Key Words: Polymer vesicle; Temperature-sensitive; Photocrosslinking; Controlled drug release;
Reversible addition fragmentation chain transfer (RAFT) polymerization
光交联固化的聚合物囊泡用于降温触发的药物释放
廖雨瑶1,2，范震2,3,*，杜建忠1,2,4,*
1同济大学附属上海市第十人民医院骨科，同济大学医学院，上海 200072
2同济大学材料科学与工程学院高分子材料系，上海 201804
3同济大学高等研究院，上海
200092
4先进土木工程材料教育部重点实验室，同济大学，上海
201804
摘要：光交联固化可以使聚合物囊泡保持稳定的结构，从而使其在生物医学领域具有应用前景。升温是常用的控制药物释放的触发手段，但是其可能会导致细胞损伤，而通过降温进行药物可控释放则能够避免该问题。本文通过可逆加成断裂链转移(RAFT)聚合制备了一种两亲性嵌段共聚物聚氧乙烯-嵌段-聚[(N-异丙基丙烯酰胺-无规-7-(2-甲基丙烯酰氧基乙氧基)-4-甲基香豆素)-嵌段-聚丙烯酸] [PEO43-b-P(NIPAM71-stat-CMA8)-b-PAA13]。该共聚物能够在水溶液中自组装形成囊泡。其中，P(NIPAM71-stat-CMA8)嵌段形成囊泡的非均相膜，而PEO链和PAA链形成囊泡的混合冠，囊泡的内部空腔可用于包载亲水性药物。可光交联的CMA基团可增强囊泡的稳定性，而PNIPAM链段赋予了囊泡温度响应特性。温度降低时，囊泡溶胀并响应性释放所包载的药物。通过动态光散射、扫描电子显微镜和透射电子显微镜表征了囊泡的尺寸分布和形貌。为了验证囊泡载药和释药的能力，将一种水溶性抗生素包载在囊泡的空腔内，其在水溶液中释放12 h后，抗生素释放率在25 °C时比在37 °C时高近35%。总体而言，这种具有温度响应特性的光交联囊泡为降温触发的药物释放提供了一个范例，有望应用于降温触发药物释放领域。
关键词：聚合物囊泡；温敏；光交联；可控释药；可逆加成断裂链转移聚合
中图分类号：O8
1 Introduction
PNIPAM and its derivatives are commonly used as temperature The stability of nanocarriers in physiological environments is responsive polymer segments that undergo a sharp transition in of great importance for biomedical applications 1–10. To enhance hydrophilic and hydrophobic properties at lower critical solution structural integrity and stability, shell crosslinking (SCL), temperatures (LCST) 28–30. For example, Narain et al. 31 reported membrane crosslinking (MCL), or nuclear crosslinking (CCL) a degradable and thermally responsive micelle for targeted drug nanocarriers have been studied and developed 11–15. However, delivery and controlled release. Swelling of the micelle core can most crosslinking approaches generate by-products and demand be achieved by heating above the phase transition temperature of non-biocompatible crosslinkers. Photocrosslinking has been PNIPAM, thereby triggering drug release. Gao et al. 32 regarded as an ideal crosslinking chemistry, which is non-toxic, developed an amphiphilic thermally-responsive ABA triblock cost-effective, does not need extra crosslinker or produce any by-copolymer that can self-assemble into micelles. The hydrophobic products 16. In addition, it has been demonstrated that the size PMMA was squeezed into the core, while the hydrophilic and shape of the nanocarriers could remain unchanged during P(NIPAM-co-PEGMEMA) formed a thermosensitive shell. When the photocrosslinking process 7,13,17–20. Meanwhile, the temperature was higher than the LCST (about 39 °C), the drug photocrosslinking process could be simply regulated through can be released without precipitation of copolymers. Currently, adjusting the wavelength and intensity of light 21,22, which makes most temperature-responsive nanocarriers are designed and photocrosslinking chemistry a good choice to develop stable synthesized to release the drugs triggered by temperature rise to nanocarriers for biomedical applications. Besides the desired about 40 °C 33,34. However, for clinical applications, some drug stability property of nanocarrier, controlled cargo release carriers and encapsulated drugs are injected subcutaneously or capability is also of natural significance for targeted and efficient intravenously and heated at the required site to trigger drug treatment.
release, which demands heating the subcutaneous layer to about Various strategies have been developed for addressing 40 °C by electromagnetic waves (such as radio waves or controlled drug release 1,4,23–26. Among existing triggering microwaves) 35,36. In addition, when the body temperature is approaches, the release of drugs through body temperature heated above 42 °C, the cells in the heated area would be changes caused by external temperature stimulation has been damaged 37.
considered to be one of the most practical methods in the clinic 27.
