Polyisobutylene and its thermoplastic elastomers: How to transform from industry to medical treatment / 中国组织工程研究

BACKGROUND: Polyisobutylene and block copolymer and its crosslinked product are a kind of novel thermoplastic elastomer. They have unique properties and excellent biocompatibility, which is a promising medical biomaterial and applied extensively. OBJECTIVE: To review the research progress and applications of polyisobutylene and its thermoplastic elastomers, and to discuss the application prospect of polyisobutylene-based polymers as medical implant materials. METHODS: A computer-based retrieval of PubMed, Web of Science, CNKI and WanFang databases was conducted for the articles about polyisobutylene published from 1958 to 2019. The key words were “polyisobutylene and block copolymer, polyisobutylene and thermoplastic elastomer, polyisobutylene and biomaterials, polyisobutylene and modification, polyisobutylene and medical application” in English and Chinese, respectively. In accordance with the inclusion and exclusion criteria, 65 eligible articles were included for review. RESULTS AND CONCLUSION: Polyisobutylene and block copolymer and its crosslinked products have favorable biocompatibility and stability. By making full use of polyisobutylene-based materials’ advantages, with the combination of other biomaterials and usage of new technology for surface modification, the copolymer will be more competitive in the field of medical implant in the future, including eye implant materials, soft biomaterials and drug delivery systems.

In vitro release and pharmacokinetics of quercetin-loaded mixed micelles composed of Pluronic P123/Poloxamer 188 in rats / 中国药理学通报

Aim: To investigate the in vitro release behavior and pharmacokinetic characteristics of quercetinloaded mixed micelles composed of Pluronic P123/ Poloxamer 188 in rats. Methods: Polymer micelles were prepared by the thin-film hydration method. The quercetin release rate of quercetin mixed micelles was investigated by dynamic membrane dialysis technique in the physiological saline contained 1% Tween-80. The drug release curves were drawn. The results were evaluated by DD Solver. Ultra performance liquid chromatography (UPLC) method was employed to measure the plasma concentration of quercetin in rats after tail intravenous administration. The plasma concentration-time curves were drawn, and the pharmacokinetic parameters were calculated with PK Solver. Results: The entrapment efficiency (EE%) and loading efficiency (DL%) of mixed micelles was (94. 25 ± 2. 13)% and (8.61 ± 0. 18)%, respectively. The quercetin release rate of quercetin mixed micelles in the physiological saline contained 1% Tween-80 was (52.90 ± 1.08)%. The quercetin mixed micelles could be described by Higuchi model and expressed by the equation; F = 6. 735 t0.5 (Rsqr-adj = 0. 960 4, AlC = 75. 584 0). T1/2β, AUC0.4 and MRT0-inf of quercetin mixed micelles were calculated to be 1.2,1.5 and 2. 4 times of free quercetin, respectively. Conclusions: The quercetin-loaded mixed micelles have high entrapment efficiency and loading efficiency, which can improve the release behavior in vitro, prolong the time of quercetin, and significantly enhance the fraction of bioavailability of quercetin in rats.

Preparation of angiopep-2-modified FITC-labeled neurotoxin nanoparticles and in vitro release characteristics / 中国中药杂志

In order to prepare angiopep-2 modified fluorescein isothiocyanate-labeled neurotoxin nanoparticles( ANG-NPs/FITCNT),emulsion/solvent evaporation method was used with m PEG-PLA and ANG-PEG-PLA( in proper proportions) as carriers and with FITC-NT as drug. With particle size and encapsulation efficiency as comprehensive indexes,the effects of different ultrasound power and ultrasound time combinations on the process were investigated. The in vitro release characteristics of nanoparticles in PBS buffer at p H 7. 4 and p H 6. 5 were investigated by dialysis method. The results indicated that the optimum process for preparing ANG-NPs/FITC-NT was as follows: ultrasonic power 90 W,ultrasonic time 30 s. In such optimal process,ANG-NPs/FITC-NT were well-shaped under the transmission electron microscope,with an average particle size of( 123. 9±0. 5) nm,Zeta potential of(-10. 5±0. 5) m V,encapsulation efficiency of( 68. 1±0. 4) %,and the drug loading of( 0. 82±0. 01) %. The in vitro drug release profiles of the nanoparticles in PBS buffer at p H 7. 4 and p H 6. 5 were both consistent with Ritger-Peppas equation,ln Q = 0. 508 8 lnt-2. 285 0,r = 0. 961 5( p H 7. 4) and ln Q= 0. 449 9 lnt-1. 855 3,r = 0. 970 3( p H 6. 5),respectively. The experiment results proved that the nanoparticles prepared by emulsion/solvent evaporation method had uniform particle size,high encapsulation efficiency and in vitro sustained release characteristic,which might be a potential carrier for NT intracerebral drug delivery.

