Self-assembled, thermosensitive micelles of a star block copolymer based on PMMA and PNIPAAm for controlled drug delivery

A four-arm star block copolymer, comprised of a hydrophobic PMMA arm and an average of three hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) arms were designed and synthesized from the molecular level. The amphiphilic star block copolymer is capable of self-assembling into micelles in water, which was confirmed by FT-IR, (1)H NMR and fluorescence spectroscopy. Transmission electron microscopy images showed that these nanoparticles were regularly spherical in shape. The micelles showed reversible dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PNIPAAm at around 34 degrees C, observed by optical absorbance measurements. Resulted polymeric micelles loaded with prednisone acetate showed a much improved drug release behavior due to the special micellar structure.     

Self-assembled thermosensitive micelles based on poly(L-lactide-star block-N-isopropylacrylamide) for drug delivery

A novel seven-arm star block copolymer poly(L-lactide-star block-N-isopropylacrylamide) (PLLA-sb-PNIPAAm), comprised of a hydrophobic poly(L-lactide) (PLLA) arm and an average of six hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) arms, was designed and synthesized. The amphiphilic PLLA-sb-PNIPAAm copolymer was capable of self-assembling into nano-sized micelle in water, which was confirmed by FT-IR, 1H NMR and fluorescence spectroscopy. Transmission electron microscopy images showed that these nano-sized micelles were regularly spherical in shape. Micelle size determined by size analysis was around 100 nm in diameter. The micelles showed reversible dispersion/aggregation in response to temperature changes through an outer polymer shell of PNIPAAm at around 31 degrees C, observed by optical absorbance measurements. The anticancer drug methotrexate (MTX) as model drug was loaded in the polymeric nano-sized micelles. In vitro release behavior of MTX was investigated, which showed a drastic thermoresponsive fast/slow switching behavior according to the temperature-responsive structural changes of a micellar shell structure. The reversible and sensitive thermoresponse of this micelle might provide opportunities to construct a novel drug delivery system in conjunction with localized hyperthermia.     

Temperature sensitivity and drug encapsulation of star-shaped amphiphilic block copolymer based on dendritic poly(ether-amide)

The star-shaped amphiphilic block copolymer (DPEA-PCL-PNIPAAms) with different PCL block lengths was prepared through ring opening polymerization of epsilon-caprolactone (CL) initiated by hydroxyl end-capped dendritic poly(ether-amide) (DPEA-OH), and then coupling with carboxyl end-capped linear poly(N-isopropylacrylamide) (PNIPAAm-COOH) via an esterification process. The molecular structure was characterized by FT-IR, (1)H NMR, and GPC analysis. As the copolymer dissolved in water, the core-shell structural nanoparticle was formed as a micelle. The fluorescence, (1)H NMR, and dynamic light scattering (DLS) techniques were utilized to confirm the formation of micelles. The optical transmittance and US-DSC measurements demonstrated that the micelles performed the reversible dispersion/aggregation behavior in response to temperature through the outer PNIPAAm polymer shell. The micelles loaded with daidzein showed a very rapid drug release speed at temperatures above the lower critical solution temperature (LCST) due to the temperature-induced structural change of the polymeric micelles.     

Emulsion Self‐Assembly Synthesis of Chitosan/Poly(lactic‐co‐glycolic acid) Stimuli‐Responsive Amphiphiles

An amphiphilic graft copolymer using chitosan (CS) as a hydrophilic main chain and poly(lactic‐co‐glycolic acid) (PLGA) as a hydrophobic side chain is prepared through an emulsion self‐assembly synthesis. CS aqueous solution is used as a water phase and PLGA in chloroform is served as an oil phase. A water‐in‐oil (W/O) emulsion is fabricated in the presence of the surfactant span‐80. The self‐assembly reaction is performed between PLGA and CS under the condensation of EDC. Fourier transform IR (FTIR) spectroscopy reveals that PLGA is grafted onto the backbone of CS through the interactions between end carboxyl and amino groups of the two components. ¹H NMR spectroscopy directly indicates the grafting content of PLGA in the CS‐graft‐PLGA (CS‐g‐PLGA) copolymer is close to 25%. X‐ray diffraction (XRD) confirms that the copolymer exhibits an amorphous structure. The CS‐g‐PLGA amphiphile can self‐assemble to form micelles with size in the range of ≈100–300 nm, which makes it easy to apply in various targeted‐drug‐release and biomaterial fields.     

