pH-sensitive polymeric micelles triggered drug release for extracellular and intracellular drug targeting delivery

Most of the conventional chemotherapeutic agents used for cancer chemotherapy suffer from multidrug resistance of tumor cells and poor antitumor efficacy.Based on physiological differences between the normal tissue and the tumor tissue,one effective approach to improve the efficacy of cancer chemotherapy is to develop pH-sensitive polymeric micellar delivery systems.The copolymers with reversible protonationedeprotonation core units or acid-liable bonds between the therapeutic agents and the micelle-forming copolymers can be used to form pH-sensitive polymeric micelles for extracellular and intracellular drug smart release.These systems can be triggered to release drug in response to the slightly acidic extracellular fluids of tumor tissue after accumulation in tumor tissues via the enhanced permeability and retention effect,or they can be triggered to release drug in endosomes or lysosomes by pH-controlled micelle hydrolysis or dissociation after uptake by cells via the endocytic pathway.The pH-sensitive micelles have been proved the specific tumor cell targeting,enhanced cellular internalization,rapid drug release,and multidrug resistance reversal.The multifunctional polymeric micelles combining extracellular pH-sensitivity with receptor-mediated active targeting strategies are of great interest for enhanced tumor targeting.The micelles with receptor-mediated and intracellular pH targeting functions are internalized via receptor-mediated endocytosis followed by endosomal-pH triggered drug release inside the cells,which reverses multidrug resistance.The pH sensitivity strategy of the polymeric micelles facilitates the specific drug delivery with reduced systemic side effects and improved chemotherapeutical efficacy,and is a novel promising platform for tumor-targeting drug delivery.

Evaluation of Cisplatin-Loaded Polymeric Micelles and Hybrid Nanoparticles Containing Poly(Ethylene Oxide)-Block-Poly(Methacrylic Acid) on Tumor Delivery

Particulate carriers such as polymeric micelles (PMs) and liposomes have been investigated to increase drug accumulation in tumors and reduce distribution to healthy tissues. In this study, we prepared PM and hybrid nanoparticles (HNPs) with poly(ethylene oxide)-block-poly(methacrylic acid) (PEO-b-PMAA) for loading cisplatin, and evaluated cisplatin release, cytotoxicity, and biodistribution in mice. PM composed of PEO-b-PMAA and HNPs composed of egg phosphatidylcholine (EPC)/PEO-b-PMAA at molar ratios of 50/2.8 (HNP-P5) and 50/50 (HNP-P50), respectively, were prepared by a nanoprecipitation method. The sizes of PM, HNP-P5, and HNP-P50 after inclusion of cisplatin were approximately 200, 100, and 55 nm, respectively, and their entrapment efficiencies were approximately 44% - 66%. In the drug-release study, HNP-P5 and HNP-P50 showed reduced release of cisplatin compared with PM. Regarding the cytotoxic assay, HNP-P5 exhibited lower cytotoxicity for mouse Lewis lung carcinoma (LLC) and mouse colon carcinoma Colon 26 cells than PM and HNP-P50. In terms of biodistribution, PM could significantly improve blood circulation and tumor accumulation after intravenous injection into Colon 26 tumor-bearing mice compared with free cisplatin, but HNP-P5 and HNP-P50 did not. EPC in HNPs might be destabilized in the circulation, although it could reduce release of cisplatin in in vitro experiments. This study suggested that polymeric micelles composed of PEO-b-PMAA are a better carrier for cisplatin than hybrid nanoparticles composed of PEO-b-PMAA and EPC.

EFFECT OF SURFACE CHARGE OF POLYMERIC MICELLES ON IN VITRO CELLULAR UPTAKE

This work focuses on the interaction between polymeric micelles with different charged surfaces and cancer cells in order to study the influence of surface charge on the in vitro cellular uptake efficiency. The amphiphilic diblock copolymers poly（e-caprolaetone）-b-poly（ethylene oxide） （PCL-b-PEO） with different functional groups at the end of hydrophilic block were synthesized. The functional groups endue the micelles with different charges on the surfaces. The cellular uptake of micelles to T-24 cells （human bladder tumor cells）, HepG2 cells （human liver hepatocellular carcinoma cell line） and Hela cells （human epithelial cervical cancer cells） was studied by means of flow cytometer and confbcal laser scanning microscopy. The results indicate that the surface charges showed great influence on zeta potential of micelles at different pH values. The in vitro cellular uptake efficiency of micelles with different charged surfaces demonstrated different cellular uptake patterns to three kinds of cancer cells.