Meanwhile, some studies have shown that cooling on the skin
.com.cn. All Rights Reserved.物理化学学报 Acta Phys. -Chim. Sin. 2021, 37 (10), 1912053 (3 of 8) for 15–30 min with ice will cause the skin surface temperature solvents were purchased from Sinopharm Chemical Reagent to be below 25 °C, and there will be no significant frostbite on Co., Ltd. (SCRC, Shanghai, China). the cooled site 38,39. In order to ensure the safety of heating-2.2 Methods triggered drug release materials, it is necessary to accurately 2.2.1 Synthesis of PEO-DDMAT control the increase in body temperature. Otherwise, such The synthetic methods of PEO-DDMAT refer to our materials will be difficult to apply to the clinic. Meanwhile, previously published article 43. many scenarios in the clinic demand drug release under mild 2.2.2 Synthesis of PEO43-b-P(NIPAM71-stat-CMA8)-b-hypothermia environments 40,41. Therefore, lowering PtBA13 copolymer by RAFT polymerization temperature triggered nanocarriers need to be developed for drug Macro chain transfer agent (macro-CTA) PEO-DDMAT (0.34 delivery and safe release during therapeutic hypothermia. g, 0.15 mmol), NIPAM (1.36 g, 12.0 mmol) and CMA (0.500 g, Here, we synthesized a photocrosslinkable, temperature-1.65 mmol) were added in a 10 mL round bottom flask. Then responsive block copolymer by reversible addition fragmentation dissolve them with 2 mL of 1,4-dioxane. Argon was bubbled chain transfer (RAFT), which self-assembled by solvent switch through the mixture for 30 minutes for deoxidation. Radical method to form photocrosslinked polymer vesicle with temperature-initiator AIBN (3.7 mg, 0.020 mmol) was then added quickly, responsive property (Scheme 1). During the self-assembly process followed by deoxygenating with argon for 30 min. The reaction was of the copolymers into vesicles, the poly[N-isopropyl acrylamide-carried out in an oil bath at 70 °C under argon balloon protection. stat-7-(2-methacryloyloxyethoxy)-4-methylcoumarin] [P(NIPAM-The molar ratio of [PEO-DDMAT]/[NIPAM]/[CMA]/[AIBN] is 1 : stat-CMA)] block forms the inhomogeneous membrane, 80 : 11 : 0.15. The polymerization was carried out for 24 h, and whereas the poly(ethylene oxide) (PEO) chains and the the reaction was terminated upon exposure to air. Then add tert-poly(acrylic acid) (PAA) chains form the mixed coronas. The butyl acrylate (0.290 g, 2.25 mmol) to the mixed solution, repeat CMA group could be photocrosslinked by ultraviolet (UV) the previous steps of deoxygenation and addition of AIBN, then irradiation and enhance the stability of vesicles for biological place the flask in an oil bath at 70 °C for 24 h. After evaporating applications. The PNIPAM moiety endows the vesicle with the solvent by rotary evaporation, the mixed solution was temperature-responsive capability by a sharp transition in dissolved in DCM, then precipitated three times in n-hexane, and hydrophilic and hydrophobic properties at LCST. The PAA finally dried in a vacuum oven at 25 °C to give a light yellow chains are designed for further functionalization. The powder. The 1H NMR spectrum is shown in Fig. S1 (see photocrosslinked vesicles could encapsulate drugs and release Supporting Information). Yield: ~67%. them upon lowering temperature. 2.2.3 Synthesis of PEO43-b-P(NIPAM71-stat-CMA8)-b-PAA13 copolymer 2 Materials and methods PEO43-b-P(NIPAM71-stat-CMA8)-b-PtBA13 (1.00 g, 0.080 2.1 Materials mmol) was added to a round bottom flask, dissolved in 5 mL of Polyethylene oxide monomethylether (PEO43; Mn = 1900) was 1,4-dioxane, and TFA (0.300 g, 5.20 mmol) was added. The purchased from Alfa Aesar. 2-(Dodecylthiocarbonothioylthio)-2-mixed solution was stirred at room temperature. After reacting methylpropanoic acid (DDMAT) was synthesized according to overnight, the solvent and TFA were removed by a rotary the general method in the reported article 42. 