Thermoreversible gel-sol behavior of biodegradable PCL-PEG-PCL triblock copolymer in aqueous solutions

A series of biodegradable PCL-PEG-PCL block copolymers were successfully synthesized by ring-opening polymerization of epsilon-caprolactone initiated by poly(ethylene glycol) (PEG), which were characterized by (1)H NMR, (13)C NMR, and FTIR. Their aqueous solution displayed special gel-sol transition behavior with temperature increasing from 4 to 100 degrees C, when the polymer concentration was above corresponding critical gel concentration (CGC). The gel-sol phase diagram was recorded using test tube inverting method and DSC method, which depended not only on chemical composition of copolymers, but also on heating history of copolymer's aqueous solution. As a result, the gel-sol transition temperature could be adjusted, which might be very useful for its application in biomedical fields such as injectable drug delivery system. And the typical shell-core structure of PCL-PEG-PCL micelles was introduced. The micelle-packing and partial crystallization might be the key gelation machanism for this gel-sol transition behavior of PCL-PEG-PCL aqueous solution.     

Constructing doxorubicin-loaded polymeric micelles through amphiphilic graft polyphosphazenes containing ethyl tryptophan and PEG segments

By changing the molar ratio of hydrophilic and hydrophobic segments, a series of novel amphiphilic graft polyphosphazenes (PEG/EtTrp-PPPs) was synthesized via thermal ring-opening polymerization and a subsequent two-step substitution reaction of hydrophilic methoxyl polyethylene glycol (MPEG) and hydrophobic ethyl tryptophan (EtTrp). ¹H-Nuclear magnetic resonance and Fourier transform infrared studies validated the expected synthesis of copolymers. The copolymer composition was also confirmed by UV–visible spectrophotometry. The molar ratio of the segment PEG to group EtTrp was 1.33:0.67, 1.01:0.99 and 0.78:1.22, respectively. Micellization behavior of PEG/EtTrp-PPPs in an aqueous phase was characterized by fluorescence technique, dynamic light scattering and transmission electron microscopy. The critical micelle concentration (CMC) of the graft copolymer in aqueous solution was 0.158, 0.033 and 0.020 g l^?1, which decreased as the hydrophobic content in amphiphilic copolymers increased. Doxorubicin (DOX) was physically loaded into micelles prepared by an O/W emulsion method with a drug loading content increasing with DOX feeding. In vitro release of DOX from micelles can be accelerated in weak acidic solution. The results of cytotoxicity study using an MTT assay method with HeLa cell showed that amphiphilic graft polyphosphazenes were biocompatible while DOX-loaded micelles achieved comparable cytotoxicity with that of free DOX. In summary, these novel amphiphilic copolymers exhibited potential to be used as injectable drug carriers for tumor treatment.     

Biodegradable cationic PEG-PEI-PBLG hyperbranched block copolymer: synthesis and micelle characterization

A novel amphiphilic biodegradable cationic hyperbranched poly(ethylene glycol)-polyethylenimine-poly(gamma-benzyl L-glutamate) (PEG-PEI-PBLG) block copolymer was successfully synthesized by ring-opening polymerization (ROP) of N-carboxyanhydride of gamma-benzyl-L-glutamate (BLG-NCA) with PEG-PEI as a macroinitiator. PEG-PEI was firstly prepared by coupling of PEG and PEI using hexamethylene diisocyanate (HMDI). The structural properties of PEG-PEI-PBLG copolymers were confirmed by 1H NMR and GPC. The copolymers were found to be self-assembled in water with critical micelle concentration (CMC) in the range of 0.00368-0.0125 g/l and high hydrophobic micelle core. The micelle size and CMC obviously depended on the hydrophobic block content in the copolymer and the ionic state of the PEI block. The CMC decreased with the increase in the PBLG block content. The decrease of micelle size and the increase of CMC simultaneously occurred with the protonated degree of PEI block by addition of HCl solution. ESEM and Gel retardation assay showed that the cationic micelles had ability to encapsulate plasmid DNA. The copolymer has potential medical applications in drug and gene delivery.     