Preparation and Characterization of Polymeric Micelles from Poly (D, L-lactide) and Methoxypolyethylene Glycol Block Copolymers as Potential Drug Carriers

Amphiphilic diblock copolymers composed of methoxy polyethylene glycol （MePEG） and poly（D,L-lactide） （PDLLA） were prepared for the preparation of polymeric micelles, The use of MePEG-PDLLA as drug carriers has been reported in the open literature, but there are only few data on the application of a series of MePEG-PDLLA copolymers with different lengths in the medical field, The shape of the polymeric micelles is also important in drug delivery, Studies on in vitro drug release profiles require a good sink condition. The critical micelle concentration of a series of MePEG-PDLLA has a significant role in drug release. To estimate their feasibility as a drug carrier, polymeric micelles made of MePEG-PDLLA block copolymer were prepared by the oil in water （O/VV） emulsion method. From dynamic light scattering （DLS） measurements, the size of the micelle formed was less than 200 nm, The critical micelle concentration of polymeric micelles with various compositions was determined using pyrene as a fluorescence probe. The critical micelle concentration decreased with increasing number of hydrophobic segments. MePEG-PDLLA micelles have a considerably low critical micelle concentration （0.4～0.5 μg/mL）, which is apparently an advantage in utilizing these micelles as drug carriers. The morphology of the polymeric micelles was observed using scanning electron microscopy （SEM） and transmission electron microscopy （TEM）, The micelles were found to be nearly spherical. The yield of the polymeric micelles obtained from the O/W method is as high as 85%.

Preparation of adhesive resveratrol micelles and determination of drug content

Objective:Resveratrol polymer micelles with tissue adhesion were prepared and the content of resveratrol in the micelles was determined by HPLC.Method:The micelle adhesion experiment was carried out by polylysine orifice plate experiment and small animal fluorescence imaging method,and the micelle prescription was optimized to obtain resveratrol micelles with good adhesion.The separation was performed on a Shiseido SPOLAR C18 column(150 mm×4.6 mm,5μm)with methanol-water(42:58)as the mobile phase.The flow rate was 1.0 mL·min^(-1),the detection wavelength was 305 nm,the column temperature was 35℃,and the injection volume was 10μL.Results:Resveratrol micelles prepared with F127 alone had the best adhesion.The peak area and concentration of resveratrol had a good linear relationship in the concentration range of 10~200μg/mL(r=0.9996).The specificity,precision,recovery and stability all met the methodological requirements.Conclusion:In this experiment,resveratrol micelles with tissue adhesion were successfully prepared,and a method for the determination of resveratrol content in micelles was established.The method is accurate,rapid and simple.

Improved Anti-tumor Efficiency against Prostate Cancer by Docetaxel-loaded PEG-PCL Micelles

This study primarily focused on the systematic assessment of both in vitro and in vivo anti-tumor effects of docetaxel-loaded polyethylene glycol（PEG）2000-polycaprolactone（PCL）2600 micelles on hormone-refractory prostate cancer（HRPC）. By using solvent evaporation method, PEG-PCL was chosen to prepare doxetaxel（DTX）-loaded mPEG-PCL micelles（DTX-PMs）, with the purpose of eliminating side effects of the commercial formulation（Tween 80） and prolonging the blood circulation time. The prepared DTX-PMs had an average particle size of 25.19±2.36 nm, a zeta potential of 0.64±0.15 mV, a polydispersity index of 0.56±0.03, a drug loading of（8.72±1.05）%, and an encapsulation efficiency of（98.1±8.4）%. In vitro cytotoxicity studies indicated that DTX-PMs could effectively kill LNCap-C4-2B cells and show a dose- and time-dependent efficacy. The hemolysis test showed that DTX-PMs had less hemocytolysis than the commercial product of Duopafei. A sustained in vitro release behavior and prolonged circulation time in blood vessels were observed in the DTX-PMs. Furthermore, when compared with Duopafei, the DTX-PMs dramatically reduced the prostate specific antigen（PSA） level and tumor growth of prostate tumor-bearing nude mice in vivo. In conclusion, the DTX-PMs can lower systemic side effects, improve anti-tumor activity with prolonged blood circulation time, and will bring an alternative to patients with HRPC.