7-hydroxy-4-evaporator. The solid polymer was then dried in a vacuum oven methylcoumarin (98%), 2-bromoethanol (95%), methacryloyl at 25 °C for 2 days. Dissolve it in DMF, dialyze against chloride (95%), N-isopropyl acrylamide (NIPAM, 98%), tert-deionized water for 2 days to remove organic solvents and by-butyl acrylate (tBA, 99%), trifluoroacetic acid (TFA, 99%), products, and lyophilize to obtain white powder solid PEO43-b-ciprofloxacin hydrochloride monohydrate (CIP, 98%), P(NIPAM71-stat-CMA8)-b-PAA13. The 1H NMR spectrum is Azobisisobutyronitrile (AIBN, 99%) were obtained from shown in Fig. S2 (see Supporting Information). Aladdin Chemistry, Co. Ltd. Dichloromethane (DCM, 99.5%), 2.2.4 Self-assembly of PEO43-b-P(NIPAM71-stat-CMA8)- 1,4-dioxane (99%), n-hexane (97%), tetrahydrofuran (THF, b-PAA13 into vesicles 99%), N,N-dimethylformamide (DMF, 99.5%), and other Polymer vesicles were prepared by solvent switch method 44. Scheme 1 Schematic illustration of photocrosslinked temperature-responsive polymer vesicle which can load and lock drugs at normal body temperature, and release them upon decreasing the temperature. .com.cn. All Rights Reserved.物理化学学报 Acta Phys. -Chim. Sin. 2021, 37 (10), 1912053 (4 of 8)
PEO43-b-P(NIPAM71-stat-CMA8)-b-PAA13 (8.0 mg) polymer was dissolved in THF at 40 °C with an initial polymer concentration of 4.0 mg∙mL−1. Then, the polymer solution was added dropwise to 8.0 mL of deionized water under heating (40 °C) to induce formation of polymer vesicles. Subsequently, the mixed solution was added to a dialysis tube (cutoff Mn = 3500), and THF was dialyzed off with a large amount of deionized water to obtain an aqueous polymer vesicle solution. 2.2.5 Photocrosslinking of polymer vesicles
The dialyzed polymer vesicles (0.5 mg∙mL−1) were placed under a UV spot curing system (8000 mW∙cm−2) at a wavelength of 365 nm, and the vesicle membrane was fixed by UV irradiation. The absorbance curve of the vesicle solution was measured with a UV-Vis spectrophotometer after irradiation with UV rays for a different period of time, and the degree of crosslinking of the polymer was calculated by the change in the UV absorption at 317 nm.
2.2.6 Preparation of CIP-loaded vesicles
CIP (1.6 mg) was added to the polymer vesicles solution (0.50 mg∙mL−1, 10 mL) and stirred at room temperature (25 °C) for more than 3 h. It was then heated to 40 °C to form CIP-loaded vesicles by stirring for 12 h. Unloaded free drug was removed by dialysis using a dialysis tube. The dialysis tube was immersed in 1000 mL of deionized water and dialyzed at 40 °C at a stirring rate of 300 r∙min−1. The deionized water was renewed 6 times in 3 h (0.5 h each). The calibration curve was established by measuring the absorbance of a series of known concentrations of CIP aqueous solution at a wavelength of 314 nm by a microplate reader (Fig. S3 (see Supporting Information)). The CIP loading in the post-dialysis vesicles can be calculated by comparing the absorbance of the solution at a wavelength of 314 nm with a calibration curve of a known concentration of CIP aqueous solution. In addition, since the vesicles also absorb UV radiation, the UV absorption rate of the pure vesicle solution is subtracted. Drug loading content (DLC) and drug loading efficiency (DLE) were calculated according to the following equations:
DLC (%) = mass of drug encapsulated in vesicles/mass of
polymer × 100%
DLE (%) = mass of drug encapsulated in vesicles/mass of
drug in feed × 100%
2.2.7 Drug release behavior of CIP-loaded vesicles
After dialysis to remove the free drug, the vesicle/CIP mixture was divided into two parts and transferred to two new dialysis tubes (cutoff Mn = 3500) to assess drug release behavior at different temperatures. The drug release process was performed by dialyzing 5.0 mL of CIP-loaded vesicles in a dialysis tube against 50 mL of deionized water in a beaker (100 mL) at 37 °C and 25 °C, respectively, and then stirring at the rate of 150 rpm. During the measurement, ensure that the amount of liquid in the beaker (outside the dialysis tube) is approximately 50 mL. At the required time interval, remove 100 μL of the solution in the beaker and add to the 96-well plate, measured by microplate reader (absorbance at 314 nm) and calculated according to the
calibration curve. The cumulative release profile of CIP was obtained.