New Carrier Materials for Particles Drug Delivery System of Irinotecan Hydrochloride / 中国药学杂志

OBJECTIVE: To prepare micelle drug delivery system of irinotecan hydrochloride, which could reduce its side effects and improve the therapeutic effects. METHODS: Firstly, the irinotecan hydrochloride was prepared as phospholipid compound to improve the lipophilicity. The synthesized polycaprolactone-polyethylene glycol copolymer was used as carrier material, then the phospholipid complex of irinotecan hydrochloride was wrapped to prepare a polymer micelle drug delivery system. The optimum prescription and preparation process of micelle drug delivery system of irinotecan hydrochloride were screened by the method of single factor combined with orthogonal test. RESULTS: The liposoluble of phospholipid compound of irinotecan hydrochloride was obviously increased compared with active compound. The irinotecan hydrochloride micelle was spherical and its particle size distribution was uniform. The average entrapment efficiency was 61.32%, and the average drug loading was 2.88%. CONCLUSION: Through this method, the particle size of irinotecan hydrochloride is small and the quality is controllable, and it is hopeful to increase the drug concentration at the target site.

Effect of Drug Carrier Melting Points on Drug Release of Dexamethasone-Loaded Microspheres

Here, we examined the effect of melting point of drug carriers on drug release of dexamethasone (Dex)-loaded microspheres. We prepared poly(L-lactide-ran-ε-caprolactone) (PLC) copolymers with varying compositions of poly(εcaprolactone) (PCL) and poly(L-lactide) (PLLA). As the PLLA content increased, the melting points of PLC copolymers decreased from 61 to 43 ℃. PLC copolymers in vials solubilized at 40–50 ℃ according to the incorporation of PLLA into the PCL segment. Dexamethasone (Dex)-loaded PLC (MCxLy) microspheres were prepared by the oil-in-water (O/W) solvent evaporation/extraction method. The preparation yields were above 70%, and the mean particle size ranged from 30 to 90 µm. The MC(x)L(y) microspheres also showed controllable melting points in the range of 40–60 ℃. Dex-loaded MC(x)L(y) microspheres showed similar in vitro and in vivo sustained release patterns after the initial burst of Dex. The in vitro and in vivo order of the Dex release was MC₈₀L₂₀>MC₉₀L₁₀>MC₉₅L₅, which agreed well with the melting point order of the drug carrier. Using in vivo fluorescence imaging of fluorescein (FI)-loaded microspheres implanted in animals, we confirmed the sustained release of FI over an extended period. In vivo inflammation associated with the PLC microsphere implants was less pronounced than that associated with Poly(lactide-co-glycolide) (PLGA). In conclusion, we successfully demonstrated that it is possible to control Dex release using Dex-loaded MC(x)L(y) microspheres with different melting points.

In vivo and in vitro MR imaging of glioma targeted block copolymer micelles / 中华放射学杂志