Micelles as potential drug delivery systems for colorectal cancer treatment

Despite the significant progress in cancer therapy,colorectal cancer(CRC)remains one of the most fatal malignancies worldwide.Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment.However,the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability,non-selective tumor targeting mechanisms,non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects.Over the last decade,there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations.Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates.Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors via the enhanced permeability and retention effect.They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site.They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer.Given that combination therapy is the new strategy implemented in cancer therapy,polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes.They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy.Here,we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment.We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.

The polymer micelles and application in tumor targeted therapy system

The current cancer chemotherapy drugs are inefficient and highly toxic,thus selecting the appropriate new forms of cancer treatment has become one of the important tasks.On the basis of domestic and foreign research,the composition,characteristics and main preparation methods of polymeric micelles,particularly the targeted polymeric micelles are illustrated.This review introduces different targeted polymeric micelles used as an anticancer drug carrier.By making use of the inside microenvironment of tumor cells,the preparation of a variety of new polymeric micelles with slight side effects and powerful effect in vitro and vivo,which can achieve effective control of drug release,is promising in application.

Polymeric complex micelle loaded with axially substituted silicon(Ⅳ) phthalocyanine

A novel axially substituted silicon（IV） phthalocyanine, namely di-pyridyloxy axially substituted silicon（IV） phthalocyanine 2 was synthesized and characterized by UV/vis, IR, elemental analysis, MS as well as IH NMR spectroscopy. Hydrophobic 2 was encapsulated by amphiphilic triblock copolymer poly[N^e-（benzyloxycarbonyl-lysine]-poly（ethylene glycol）-poly [N^e-（benzyl oxycarbonyl） （PLL（Z）-b-PEG-b-PLL（Z）） to form hydrophobic 2-loaded polymeric complex micelle （PIC） （2-loaded P/C）. Atom force microscopy （AFM） image showed that 2-loaded PIC formed a spherical nanocarrier with approximately 35-50 nm in diameter. The fluorescence intensity and lifetime of 2-loaded PIC was significantly enhanced bv the incorporation 2 into PIC nanocarrier.

An overview of polymeric nanomicelles in clinical trials and on the market

Polymeric nanomedicine is a promising and rapidly evolving field.Among the different polymeric carriers,polymeric micelle(PM) with nanoscale size exhibit potent physical and biological advantages including excellent solubility and pharmacokinetics,enhanced efficacy and lower toxicity.PM has garnered increasing intere st in research and in the clinic.This review will highlight the clinical outcomes of several PM-based formulations,and further summarized their preparation methods,strengths and challenges.

Polymeric nanocarriers for nose-to-brain drug delivery in neurodegenerative diseases and neurodevelopmental disorders

Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system(CNS)and result in their damage and death.Neurodevelopmental disorders include intellectual disability,autism spectrum disorder,and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes.The treatment of neurodegenerative and neurodevelopmental conditions,together affecting~120 million people worldwide,is challenged by the blood—brain barrier(BBB)and the blood—cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS.The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions.This pathway is more efficient for nanoparticles than for solutions,hence,the research on intranasal nano-drug delivery systems has grown exponentially over the last decade.Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility.This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions,the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them.Then,a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.

Analysis on the Characteristic Properties of PEDOT Nano-particle Based on Reversed Micelle Method

Based on the study of a new type of conducting polymer poly （3,4-ethylenedioxythiophene） （PEDOT）,we focussed on the preparation and characteristics of PEDOT nanoparticles made by reversed micelle method.Moreover,we deeply investigated the optical,electrical and the thermal stability of PEDOT nanoparticles.The main results are as follows： the small-sized PEDOT nanoparticles were prepared and utilized by different methods,such as ultraviolet/visible （UV-Vis） spectroscopy,Fourier-transform infrared （FT- IR） spectrum,scanning electron microscopy（SEM） and so on.The results show that the amount of oxidizer,ultrasonic treatment,polymerizing temperature and doping degree can influent morphology,electrical ability and gas sensitivity of PEDOT nanoparticles.The Bragg peaks of nanoparticles at 6.7°,12.7°,25° were observed by XRD and the better orientation of molecular chain was attributed to the effective doping of toluene-p-sulfonic acid,which also resulted in an enhancement of thermal stability of nanoparticles than conventional PEDOT.