2.3 Characterization 2.3.1 1H NMR analysis
1H NMR spectrum were recorded at room temperature by Bruker AV 400 MHz spectrometers with chloroform-d (CDCl3) as the solvent and tetramethylsilane (TMS) as the standard. For polypeptide, a drop of trifluoroacetic acid-d (CF3COOD) was added to break the hydrogen bond.
2.3.2 Size exclusion chromatography (SEC)
Three MZ-Gel SDplus columns (pore size 103, 104 and 105 Å (1 Å = 0.1 nm), with molecular weight ranges within 1000–2000000, respectively) with a 10 μm bead size and an Agilent differential refractive index (RI) detector were used to measure number-averaged molecular weight (Mn) and polymer dispersity index (Ð). DMF was used as an eluent at 40 °C at a flow rate of 1.0 mL·min−1 and polymethyl methacrylate standard samples were used to calibrate the samples.
2.3.3 Dynamic light scattering (DLS)
Nano-ZS 90 Nanosizer (Malvern Instruments Ltd., Worcestershire, UK) was used to characterize the size distribution of copolymer micelles at a fixed scattering angle of 90°. Each measurement was tested for three times. Aisposable cuvettes were used to analyze the solutions. Cumulative analysis of the experimental correlation function was used to obtain the data, and the computed diffusion coefficients from the Stokes-Einstein equation was used to calculate the particle diameters. 2.3.4 Transmission electron microscopy (TEM)
JEOL JEM-2100F instrument at 200 kV equipped with a Gatan 4 Ultrascan 1000 CCD camera was used to take TEM images. To prepare TEM samples were prepare according to the following steps. Diluted micelle solution (5.0 μL) was dropped on carbon-coated copper grid and then dried overnight under ambient environment. Next, phosphotungstic acid solution (PTA; pH 7.0, 1%) was dropped on the hydrophobic film (parafilm), and then the grids were laid upside down on the top of the PTA solution for one minute. A filter paper was used to blot up the excess PTA solution slightly. After that, the grids were dried overnight in ambient environment. 2.3.5 UV-Vis spectroscopy
The photocrosslinking process of the vesicles (0.5 mg∙mL−1 in DI water) was monitored by a UV759S UV-Vis spectrophotometer (Shanghai Precision & Scientific Instrument Co., Ltd.) with a scan speed of 300 nm∙min−1. The absorbance and transmittance spectra of the aqueous vesicles solutions were recorded in the range of 250–400 nm. DI water was used as the blank. All samples were analyzed using quartz cuvettes with a path length of 10 mm.
3 Results and discussion
3.1 Synthesis of PEO43-b-P(NIPAM71-stat-CMA8)-b-PAA13 block copolymer
This copolymer was synthesized in three steps (Fig. 1). First, PEO43-b-P(NIPAM71-stat-CMA8) block copolymer was
.com.cn. All Rights Reserved.物理化学学报 Acta Phys. -Chim. Sin. 2021, 37 (10), 1912053 (5 of 8) Fig. 1 Synthetic route to PEO43-b-P(NIPAM71-stat-CMA8)-b-PAA13 block copolymer by RAFT polymerization. Fig. 2 TEM images of photocrosslinked polymer vesicles at (a, b) day 1 and (c) day 7. synthesized using initiator AIBN, monomers NIPAM and CMA (Fig. 2), which is in accordance with that measured by DLS. in an oxygen-free RAFT polymerization. Second, the monomer 3.3 Photocrosslinking of block copolymer vesicles tBA was added to the above reaction solution under the same In general, the PNIPAM segment is hydrophobic at 32 °C or conditions to synthesize PEO43-b-P(NIPAM71-stat-CMA8)-b-higher and hydrophilic below 32 °C 47. Therefore, all self-PtBA13 copolymer. Finally, PEO43-b-P(NIPAM71-stat-CMA8)-b-assembly processes are carried out at 40 °C, and the block PAA13 copolymer was obtained by completely hydrolyzing the copolymer can be self-assembled into vesicles by a solvent tert-butyl ester groups of PtBA with TFA. switch method. The dialyzed aqueous vesicle solution was The chemical structures of related intermediate and end diluted to 0.5 mg∙mL−1, and the CMA on the membrane was products were confirmed by 1H NMR (Fig. S1–Fig. S2 in the crosslinked under a UV spot curing system at a wavelength of Supporting Information). The SEC traces of PEO43-b-365 