Objective To explore the in vivo/in vitro MR imaging effect of Angiopep2 modified glioma targeted block copolymer micelles(ANPs/CPT). Methods Angiopep2 modified DOTA-Gd conjugated polymeric micelles based on beta-cyclodextrin(β-CD) were successfully synthesized.Water proton longitudinal relaxation rate (1/T1) were calculated to compare the r1of DOTA-Gd and ANPs/CPT. Different concentration of DOTA-Gd, NP/CPT, ANP/CPT were co-cultured with C6 cells, the intracellular content of Gd3+was analyzed by ICP-AES;The signal intensity(SI) and contrast to noise ratio(CNR) were measured by 1.5 T MR;The CNR of ANPs/CPT was evaluated on different organs of normal rats. The enhancement feature of ANP/CPT in glioma as well as T/N and CNR between tumor and normal brain tissue were also investigated.Several comparisons were made between the 3 groups by one-way ANOVA,and the difference were significant when P<0.05.Results The r1of ANPs/CPT(13.900 s-1·mmol/L-1)was 3 times as much as DOTA-Gd(4.927 s-1·mmol/L-1).C6 cells uptake different concentrations of Gd3 +had significant difference among groups(F=362.502,1636.136,386.880,918.173, P<0.001).The difference of SI and CNR among groups were significant(F=55.240,155.419,P<0.001).The CNR of the brain tissue had significant difference with other organs at all times after tail vein injection of ANPs/CPT(F=9.417,21.808, 21.383,107.318,178.762,P<0.01).The ANPs/CPT showed excellent brain-targeting efficiency and theT/N ratio(30 min after),CNR in different time point had significant difference among groups (F=5.349,6.594,24.078,18.508 and 6.840,6.780,5.895,12.620,37.139,368.893, P<0.05).Conclusions ANPs/CPT shows nice agnetic relaxation performance,extended blood circulation duration,excellent brain-targeting efficieney, which will render the theranosticnano-carriers with important reference for the construction of new generation multifunctional nanomedicine.

Synthesis and characterization of amphiphilic block copolymer of poly (L-phenylalanine)-b-poly(L-aspartic acid) / 国际药学研究杂志

Objective To design and synthesize a different molecular mass block copolymer of poly(L-phenylalanine)-b-poly (L-aspartic acid)(PPA-PAA). Methods The L-phenylalanine and L-aspartic acid were used as raw materials to synthesize L-phenyl?alanine N-carboxy-ɑ-amino acid anhydride and L-aspartic acid-β-benzylester N-carboxy-ɑ-amino acid anhydride. The target com?pounds of amphiphilic block copolymer of PPA-PAA were synthesized by ring-opening polymerization. The critical micelle concentra?tion of the amphiphilic polymer was determined by pyrene fluorescence probe method. Results The copolymers of hydrophobic chain segment 500,2000,and 4000 were synthesized and the structures were confirmed by hydrogen nuclear magnetic resonance and Fouri?er transformed infrared. The critical micelle concentration of polymers changed with adjusting the feed ratio of PPA to PAA. Conclu?sion The results show that the longer the hydrophobic chain segment of PPA is,the smaller the critical micelle concentration of poly?mers. The results lay the groundwork for further studying the stabilizing effect of the drug polymer nanoparticles with different proper?ties.

Synthesis and characterization of amphiphilic block copolymer of poly(L-phenylalanine)-b-poly(L-aspartic acid) / 国际药学研究杂志

Objective: To design and synthesize a different molecular mass block copolymer of poly(L-phenylalanine)-b-poly(L-aspartic acid)(PPA-PAA). Methods: The L-phenylalanine and L-aspartic acid were used as raw materials to synthesize L-phenylalanine N-carboxy-α-amino acid anhydride and L-aspartic acid-β-benzylester N-carboxy-α-amino acid anhydride. The target compounds of amphiphilic block copolymer of PPA-PAA were synthesized by ring-opening polymerization. The critical micelle concentration of the amphiphilic polymer was determined by pyrene fluorescence probe method. Results: The copolymers of hydrophobic chain segment 500, 2000, and 4000 were synthesized and the structures were confirmed by hydrogen nuclear magnetic resonance and Fourier transformed infrared. The critical micelle concentration of polymers changed with adjusting the feed ratio of PPA to PAA. Conclusion: The results show that the longer the hydrophobic chain segment of PPA is, the smaller the critical micelle concentration of polymers. The results lay the groundwork for further studying the stabilizing effect of the drug polymer nanoparticles with different properties.

