free drug. In addition, highly increased anti-tumor efficacy of the micellar polymer nanotherapeutics, even at a sub-optimal dose, was observed. The presence of PPO in the structure of the diblock polymer ensured, during in vitro tests on human and mouse drug-sensitive and resistant cancer cell lines, the inhibition of P-glycoprotein, one of the most frequently expressed ATP-dependent efflux pump that causes multidrug resistance. In addition, we observed highly increased rate of the uptake of the diblock polymer nanotherapeutics within the cells. We suppose that combination of unique properties based on MDR inhibition, stimuli sensitiveness (pH sensitive activation of drug), improved pharmacokinetics and increased uptake into the cells made the described polymer micelle a good candidate for investigation as potential drug delivery system.

Preparation of plasmonic vesicles from amphiphilic gold nanocrystals grafted with polymer brushes.

Gold nanovesicles contain multiple nanocrystals within a polymeric coating. The strong plasmonic coupling between adjacent nanoparticles in their vesicular shell makes ultrasensitive biosensing and bioimaging possible. In our laboratory, multifunctional plasmonic vesicles are assembled from amphiphilic gold nanocrystals (such as gold nanoparticles and gold nanorods) coated with mixed hydrophilic and hydrophobic polymer brushes or amphiphilic diblock co-polymer brushes. To fulfill the different requirements of biomedical applications, different polymers that are either pH=responsive, photoactive or biodegradable can be used to form the hydrophobic brush, while the hydrophilicity is maintained by polyethylene glycol (PEG). This protocol covers the preparation, surface functionalization and self-assembly of amphiphilic gold nanocrystals grafted covalently with polymer brushes. The protocol can be completed within 2 d. The preparation of amphiphilic gold nanocrystals, coated with amphiphilic diblock polymer brushes using a 'grafting to' method or mixed hydrophilic and hydrophobic polymer brushes using tandem 'grafting to' and 'grafting from' methods, is described. We also provide detailed procedures for the preparation and characterization of pH-responsive plasmonic gold nanovesicles from amphiphilic gold nanocrystals using a film-rehydration method that can be completed within ∼3 d.

Fabrication of a Targeted Drug Delivery System from a Pillar[5]arene‐Based Supramolecular Diblock Copolymeric Amphiphile for Effective Cancer Therapy

Effective cancer therapy will profit from the development of sophisticated drug delivery systems with stimuli‐responsive properties that are capable of delivering therapeutic doses to the active sites, while minimizing the accumulation of highly toxic drugs in off‐target sites. Herein, the fabrication of a pillararene‐based amphiphilic supramolecular diblock polymer (P5‐PEG‐Biotin⊃PCL‐C2V) based on the host–guest recognition between a water‐soluble pillar[5]arene and a viologen salt is reported. P5‐PEG‐Biotin⊃PCL‐C2V self‐assembles into polymersomes, which are utilized as drug delivery vehicles for doxorubicin hydrochloride (DOX). Decorated by the biotin groups, these smart nanocarriers deliver the anticancer drug preferentially to biotin receptor over‐expressing cancer cells. After internalization by the cells, the viologen group is reduced into the cationic radical state by the intracellular reductase NAD(P)H, leading to the release of the loaded DOX by the disassembly of the polymersomes. More importantly, DOX‐loaded polymersomes maintain the therapeutic efficacy towards cancerous HeLa cells, while exhibiting relatively low cytotoxicity towards normal HEK293 cells. In vivo studies reveal that the DOX‐loaded supramolecular polymersomes prolong the circulation time in the bloodstream, promote the antitumor efficacy and reduce the systematic toxicity of the drug through flexible and modular supramolecular strategy.

Toughening Glassy Poly(lactide) with Block Copolymer Micelles.

Poly(lactide) (PLA), a compostable bioderived polyester, can be produced at a cost and scale that makes it an attractive replacement for nondegradable petroleum-derived thermoplastics. However, pristine PLA is brittle and unsuitable for use in applications where high impact strength and ductility are required. In this work we demonstrate that poly(l-lactide) (PLLA) in the glassy state can be toughened significantly via addition of an amphiphilic diblock polymer. Notably, a PLLA blend containing only 5 wt% poly(ethylene oxide)-b-poly(butylene oxide) (PEO-PBO) exhibited tensile toughness and notched Izod impact strength over an order of magnitude higher than neat amorphous PLLA without a significant reduction in transparency or elastic modulus. For a series of PLLA blends containing PEO-PBO of fixed composition (∼70% volume fraction PBO), the toughness was inversely related to the molar mass of the added modifier with the highest toughness observed for the blend containing the smallest diblock (∼7 kg/mol). Interestingly, at fixed composition and molar mass poly(l-lactide)-b-poly(butylene oxide) (PLLA-PBO) exhibited a substantial but reduced toughening efficiency compared to PEO-PBO. We attribute this difference to a change in the solubility parameter of the amphiphilc block. Using TEM, we show that the greatest toughening is observed when the diblock modifier forms small cylindrical micelles that are well dispersed in the PLLA matrix. This morphology is facilitated by a negative Flory-Huggins interaction parameter (χ) between PEO and PLLA. These insights suggest a new and versatile strategy for the facile and efficient toughening of brittle thermoplastics.