A biomimetic and pH-sensitive polymeric micelle as carrier for paclitaxel delivery

As nano-scale drug delivery systems,smart micelles that are sensitive to specific biological environment and allowed for target site-triggered drug release by reversible stabilization of micelle structure are attractive.In this work,a biocompatible and pH-sensitive copolymer is synthesized through bridging poly(2-methacryloyloxyethyl phosphorylcholine)(PMPC)block and poly(D,L-lactide)(PLA)block by a benzoyl imine linkage(Blink).Biomimetic micelles with excellent biocompatibility based on such PLA-Blink-PMPC copolymer are prepared as carriers for paclitaxel(PTX)delivery.Due to the rapid breakage of the benzoyl imine linkage under acidic condition,the micelle structure is disrupted with accelerated PTX release.Such pH-sensitive triggered drug release behavior in synchronization with acidic conditions at tumor site is helpful for improving the utilization of drug and facilitating antitumor efficacy.These micelles can be used as promising drug delivery systems due to their biocompatible and smart properties.

A fully absorbable biomimetic polymeric micelle loaded with cisplatin as drug carrier for cancer therapy

cis-dichlorodiammineplatinum(II)(CDDP)-loaded polymeric micelles for cancer therapy have been developed to reduce the serious side effects of cisplatin CDDP.Herein,polymeric micelles incorporated with cisplatin are prepared based on the complexation between CDDP and hydrophilic poly(L-glutamic acid)-b-poly(2-methacryloyloxyethyl phosphorylcholine)(PLG-b-PMPC)diblock copolymers.These CDDP-loaded micelles possess an average size of 91nm with narrow distribution,providing remarkable stability in media containing proteins.The release of CDDP from the micelles is faster at pH 5.0 and pH 6.0 than that at pH 7.4 and in a sustained manner without initial burst release.In addition,there is almost no difference in cellular uptake between these CDDP-loaded micelles and free CDDP.Moreover,in vitro cytotoxicity test shows they possess high efficacy to kill 4T1 cells as compared with free drug.Thus,PLG-b-PMPC copolymer might be a promising carrier for CDDP incorporating in cancer therapy.

FOLATE-TARGETED OPTICAL AND MAGNETIC RESONANCE DUAL-MODALITY PCL-b-PEG MICELLES FOR TUMOR IMAGING

A biodegradable tumor targeting nano-probe based on poly（ε-caprolactone）-b-poly（ethylene glycol） block copolymer （PCL-b-PEG）micelle functionalized with a magnetic resonance imaging （MRI） contrast agent diethylenetriaminepentaacetic acid-gadolinium （DTPA-Gd＋） on the shell and a near-infrared （NIR） dye in the core for magnetic resonance and optical dual-modality imaging was prepared. The longitudinal relaxivity （rl） of the PCL-b-PEG- DTPA-Gd3＋ micelle was 13.4 （mmol/L）^-1s^-1, three folds of that of DTPA-Gd3＋, and higher than that of many polymeric contrast agents with similar structures. The in vivo optical imaging of a nude mouse bearing xenografied breast tumor showed that the dual-modality micelle preferentially accumulated in the tumor via the folic acid-mediated active targeting and the passive accumulation by the enhanced permeability and retention （EPR） effect. The results indicated that the dualmodality micelle is a promising nano-probe for cancer detection and diagnosis.

A BODIPY-modified polymeric micelle for sustaining enhanced photodynamic therapy

Photodynamic therapy(PDT) has been gaining popularity in both scientific research and clinic applications due to its non-invasiveness and spatiotemporal targeting properties. Nevertheless, the local hypoxic microenvironment in tumor tissue impedes PDT universality. To overcome this drawback, a 2-pyridonebearing BODIPY photosensitizer was synthesized rationally and introduced to polyethyleneglycol-bpoly(aspartic acid) to form a photosensitizer-^(1)O_(2) generation, storage/release agent dual-loading system(PEG-b-PAsp-BODIPY). The investigation of the PDT effect at different illumination conditions in vitro and in vivo revealed that the system tremendously inhibited tumor proliferation, indicating that this new PEG-b-PAsp-BODIPY could act as a potentially effective photo therapeutic system for cancer therapeutics.