Preparation and quality evaluation of comet-shaped hydroxy camptothecin-loaded amphiphilic block copolymer / 药学学报

In this study, we used Shirasu porous glass membrane (SPG) as a template and hydroxy camptothecin (HCPT) as a model drug to prepare the comet-shaped MePEG[methoxyl poly(ethylene glycol)]-PLGA[poly(lactic-co-glycolic acid)-HCPT amphiphilic block copolymer. Our method was optimized by the orthogonal design method. The partical size, zeta potential, drug-loaded content, yield, shape and status of the obtained comet-shaped MePEG-PLGA-HCPT particles were further characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM)/transmission electron microscopy (TEM), X-ray diffraction (XRD) and differential scanning calorimetry (DSC) et al, respectively. In vitro release was preliminary evaluated. MTT assay to preliminary evaluate the cytotoxicity of particles against human liver BEL-7402 cells. Based on these experimental results, the optimal preparation conditions contain:weight ratio of HCPT to MePEG-PLGA was 1:1, nitrogen pressure was 100 kPa and SPG membrane pore size was 1.1 μm. The particles exhibited a comet-shaped shape, fairly uniform size and were well dispersed. The drug-loading content was 46.2%, with yield of 96.4%, and zeta -31.4 mV. The distribution of HCPT in particles was very uniform, and HCPT showed a amorphous state existed in particles. The release behavior in vitro showed sustained releasing,and with the drug loading content in proportion to the release of the drug. MTT test indicated that the HCPT-loaded comet-shaped particles had enhanced the cytotoxicity against human liver BEL-7402 cells relatively to the HCPT-loaded spherical particles in vitro. The results showed a promising potential application of the preparation in clinical treatment of tumor.

Study on doxoru bicin-loaded star-shaped multi-arm PLGA-PEG-NH2 nanomicelles / 国际生物医学工程杂志

ObjectiveTo develop doxorubicine-loaded nanomicelles based on a type of novel starshaped 4-arm PLGA-PEG-NH2 amphiphilic block copolymers.Methods 4s-(PLGA-PEG-NH2) synthesized by 4s-PLGA and (H2N-PEG-NH2) according to N,N'-dicyclohexylcarbodiimide(DCC) condensation reaction was demonstrated by 1H NMR spectroscopy and gel permeation chromatography(GPC); DOX-loaded 4s-(PLGA-PEG-NH2) nanomicelles were self-assembled by doxorubicin(DOX) and 4s-(PLGA-PEG-NH2) via emulsion-solvent evaporation method and characterized in terms of morphology,particle size and size distribution,drug loading,encapsulation efficacy,cell uptake and cytotoxicity studies.Results4s-(PLGA-PEG-NH2) were capable of selfassembling intocore-shell nanomicelles structure and encapsulating DOX into their hydrophobic cores.The mean size of DOX-loaded 4s-(PLGA-PEG-NH2) was nanometer size; drug loading and encapsulation efficacy were around 7.5％ and 75.2％,respectively.Mean surface charge of the micelles was around -17.6 mV.In vitro cell uptake and cytotoxicity studies indicated that comparing to the DOX-loaded linear-(PLGA-PEG-PLGA)nanomicelles,DOX-loaded 4s-(PLGA-PEG-NH2) nanomicelles showed better performance in uptaking by HeLa cells and higher cytotoxicity to cancer cells.Conclusion4s-(PLGA-PEG-NH2) amphiphilic block copolymers can be successfully used in encapsulating DOX,self-assemblingcore-shell nanomicelles in aqueous solvent.Therefore,4s-(PLGA-PEG-NH2) copolymers can be considered as a promising drug carrier in effectively carrying hydrophobic drug,improving the efficacy while reducing the side effect.