nm. After 120 seconds of UV irradiation, the degree of P(NIPAM71-stat-CMA8)-b-PtBA13 and PEO43-b-P(NIPAM71-crosslinking of the vesicles was 88% (Fig. 4). As a result, the stat-CMA8)-b-PAA13 were provided in Fig. S4 (see Supporting CMA crosslinking fixes the vesicle structure and enhances its Information). The above analyses confirmed that the block stability in biological applications. When the temperature is copolymers were successfully synthesized. decreased to 25 °C, the structure of the crosslinked vesicles will 3.2 Self-assembling block copolymer into not change, but the permeability of the vesicle membrane will temperature-sensitive vesicles increase 47. Thus, crosslinked and temperature-sensitive polymer Polymer vesicles were prepared by solvent switch method 44. vesicles can be used as drug carriers for controlled release under The hydrophilic PEO and PAA chains form the coronas of the vesicle, while the P(NIPAM71-stat-CMA8) chains form the membrane in which PNIPAM is temperature-responsive and by intensityPCMA is crosslinkable. The size distribution and morphology of Dh = 208 nmPD = 0.075the vesicles were characterized by DLS, SEM and TEM. After stained with phosphotungstic acid, the hollow morphology of the collapsed vesicles with a phase-separated inhomogeneous membrane was observed from TEM and SEM images (Fig. 2 and Fig. S5 (see Supporting Information)) 45,46. The DLS results showed the hydrodynamic diameter (Dh) of vesicles is 208 nm and the polydispersity (PD) is 0.075 (Fig. 3). The morphology of 10100100010000the photocrosslinked vesicles at day 1 and day 7 was Hydrodynamic Diameter/nm characterized by TEM with diameter between 180 and 200 nm Fig. 3 Size distribution of vesicles as determined by DLS at 25 °C. .com.cn. All Rights Reserved.物理化学学报 Acta Phys. -Chim. Sin. 2021, 37 (10), 1912053 (6 of 8)
0.9UV exposure time 0 s 5 s)u 10 s.a 15 s/(e0.6 20 s 30 scn 60 sa 120 sb 180 sro 300 ssbA0.3 420 s0.0260280300320340360380400Wavelength/nm
Fig. 4 Photocrosslinking degrees of block polymer vesicles
exposed to UV light at different time.
temperature changes.
3.4 In vitro stability of photocrosslinked polymer
vesicles
In vitro stability of photocrosslinked polymer vesicles were evaluated in the aspects of size and morphology. As shown in Fig. 2, no obvious change was observed of the morphology and diameter after one week. In addition, the hydrodynamic diameters and the size distribution of the photocrosslinked polymer vesicles in water and phosphate buffered saline (PBS; 0.01 mol∙L−1 at pH 7.4) at 25 °C were evaluated by DLS (Fig. 5). From day 1 to day 7, the average hydrodynamic diameter of
the vesicles in aqueous solution was between 203 and 216 nm
with PD less than 0.25 during the whole process. Similarly, the average hydrodynamic diameter of the vesicles in PBS solution
(a)300Vesicles in water1.02500.8m200n0.6/ez150PDiS1000.4500.2012345670.0(b)Time/day300Vesicles in 0.01 M PBS at pH 7.41.02500.8m200n0.6/ez150PDiS1000.4500.2012345670.0Time/day
Fig. 5 Hydrodynamic diameter and polydispersity of photocrosslinked polymer vesicles in (a) water and
(b) 0.01 mol∙L−1 PBS at 25 °C.
was between 197 and 215 nm with PD less than 0.25. The above experimental data indicated that the size and morphology of vesicles remained stable.
3.5 Temperature-sensitive behavior of block
copolymer vesicles
The temperature-responsive behavior of the uncrosslinked and crosslinked vesicles solution was evaluated by DLS. The temperature of uncrosslinked vesicles solution was gradually decreased from 45 to 10 °C. A longer equilibration time of 30 min was applied here to allow the temperature-sensitive PNIPAM chains to reach equilibrium. As shown in Fig. 6, the size of the uncrosslinked vesicles increased during cooling process when the temperature was above 25 °C. As the temperature was below 25 °C, the uncrosslinked vesicles started to disassemble with increased PD. The above results indicated that the uncrosslinked vesicles were not stable and would disassemble at low temperatures.