Photo-Dimerization Characteristics of Coumarin Pendants within Amphiphilic Random Copolymer Micelles

The photo-dimerization characteristics of coumarin pendants within amphiphilic random copolymer micelles in aqueous solution was comprehensively investigated using various selected wavelength light in the UV-Vis-NIR region. The time-dependent photo-dimerization degree （PD） changes in the photo-dimerization experiments showed saturating behaviors with intensity-independent of PDmax values at 28%, 44%, 92%, 85%, 36%, 35%, 32% and 31% for 254, 288, 320, 360, 400, 500, 650 and 900 nm irradiations, respectively. The irradiation experiments at 254 and 288 nm announced the occurring of an asymmetric equilibrium of photo-dimerization and photo-cleavage at the used conditions. Both the alternative irradiation cycles of 360 and 254 nm, 650 and 254 nm showed a partially, but evidently reversible photo-dimerization tendency.

Enhanced bioavailability and biosafety of cannabidiol nanomicelles for effective anti-inflammatory therapy

Cannabidiol(CBD)shows great anti-inflammatory potential;however,the hydrophobicity and strong first-pass effect of CBD leads to its extremely low oral bioavailability.Poloxamer 407(P407)is a tri-block copolymer composed of(poly)ethylene oxide(PEO)and(poly)propylene oxide(PPO)sections.It has a PEO-PPO-PEO structure,which is widely used in the preparation of drug delivery systems that are highly biocompatible.When it reaches a certain concentration in water,P407 can self-assemble into a micelle structure containing a hydrophobic core and a hydrophilic shell.A potential approach to enhanc-ing the oral bioavailability of hydrophobic drugs incorporating them into the hydrophilic carrier.We prepared CBD nanomicelles with a drug loading of 14.29%by a cosolvent evaporation method using P407 with appropriate antioxidants.Cell experiments indicated that anti-inflammatory markers(IL-4 and IL-10)increased,while inflammatory markers(TNF-αand IL-6)decreased.Moreover,animal experiments showed that inflammatory cells were inhibited by CBD nanomicelles,and the anti-inflammatory effect of micelles was better than that of CBD,while no obvious evidence indicated toxicity to the liver and kidney.

Amphiphilic Block Copolymer Micelles for Gene Delivery

Gene therapy is a promising method to treat acquired and inherited diseases by introducing exogenous genes into specific recipient cells.Polymeric micelles with different nanoscopic morphologies and properties hold great promise for gene delivery system.Conventional cationic polymers,poly(ethyleneimine)(PEI),poly(L-lysine)(PLL),poly(2-dimethylaminoethyl methacrylate)(PDMAEMA)and novel cationic polymers poly(2-oxazoline)s(POxs),have been incorporated into block copolymers and decorated with targeting moieties to enhance transfection efficiency.In order to minimize cytotoxicity,nonionic block copolymer micelles are utilized to load gene through hydrophilic and hydrophobic interactions or covalent conjugations,recently.From our perspective,properties(shape,size,and mechanical stiffness,etc.)of block copolymer micelles may significantly affect cytotoxicity,transfection efficiency,circulation time,and load capacity of gene vectors in vivo and in vitro.This review briefly sums up recent efforts in cationic and nonionic amphiphilic polymeric micelles for gene delivery.

ROS-removing nano-medicine for navigating inflammatory microenvironment to enhance anti-epileptic therapy

As a neurological disorder in the brain,epilepsy is not only associated with abnormal synchronized discharging of neurons,but also inseparable from non-neuronal elements in the altered microenvironment.Anti-epileptic drugs(AEDs)merely focusing on neuronal circuits frequently turn out deficient,which is necessitating comprehensive strategies of medications to cover over-exciting neurons,activated glial cells,oxidative stress and chronic inflammation synchronously.Therefore,we would report the design of a polymeric micelle drug delivery system that was functioned with brain targeting and cerebral microenvironment modulation.In brief,reactive oxygen species(ROS)-sensitive phenylboronic ester was conjugated with poly-ethylene glycol(PEG)to form amphiphilic copolymers.Additionally,dehydroascorbic acid(DHAA),an analogue of glucose,was applied to target glucose transporter 1(GLUT1)and facilitate micelle penetration across the blood‒brain barrier(BBB).A classic hydrophobic AED,lamotrigine(LTG),was encapsulated in the micelles via self-assembly.When administrated and transferred across the BBB,ROS-scavenging polymers were expected to integrate anti-oxidation,anti-inflammation and neuro-electric modulation into one strategy.Moreover,micelles would alter LTG distribution in vivo with improved efficacy.Overall,the combined anti-epileptic therapy might provide effective opinions on how to maximize neuroprotection during early epileptogenesis.