Pharmacokinetics of amphiphilic long-circulating hydroxycamptothecin nanoparticles / 中国药学杂志

OBJECTIVE: To prepare amphiphilic long-circulating hydroxycamptothecin nanoparticles and investigate its physicochemical properties and pharmacokinetic characteristics in rats. METHODS: Polyethyleneglycol-polycaprolactone (PEG-PCL) was synthesized. HCPT-PEG-PCL-NPs were prepared by solvent-diffusion method using PEG-PCL block copolymer as the matrix. The obtained NPs were evaluated, and the physical stabilities of both suspl and freeze-dried powder were investigated. High-performance liquid chromatography (HPLC) was used to determine and compare the pharmacokinetic parameters of HCPT injection and HCPT-PEG-PCL-NPs prepared with different copolymers in rats. RESULTS: When using PEG4000-PCL1250, PEG4000-PCL2000, PEG2000-PCL1250, PEG2000-PCL2000 as the carrier materials, the average particle sizes of NPs were 110.0, 116.1, 99.1 and 119.9 nm; the Zeta potentials were -16.9, -22.4, -28.8 and -33.5 mV; the entrapment efficiency were 83.10%, 88.29%, 77.46% and 80.67%; and the drug loading percentages were 2.56%, 2.96%, 2.14% and 2.31%, respectively. The physical stability of the freeze-dried powder was better, and hot environment seemed to be bad for the stability. The t1/2s of HCPT-PEG4000-PCL1250-NPs, HCPT-PEG2000-PCL1250-NPs, HCPT-PEG4000-PCL2000-NPs and HCPT-PEG2000-PCL2000-NPs were 18.07, 9.08, 5.25 and 5.14 times longer than that of HCPT injection which was 0.1418 h. CONCLUSION: The HCPT-PEG-PCL-NPs show sustained-release effect and long-circulation property compared with HCPT injection. Copyright 2012 by the Chinese Pharmaceutical Association.

Effects of P85 and microbubbles on the efficiency of ultrasound-induced gene transduction in skeletal muscle of mice in vivo / 中华超声影像学杂志

Objective To explore the effects of P85,microbubbles and ultrasound on plasmid DNA skeletal muscle gene transduction of mice in vivo. Methods Plasmid encoding green fluorescent protein (GFP) ,which conjugated with 0.05% P85 and/or microbubbles, 10% Optison,was injected into the tibialis anterior(TA) muscle of mice with or without ultrasound irradiation (1 MHz, 1 W/cm2 2 min,20% duty cycle). Mice were killed 1 week after injection. The TA muscles were removed and snap-frozen immediately in isopentane cooled by liquid nitrogen and sections 7 μm thick were cut at intervals. One set of sections mounted with DAPI were used to assess the transfection efficiency by counting the number of GFP-positive fibers under fluorescence microscopy,and the other set of sections were stained with haematoxylin and eosin to assess the tissue damage area. Results The P85 and Optison significantly enhanced the plasmid DNA skeletal muscle gene delivery in vivo separately (P<0.01, P<0.05).Ultrasound exposure could significantly enhance the efficiency of P85 induced gene delivery(P<0.01) but not of Option(P>0.05).The gene delivery efficiency induced by P85 was higher than that by Optison no matter with or without ultrasound irradiation(P<0.01). When the P85 conjugated with Optison, they could further significantly enhance gene delivery efficiency with ultrasound exposure (P<0.01). Meanwhile, ultrasound exposure could increase the muscle damage areas in the groups with microbubbles (P<0.01). Conclusions The P85,microbubbles and ultrasound exposure display synergistic effect to enhance plasmid DNA transduction in skeletal muscle of mice in vivo.

Block copolymer micelles as delivery system for poorly soluble antineoplastic carrier / 中草药

To review the research of block copolymer micelles as delivery system for poorly soluble(antineoplastic) carrier over the last 10 years,including the composition,preparation methods and factors which influence the loading efficiency,physicochemical properties,and targeting characteristics of block copolymer micelles.Block copolymer micelles are self-assembled structures formed from amphiphilic block copolymers by dispersing in aqueous media.The hydrophilic blocks of the copolymer form the outer shell of the micelle,while the hydrophobic blocks form the inner core,and the proper coreshell micellar architecture was constituted.Block copolymer micelles have a whole set of unique properties,such as small sizes,narrow particle size distribution,high drug loading capacities,and available disposition characteristics in the body.Block copolymer micelles have been found as promising drug carriers due to making poorly soluble antineoplastic lysis,toxicities and side effects decrease,bioavailability increase,and targeting the drugs to specific sites in a passive way or attaching ligands in an active way,which can be specifically(recognized) by receptors onto the surface of copolymers.