Thermally responsive polymeric micelles self-assembled by amphiphilic polyphosphazene with poly(N-isopropylacrylamide) and ethyl glycinate as side groups: polymer synthesis, characterization, and in vitro drug release study

Thermally responsive amphiphilic poly(N-isopropylacrylamide) (PNIPAm)-grafted-polyphosphazene (PNIPAm-g-PPP) was synthesized by stepwise cosubstitution of chlorine atoms on polymer backbones with amino-terminated NIPAm oligomers and ethyl glycinate (GlyEt). Polymer structure was confirmed by FT-IR, (1)H NMR, elemental analysis, and GPC. The thermosensitivity of PNIPAm-g-PPP aqueous solution was investigated by turbidity method. The lower critical solution temperature (LCST) of PNIPAm-g-PPP was observed to be approximately 30 degrees C in water, while it was 24 degrees C in 0.1M PBS (pH 7.4). Micellization behavior of PNIPAm-g-PPP in aqueous solution was characterized by fluorescence probe technique, TEM, and DLS. The critical micelle concentration (CMC), thus, determined was 0.0187 g/L. Both TEM and DLS measurement suggested that the diameter of micelles was approximately 190 nm at 20 degrees C. Diflunisal (DIF)-loaded micelles were prepared by dialysis method. In vitro release test at various temperatures was also performed to study the effect of temperature on the drug release profiles. It was demonstrated that DIF release from PNIPAm-g-PPP micelles was slower at the temperature of 37 degrees C than that at 4 degrees C.     

Biotinylated thermoresponsive micelle self-assembled from double-hydrophilic block copolymer for drug delivery and tumor target

A multifunctional micellar drug carrier formed by the thermosensitive and biotinylated double-hydrophilic block copolymer (DHBC), biotin-poly(ethylene glycol)-block-poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide) (biotin-PEG-b-P(NIPAAm-co-HMAAm)), was designed and prepared. The P(NIPAAm-co-HMAAm) block with an molar feed ratio of NIPAAm and HMAAm (10:1) was identified to exhibit the reversible phase transition at the lower critical solution temperature (LCST) of 36.7 degrees C. Cytotoxicity study indicated that the biotin-PEG-b-P(NIPAAm-co-HMAAm) copolymer did not exhibit obvious cytotoxicity. The block copolymer was capable of self-assembling into micelle in water. Transmission electron microscopy showed that the self-assembled micelles were regularly spherical in shape. The anticancer drug methotrexate (MTX) was loaded in the micelles and the in vitro release behaviors of MTX at different temperatures were investigated. The association of biotin molecule with the copolymer was confirmed by a unique capillary electrophoresis immunoassay (CEIA) method based on enhanced chemiluminescence (CL) detection. The fluorescence spectroscopy analysis as well as confocal microscopy studies confirmed the DHBC drug carriers could specifically and efficiently bind to cancer cells with pretreatment of biotin-transferrin, suggesting that the multifunctionalized DHBC micelle may be a useful drug carrier for tumor targeting.     

Mixed micelles formed from graft and diblock copolymers for application in intracellular drug delivery

A novel mixed micelle that comprised of poly(N-isopropylacrylamide-co-methacrylic acid)-graft-poly(D,L-lactide) (P(NIPAAm-co-MAAc)-g-PLA) with methoxy poly(ethylene glycol)-b-poly(D,L-lactide) (mPEG-b-PLA) was developed for application in cancer therapy. The mixed micelle had an multi-functional inner core of P(NIPAAm-co-MAAc)-g-PLA to enable intracellular drug delivery and an extended hydrophilic outer shell of mPEG to hide the inner core. Stability analysis of the mixed micelles in bovine serum albumin (BSA) solution indicates that the diblock copolymer mPEG efficiently protected the BSA adsorption on the mixed micelles because the hydrophobic groups of graft copolymer were efficiently screened by mPEG. From the drug release study, the mPEG-PLA diblock copolymer in mixed micelles slightly affected the functionalities of the P(NIPAAm-co-MAAc)-g-PLA graft copolymer; the graft copolymer still exhibited pH- and thermo-sensitivities in this core-shell structure. A change in pH deformed the structure of the inner core from that of aggregated P(NIPAAm-co-MAAc), causing the release of a significant quantity of doxorubicin (Dox) from mixed micelles. Clear differences between free Dox and Dox-mixed micelles were observed using confocal laser scanning microscopy (CLSM). This study presents not only a new micelle structure for a graft-diblock copolymer system, but also a method for overcoming some of the limitations on biomaterials used in intravenous injection.     