Similarly, the temperature of the photocrosslinked vesicles solution was gradually increased from 5 to 45 °C and then decreased from 45 to 5 °C. The hydrodynamic diameter of the crosslinked vesicles during temperature variation was shown in Fig. 7. During the temperature-rising process, the Dh of the crosslinked vesicles gradually decreased from 218 to 193 nm with PD less than 0.20. Then, the Dh of the vesicles gradually increased from 191 to 223 nm with PD less than 0.20 during the cooling process. The above experimental data confirmed the temperature responsiveness and reversible size change during temperature variation of the crosslinked vesicles. The temperature rising and dropping processes were repeated three times with excellent repeatability.
3.6 Drug release behavior of block copolymer
vesicles
The cavity and membrane of vesicles can entrap hydrophilic and hydrophobic drugs, respectively. To verify the drug loading and controlled release capability, antibiotics were encapsulated by vesicles. CIP is a water-soluble antibiotic in the form of a
1.0m270Un-cross-linked polymer vesiclesn/re240tdecrease of temperature0.8em210aid1800.6 cDim150Pan1200.4ydo90rdyH600.23051015202530354045500.0Temperature/oC
Fig. 6 Thermally controlled behavior of uncrosslinked polymer vesicles evaluated by temperature-dependent changes in size in aqueous solution. The temperature interval is 5 °C and the equilibration time is 30 min. During the temperature decrease process, the vesicles swelled and then dissociated below 25 °C.
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(a)1.0mn220/re0.8temincrease of temperaturea210id0.6 cDimPan2000.4ydord0.2yH190010203040500.0(b)Temperature/oC1.0m230n/re0.8te220mdecrease of temperatureaid0.6 c210DimPan2000.4ydordy1900.2H180010203040500.0Temperature/oC
Fig. 7 Thermally controlled behavior of photocrosslinked polymer vesicles evaluated by temperature-dependent changes in size in aqueous solution. The size of vesicles changed in the direction of
(a) the temperature rising, and (b) the temperature decreasing. The
temperature interval is 5 °C and the equilibration time is 30 min.
hydrochloride, which was loaded into the polymer vesicles at
40 °C.
The temperature-regulated release profile of CIP in the vesicles is shown in Fig. 8. The drug loading content was estimated to be 10.4% relative to the vesicles. The drug loading efficiency was about 32.7%. The release experiments were carried out in deionized water at 37 and 25 °C, respectively. The experimental results showed that for the same CIP-containing vesicles, after 12 h, the CIP release rate in the surrounding of the deionized aqueous solution is nearly 35% higher at 25 °C than at 37 °C. In the first two hours, vesicles showed an initial burst of
%100/esa80eler P60IC ev40italum20 CIP-loaded vesicles at 25 oC u CIP-loaded vesicles at 37 oC C0024681012Time/h
Fig. 8 Cumulative release profile of CIP-loaded vesicles at
37 and 25 °C.
CIP release, reaching 68% and 52% at 25 and 37 °C, respectively. After that, the cumulative CIP release of vesicles continued to increase slowly at 25 °C, reaching 92% at 12 h. At 37 °C, the amount of CIP released continued to increase, stabilized after 2 h, and then the cumulative release of CIP eventually remained at about 57%. And the amount of CIP released during the whole cooling process was higher than at 37 °C. The release rate at different temperatures indicated that the drug release was significantly retarded at 37 °C due to its entrapment within the polymer vesicles, suggesting that the temperature-triggered vesicles swelling was the primary drug release mechanism.
4 Conclusions
In summary, we have proposed a kind of temperature-sensitive polymer vesicles for lowering temperature triggered drug. TEM and SEM studies confirmed the structure of the vesicles, and DLS revealed their excellent stability against various temperatures after photocrosslinking. Moreover, for the same CIP-loaded vesicles, after 12 h, the CIP release rate was nearly 35% higher at 25 °C than at 37 °C. Overall, this photocrosslinked polymer vesicle with temperature-responsive properties has potential for future applications in the fields of lowering temperature triggered drug release for therapeutic hypothermia.
Supporting Information: 1H NMR spectrum, calibration curve, SEC curve and SEM study (Fig. S1–Fig. S5) are available free of charge via the internet at http://www.whxb.pku.edu.cn. References
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