Redox-sensitive micelles assembled from amphiphilic mPEG-PCL-SS-DTX conjugates for the delivery of docetaxel

Docetaxel (DTX) can produce anti-tumor effects by inhibiting cell growth and inducing apoptosis. However, the poor solubility of DTX restricts its application and its clinical formulation has caused serious adverse reaction due to the use of Tween-80. In the present study, DTX was conjugated to an amphiphilic di-block polymer to solve these problems. Methoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) was selected as the polymer skeleton and a redox sensitive disulfide bond was used as the linker between DTX and mPEG-PCL. The synthesized mPEG-PCL-SS-DTX conjugates were characterized by 1H-nuclear magnetic resonance (1H NMR) and Fourier transform infrared spectroscopy (FTIR). Interestingly, the mPEG-PCL-SS-DTX conjugates could self-assemble into micelles in aqueous solution. The critical micelle concentration (CMC) of mPEG-PCL-SS-DTX micelles was about 2.3mgL−1 determined using pyrene molecule fluorescent probe method while the size of mPEG-PCL-SS-DTX micelles was determined to be ca. 17.6nm and 116.0nm with a bimodal distribution by dynamic light scattering (DLS). The in vitro release results indicated that the as-prepared micelles exhibited a sustained release profile with good redox sensitive properties. In particular, the hemolytic toxicity test indicated the as-prepared mPEG-PCL-SS-DTX micelles had negligible hemolytic activity, demonstrating their safety in drug delivery system. Cytotoxicity assay of the mPEG-PCL-SS-DTX micelles verified their highly enhanced cytotoxicity to MCF-7/A and A549 cells. These results thus demonstrated that the present redox-sensitive mPEG-PCL-SS-DTX micelle was an efficient and safe sustained drug delivery system in the biomedical area.

Redesigning Photosynthetic Membranes: Development of Bio-Inspired Photonic Nanomaterials

Biological cell membranes rely upon hierarchical organization to elicit functional responses. In natural photosynthetic membranes, light harvesting (LH) membrane protein complexes act as a framework for coordination of chromophores which absorb solar energy and channel it to downstream bioenergetic processes. Supported lipid bilayers (SLBs) are established as simple model membranes, into which membrane proteins can be incorporated. As an alternative to lipids, certain diblock copolymers can from membrane-mimetic systems with potential advantages (increased robustness, functionality, responsivity). Here, we present research into two different bio-inspired LH systems.Firstly, a modular, artificial LH system is described, where amphiphilic diblock polymers, poly(ethylene oxide)-block-poly(butadiene), act a matrix for noncovalent arrangement of BODIPY energy donor and bacteriochlorin energy acceptor chromophores. The polymer/ chromophore composites form nanoscale micelles in aqueous solution and defect-free monolayer and bilayer films on solid substrates. Donor-acceptor Forster resonance energy transfer is shown by steady state and time-resolved fluorescence spectroscopy and the system is modelled by theoretical calculations. Supported polymer bilayers demonstrated energy transfer efficiency up to 90%. Secondly, we present ongoing research into the redesign of protein/ lipid LH systems. Purified plant proteins and lipids are used as building blocks to form novel reconstructed protein/SLBs with defined compositions and 3-D organization using a combination of surface patterning and photolithography techniques. Atomic force and fluorescence microscopy and spectroscopy show protein arrangement and light harvesting functionality can be controlled. These new protein/chromophore and polymer/chromophore bio-inspired systems could act as a platforms to investigate membrane self-assembly and organization and could lead to applications in chip-based nanodevices.

A nanocomposite of Au-AgI core/shell dimer as a dual-modality contrast agent for x-ray computed tomography and photoacoustic imaging.