Novel thermosensitive polymeric micelles for docetaxel delivery

Targeted delivery of antitumor drugs triggered by hyperthermia has significant advantages in clinical applications, since it is easy to implement and side effects are reduced. To release drugs site-specifically upon local heating often requires the drugs to be loaded into a thermosensitive polymer matrix with a low critical solution temperature (LCST) between 37 and 42 degrees C. However, the LCSTs of most thermosensitive materials were below 37 degrees C, which limits their application in clinic because they would precipitate once injected into human body and lost thermal targeting function. Herein, we prepared a novel thermosensitive copolymer (poly(N-isopropylacrylamide-co-acrylamide)-b-poly (DL-lactide)) that exhibits no obvious physical change up to 41 degrees C when heated. Docetaxel loaded micelles made of such thermosensitive polymer were prepared by dialysis method and the maximum loading content was found to be up to 27%. The physical properties, such as structure, morphology, and size distribution of the micelles with and without docetaxel were investigated by NMR, X-ray diffraction, dynamic light scattering, atomic force microscopy, etc. The efficacy of this drug delivery system was also evaluated by examining the proliferation inhibiting activity against different cell lines in vitro. After hyperthermia, the cytotoxicity of docetaxel-loaded micelles increased prominently. Our results demonstrated that this copolymer could be an ideal candidate for thermal targeted antitumor drug delivery.     

Folate-conjugated amphiphilic hyperbranched block copolymers based on Boltorn® H40, poly(l-lactide) and poly(ethylene glycol) for tumor-targeted drug delivery

Folate-conjugated amphiphilic hyperbranched block copolymer (H40–PLA-b-MPEG/PEG–FA) with a dendritic Boltorn^® H40 core, a hydrophobic poly(l-lactide) (PLA) inner shell and a hydrophilic methoxy poly(ethylene glycol) (MPEG) and folate-conjugated poly(ethylene glycol) (PEG–FA) outer shell was synthesized as a carrier for tumor-targeted drug delivery. The block copolymer was characterized using ¹H NMR and gel permeation chromatography (GPC) analysis. Due to its core–shell structure, this block polymer forms unimolecular micelles in aqueous solutions. The micellar properties of H40–PLA-b-MPEG/PEG–FA block copolymer were extensively studied by dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopy (TEM). An anticancer drug, doxorubicin in the free base form (DOX) was encapsulated into H40–PLA-b-MPEG/PEG–FA micelles. The DOX-loaded micelles provided an initial burst release (up to 4 h) followed by a sustained release of the entrapped DOX over a period of about 40 h. Cellular uptake of the DOX-loaded H40–PLA-b-MPEG/PEG–FA micelles was found to be higher than that of the DOX-loaded H40–PLA-b-MPEG micelles because of the folate-receptor-mediated endocytosis, thereby providing higher cytotoxicity against the 4T1 mouse mammary carcinoma cell line. In vitro degradation studies revealed that the H40–PLA-b-MPEG/PEG–FA block copolymer hydrolytically degraded into polymer fragments within six weeks. These results indicated that the micelles prepared from the H40–PLA-b-MPEG/PEG–FA block copolymer have great potential as tumor-targeted drug delivery nanocarriers.     

A Poly(vinyl alcohol)‐graft‐Copolyester: Synthesis of a Novel Graft Copolymer Containing Adamantane Moieties as Guest for Cyclodextrin

A novel graft copolymer is synthesized from commercially available poly(vinyl alcohol) using ring‐opening polymerization. For the polymerization reaction of novel brush‐like poly(vinyl alcohol)‐graft‐poly(?‐caprolactone‐co‐(3‐/7‐(prop‐2‐ynyl)oxepan‐2‐one) 5 Sn(Oct)₂ is used as a catalyst. The formation of the graft copolymer is confirmed by ¹H NMR, ¹³C NMR, and Fourier transform infrared (FTIR) spectroscopy. Furthermore, the modification of the novel synthesized graft copolymer via a “click” reaction to implement adamantane groups is described. The success of the “click” reaction is proven by ¹H NMR spectroscopy and visualized by decomplexation of cyclodextrin with included phenolphthalein.

     

Micelles with a Loose Core Self‐Assembled from Coil‐g‐Rod Graft Copolymers Displaying High Drug Loading Capacity

High drug loading capacity is one of the critical demands of micellar drug‐delivery vehicles; however, it is a challenging work. Herein, it is demonstrated that micelles self‐assembled from poly(ethylene glycol)‐graft‐poly(γ‐benzyl‐l ‐glutamate) (PEG‐g‐PBLG) coil‐g‐rod graft copolymers display high drug‐loading capacity for doxorubicin (DOX) model drugs. As revealed by a combination study of experiments and dissipative particle dynamics simulations, the high drug‐loading capacity of the micelles is related to the loose core structure of the micelles. In these micelles, the hydrophobic PBLG grafts randomly disperse in the micelle core due to their rigid nature and the coil‐g‐rod topology of the graft copolymers, which results in a loose core of the micelles. The structure of the graft copolymer, including the length of rod grafts, the length of coil backbone, and the grafting ratio of the rod grafts affecting the arrangement of the rod grafts in the micelle core has influence on the drug‐loading capacity of the micelles. Besides, the strong π–π stacking interaction between graft copolymers and DOX also plays an important part in achieving high drug‐loading capacity. In vitro studies reveal that these drug‐loaded micelles show good biocompatibility, and the DOX can be gradually released from the micelles.     

Self‐assembled UCST‐Type Micelles as Potential Drug Carriers for Cancer Therapeutics

A methoxy‐poly(ethylene glycol)‐block‐poly(acrylamide‐co‐acrylonitrile) (mPEG‐b‐P(AAm‐co‐AN)) amphiphilic copolymer exhibiting upper critical solution temperature (UCST) behavior is synthesized, and micelles from this copolymer are fabricated. It is found that the thermal responses of these micelles are tunable through balancing the hydrophobic/hydrophilic blocks in the copolymer. The size of the doxorubicin (DOX)‐loaded micelles is dependent on the hydrophobic interaction as well as hydrogen bonding between polymer and drug molecules. As a proof of concept, the drug release behavior is studied in vitro, and the cumulative release of DOX increases at temperature above the UCST of blank micelles. 3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) assays indicate that these polymers are non‐toxic towards human hepatic carcinoma cells (Bel 7402 cells) as well as human embryonic hepatocytes (L02 cells). DOX‐loaded micelles could effectively enter Bel 7402 cells in 2 h, and display much lower half inhibitory concentration compared with free DOX. These micelles may be exploited as a promising drug carrier for cancer therapeutics.

     

Amphiphilic multi-arm-block copolymer conjugated with doxorubicin via pH-sensitive hydrazone bond for tumor-targeted drug delivery

Folate-conjugated unimolecular micelles based on amphiphilic hyperbranched block copolymer, Boltorn^® H40-poly(l-aspartate-doxorubicin)-b-poly(ethylene glycol)/FA-conjugated poly(ethylene glycol) (H40-P(LA-DOX)-b-PEG-OH/FA), were synthesized as a carrier for tumor-targeted drug delivery. The anticancer drug DOX was covalently conjugated onto the hydrophobic segments of the amphiphilic block copolymer arms by pH-sensitive hydrazone linkage. The size of the unimolecular micelles was determined as 17–36 and 10–20 nm by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The release profiles of the DOX from the H40-P(LA-DOX)-b-PEG-OH/FA micelles showed a strong dependence on the environmental pH values. The DOX release rate increased in the acidic medium due to the acid-cleavable hydrazone linkage between the DOX and micelles. Cellular uptake of the H40-P(LA-DOX)-b-PEG-OH/FA micelles was found to be higher than that of the H40-P(LA-DOX)-b-PEG-OH micelles because of the folate-receptor-mediated endocytosis, thereby providing higher cytotoxicity against the 4T1 mouse mammary carcinoma cell line. Degradation studies showed that the H40-P(LA-DOX)-b-PEG-OH/FA copolymer hydrolytically degraded into polymer fragments within six weeks. These results suggest that H40-P(LA-DOX)-b-PEG-OH/FA micelles could be a promising nanocarrier with excellent in vivo stability for targeting the drugs to cancer cells and releasing the drug molecules inside the cells by sensing the acidic environment of the endosomal compartments.     

Biamphiphilic triblock copolymer micelles as a multifunctional platform for anticancer drug delivery

Novel micelles from biamphiphilic triblock copolymer poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(acrylic acid) (PEG-b-PCL-b-PAA) as new multifunctional nanocarriers to delivery anticancer drugs were evaluated. The well-defined triblock copolymers prepared by controlled polymerizations self-assembled into micelles in aqueous solution with a hydrodynamic radius of 13 nm as obtained by dynamic light scattering (DLS) and a low critical micellization concentration of 2.9 × 10(-4) g/L. The hydrophobic PCL cores of micelles were applied to load hydrophobic drug doxorubicin and the functional PAA subcoronas clung to the micellar core were used to carry cisplatin through covalent interaction. The results indicated that two anticancer drugs had been loaded by different mechanism either separately or simultaneously. Drug loading content and efficiency as well as release profiles were evaluated. Furthermore, internalization and cytotoxicity of the anticancer nanoparticles against human bladder carcinoma EJ cells were studied. The biamphiphilic triblock copolymer micelles provided not only biocompatibility and biodegradability, but also abilities for loading single and dual anticancer drugs, indicating that this was a useful multifunctional platform for anticancer drug delivery.     