To develop a core/shell nanodimer of gold (core) and silver iodine (shell) as a dual-modal contrast-enhancing agent for biomarker targeted x-ray computed tomography (CT) and photoacoustic imaging (PAI) applications. The gold and silver iodine core/shell nanodimer (Au/AgICSD) was prepared by fusing together components of gold, silver, and iodine. The physicochemical properties of Au/AgICSD were then characterized using different optical and imaging techniques (e.g., HR- transmission electron microscope, scanning transmission electron microscope, x-ray photoelectron spectroscopy, energy-dispersive x-ray spectroscopy, Z-potential, and UV-vis). The CT and PAI contrast-enhancing effects were tested and then compared with a clinically used CT contrast agent and Au nanoparticles. To confer biocompatibility and the capability for efficient biomarker targeting, the surface of the Au/AgICSD nanodimer was modified with the amphiphilic diblock polymer and then functionalized with transferrin for targeting transferrin receptor that is overexpressed in various cancer cells. Cytotoxicity of the prepared Au/AgICSD nanodimer was also tested with both normal and cancer cell lines. The characterizations of prepared Au/AgI core/shell nanostructure confirmed the formation of Au/AgICSD nanodimers. Au/AgICSD nanodimer is stable in physiological conditions for in vivo applications. Au/AgICSD nanodimer exhibited higher contrast enhancement in both CT and PAI for dual-modality imaging. Moreover, transferrin functionalized Au/AgICSD nanodimer showed specific binding to the tumor cells that have a high level of expression of the transferrin receptor. The developed Au/AgICSD nanodimer can be used as a potential biomarker targeted dual-modal contrast agent for both or combined CT and PAI molecular imaging.

PH‐ and NIR Light‐Responsive Micelles with Hyperthermia‐Triggered Tumor Penetration and Cytoplasm Drug Release to Reverse Doxorubicin Resistance in Breast Cancer

The acquisition of multidrug resistance (MDR) is a major hurdle for the successful chemotherapy of tumors. Herein, a novel hybrid micelle with pH and near‐infrared (NIR) light dual‐responsive property is reported for reversing doxorubicin (DOX) resistance in breast cancer. The hybrid micelles are designed to integrate the pH‐ and NIR light‐responsive property of an amphiphilic diblock polymer and the high DOX loading capacity of a polymeric prodrug into one single nanocomposite. At physiological condition (i.e., pH 7.4), the micelles form compact nanostructure with particle size around 30 nm to facilitate blood circulation and passive tumor targeting. Meanwhile, the micelles are quickly dissociated in weakly acidic environment (i.e., pH ≤ 6.2) to release DOX prodrug. When exposed to NIR laser irradiation, the hybrid micelles can trigger notable tumor penetration and cytosol release of DOX payload by inducing tunable hyperthermia effect. In combination with localized NIR laser irradiation, the hybrid micelles significantly inhibit the growth of DOX‐resistant MCF‐7/ADR breast cancer in an orthotopic tumor bearing mouse model. Taken together, this pH and NIR light‐responsive micelles with hyperthermia‐triggered tumor penetration and cytoplasm drug release can be an effective nanoplatform to combat cancer MDR.

Effect of hydrophobicity of core on the anticancer efficiency of micelles as drug delivery carriers.

Recently, micelles, which are self-assembled by amphiphilic copolymers, have attracted tremendous attention as promising drug delivery systems for cancer treatment. Thus, the hydrophobic core of the micelles, which could efficiently encapsulate small molecular drug, will play a significant role for the anticancer efficiency. Unfortunately, the effect of hydrophobicity of micellar core on its anticancer efficiency was rarely reported. Herein, the amphiphilic diblock polymers of poly(ethylene glycol) and polyphosphoester with different side groups (butyl, hexyl, octyl) were synthesized to tune the hydrophobicity of the micellar core. We found that the in vitro cytotoxicity of the DOX-loaded micelles decreased with the increasing hydrophobicity of micellar core due to the drug release rate. However, following systemic delivery, the DOX-loaded micelles with the most hydrophobic core exhibited the most significant inhibition of tumor growth in a MDA-MB-231 tumor model, indicating the importance of hydrophobicity of core on the antitumor efficacy of drug delivery systems.

Oxidation responsive mono-cleavable amphiphilic di-block polymer micelles labeled with a single diselenide

A novel diselenide-containing mono-cleavable amphiphilic di-block polymer, denoted MPEG-IPDI-SeSe-IPDI-PPG, composed of one hydrophilic poly(ethylene glycol) monomethyl ether (MPEG) block and one hydrophobic polypropylene glycol (PPG) block, was synthesized via four coupling reactions in sequence. MPEG-IPDI-SeSe-IPDI-PPG is able to self-assemble into spherical micelles in aqueous solution. Subsequently, it was found that the spherical micelles have a oxidation-responsiveness and undergo a morphology transformation from spherical micelles to large compound micelles (LCMs) in an oxidative environment (0.5%wt H2O2) due to the unique oxidation-responsive cleavage of the diselenide group, resulting in an initially fast release of loaded Rhodamine B (RB), followed by slow, continuously increasing release. It is anticipated that these mono-cleavable polymer micelles containing diselenide may find application in the field of drug delivery systems.