Thermo- and pH-responsive copolymers based on PLGA-PEG-PLGA and poly(l-histidine): Synthesis and in vitro characterization of copolymer micelles

A series of novel thermo- and pH-responsive block copolymers of PHis-PLGA-PEG-PLGA-PHis composed of poly(ethylene glycol) (PEG), poly(d,l-lactide-co-glycolide) (PLGA) and poly(l-histidine) (PHis) were synthesized and used for the construction of stimuli-responsive copolymer micelles. The starting polymers of PLGA-PEG-PLGA and PHis were synthesized by ring-opening polymerization of dl-lactide and glycolide with PEG as an initiator and l-histidine N-carboxylanhydride with isopropylamine as an initiator, respectively. The final copolymer was obtained by the coupling reaction of PHis with PLGA-PEG-PLGA. The copolymer micelles were constructed to have an inner core consisting of two hydrophobic blocks (PLGA and deprotonated PHis) and an outer hydrophilic PEG shell. The temperature- and pH-induced structure changes of the micelles were characterized by an alteration in particle size, a decrease in pyrene florescence intensity, and a variation of ¹H NMR spectra in D₂O. It was speculated that the hydrophobic–hydrophilic transitions of PEG and PHis in response to temperature and pH variations accounted for the destabilization of micelles. In vitro release profiles, cell cytotoxicity and intracellular location studies further confirmed the temperature- and pH-responsive properties of the copolymer micelles. These results demonstrate the potential of the developed copolymers to be stimuli-responsive carriers for targeted delivery of anti-cancer drugs.     

Poly(N-isopropylacrylamide-co-acrylamide) cross-linked thermoresponsive microspheres obtained from preformed polymers: Influence of the physico-chemical characteristics of drugs on their release profiles

Poly(N-isopropylacrylamide-co-acrylamide) copolymer was synthesized as an interesting thermoresponsive material possessing a phase transition temperature of around 36 degrees C in phosphate buffer, pH 7.4 (PB); the concentration was 10%, w/v. The copolymer maintains a sharp phase transition at a relatively high percentage of acrylamide. The lower critical solution temperature (LCST) of the copolymer is influenced by the concentration of copolymer solution in PB. The copolymer was transformed in thermoresponsive microspheres by chemical cross-linking of amide groups with glutaraldehyde. The key factors for the successful preparation of microspheres are the use of a concentrated polymer solution, a temperature (38 degrees C) that is high enough but lower than LCST, and a long reaction time (48h). The microspheres were characterized by optical and scanning electron microscopy, swelling/deswelling kinetics, swelling degree, and PB retention at different temperatures. Finally, the influence of hydrophilicity/hydrophobicity and the molecular weight of the drugs (propranolol, lidocaine, vitamin B(12)) on their release profile from thermoresponsive microspheres were examined. Above LCST the hydrogel matrix is in the dehydrated state and hydrophobic interactions between the hydrophobic drugs and the polymer occur, modulating the release rate of the drugs. For hydrophilic drugs, the release rate is modulated mainly by the steric interaction between the drug molecule and the matrix.     

基于改性壳聚糖纳米胶束的制备和表征及其细胞毒性评价

背景：壳聚糖进行化学改性以制备性能优良且细胞毒性低、生物相容性高、可降解的聚合物纳米胶束,在药物控释、组织工程等领域获得普遍应用。 目的：将强疏水链十八烷氧基接枝到N-琥珀酰壳聚糖分子中,制备结构稳定、粒径较小的聚合物胶束,以获得可适用于药物传递载体或医学生物材料领域的聚合物纳米胶束。 方法：用N-琥珀酰壳聚糖和十八烷基缩水甘油醚反应,在壳聚糖衍生物中引入长链疏水基。 结果与讨论：成功制备出聚合物纳米胶束,通过红外光谱和1H核磁波谱表征,证实壳聚糖分子中成功引入了琥珀酰基和十八烷氧基。通过动态激光散射测量出其粒径在136~166 nm,其临界胶束溶度在1.67×10^-3~3.35×10^-3 g/L,反映出胶束具有非常好的稳定性,而且其临界胶束浓度值和粒径随着疏水链接枝率的增加而减少。MTT法检测说明该胶束对细胞毒性极低。