JoVE Journal > Chemistry
Summary
Abstract
Introduction
Protocol
Resultados
Discussion
Divulgaciones
Acknowledgements
Materials
Referencias
Quimica

Nanosponge afinabilidad de tamaño y densidad de entrecruzamiento

Published: August 04, 2017
doi:
10.3791/56073
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,
1Chemistry Department,Vanderbilt University

Summary

Este artículo describe un proceso para ajustar la densidad tamaño y reticulación de covalente reticulado nanopartículas de poliésteres lineales que contienen funcionalidad colgante. Por adaptación de parámetros de síntesis (peso molecular de polímero, incorporación de funcionalidad colgante y crosslinker equivalentes), se logra una densidad de tamaño y reticulación deseado nanopartículas para solicitudes de entrega de medicamentos.

Abstract

Se describe un protocolo para la síntesis de poliésteres lineales que contienen funcionalidad epóxido de colgante y su incorporación a un nanosponge con dimensiones controladas. Este enfoque comienza con la síntesis de una lactona funcionalizada que es clave para la funcionalización del colgante del polímero resultante. Valerolactone (VL) y alílico-valerolactone (AVL) son copolymerized entonces mediante la polimerización de la anillo-abertura. Modificación después de la polimerización entonces se utiliza para instalar un grupo epóxido en algunos o todos los grupos alilo de colgante. Química de epoxy-amina se emplea en forma de nanopartículas en una solución diluida de polímeros y pequeñas moléculas diamina crosslinker basado en la densidad deseada de nanosponge tamaño y reticulación. Tamaños de Nanosponge se caracteriza por la transmisión imágenes de microscopía electrónica (TEM) para determinar la dimensión y distribución. Este método proporciona un camino por el cual poliéster altamente armonioso puede crear nanopartículas sintonizables, que pueden ser utilizadas para la encapsulación de fármacos de molécula pequeña. Debido a la naturaleza de la columna vertebral, estas partículas son hidrolítico y enzimáticamente degradables para una liberación controlada de una amplia gama de pequeñas moléculas hidrofóbicas.

Introduction

Precisamente, ajuste la densidad tamaño y reticulación de nanopartículas basadas en la reticulación intermolecular es de gran importancia para influir y orientar el perfil de liberación de fármaco de estos nanosistemas1. Diseño afinabilidad de nanosponge, es decir, preparación de partículas de densidad de red diferente, es dependiente sobre la funcionalidad del colgante del polímero precursor y los equivalentes del crosslinker hidrofílico incorporado. En este enfoque, la concentración de los precursores y el crosslinker en el solvente es importante forma de nanopartículas de un tamaño discreto, en lugar de un gel a granel. Utilizando espectroscopia cuantitativa de resonancia magnética nuclear (RMN) como una técnica de caracterización permite la determinación precisa de funcionalidad incorporado colgante y peso molecular de polímero. Una vez que las nanopartículas se forman, pueden ser concentrados y solubilizados en materia orgánica sin tener el carácter de un nanogel.

Trabajo reciente en el suministro de medicamentos nanopartículas se ha centrado en el uso de poli (láctico-co-ácido glicólico) (PLGA) montado por nanopartículas2,3,4,5,6. EGLP tiene vínculos éster degradable que hacen conveniente para aplicaciones de suministro de drogas y se combina a menudo con poly(ethylene glycol) (PEG) debido a sus propiedades stealth7. Sin embargo, debido a la naturaleza uno mismo-montada de la formación de partículas PLGA, las partículas no solubilizadas en materia orgánica para otros funcionalización. En contraste con nanopartículas PLGA, el método propuesto proporciona reticulación covalente formando una nanopartícula con tamaños definidos y morfología, que son estables en materia orgánica y degradan en soluciones acuosas1. Ventajas de este enfoque son la capacidad más funcionalizar químicamente la superficie de la nanosponge8, y su estabilidad en solventes orgánicos puede ser utilizado para la posterior carga de las partículas con compuestos farmacéuticos1,9. Con este método, encapsulación de pequeñas moléculas hidrofóbicas se logra por precipitación en medios acuosos. La hidrofobicidad de la columna vertebral poliéster junto con el crosslinker corto hidrofílico le da a estas partículas un carácter amorfo a la temperatura corporal. Además, después del cargamento de droga, las partículas pueden formar suspensiones finas en medios acuosos para ser fácilmente inyectados en vivo. Es nuestro objetivo en este trabajo para evaluar los parámetros de la síntesis de estos nanosponges poliéster y determinarlos que son de vital importancia para el diseño y control de tamaño y morfología.

Protocol

1. Synthesis and Characterization of AVL

  1. Place a magnetic stir bar inside a 2 neck 500 mL round bottom flask (Flask 1) and seal with an appropriate sized rubber septum and steel wire. Flame dry the flask to remove moisture by purging with nitrogen gas connected through an inlet needle and open outlet needle in the septum, while using a butane flame torch to gently heat the outside of the flask by moving the flame along the surface.
    1. Continue heating the entire flask by running the flame across the surface until moisture clouding the inside of the flask is not seen. Remove the flame and let the flask cool to room temperature while continuing the nitrogen flow throughout the reaction.
  2. Add 156.25 mL anhydrous tetrahydrofuran (THF) via a 30 mL syringe to Flask 1. Cool Flask 1 to -78 °C with a dry ice/acetone bath. Monitor the temperature with a thermometer throughout the reaction and add dry ice as needed to maintain -78 °C. Begin stirring the magnetic stir bar using a magnetic stir plate to create a gentle vortex.
  3. Add N,N-diisopropylethylamine (DIPA) (3.30 mL, 2.3 x 10-2 mol) via a 5 mL syringe, followed by the dropwise addition of 2.5 M n-Butyllithium (9.34 mL, 2.3 x 10-2 mol) via a 10 mL glass syringe equipped with a needle locking mechanism and metal needle to Flask 1. Continue to stir using a magnetic stir plate for 15 min at -78 °C.
  4. Flame dry (as described in step 1.1) and purge with argon gas (as described in step 1.1 with nitrogen gas) a 100 mL round bottom flask (Flask 2). Remove the argon gas inlet and outlet at the same time once the flask is cool enough to touch. Add 56 mL anhydrous THF via a 30 mL syringe and δ-valerolactone (VL) (1.97 mL, 2.1 x 10-2 mol) via a 5 mL syringe.
  5. Add the solution in Flask 2 to Flask 1 via a small cannula dropwise over 45 min while continuously stirring via a magnetic stir bar. Once Flask 2 is empty, remove the cannula and allow Flask 1 to continue stirring for 15 min at -78 °C.
  6. Flame dry (as described in step 1.1) and purge with argon gas (as described in step 1.1 with nitrogen gas) a 25 mL round bottom flask (Flask 3). Remove the argon gas inlet and outlet at the same time once the flask is cool enough to touch, to maintain positive pressure inside the flask. Add ally bromide (2.02 mL, 2.3 x 10-2 mol) and hexamethyphosphoramide (HMPA) (4.43 mL, 2.5 x 10-2 mol) each via a 5 mL syringe.
  7. Add Flask 3 to Flask 1 via a small cannula dropwise. Once Flask 3 is empty, remove the cannula.
    1. Remove as much dry ice and cold acetone as possible from the dry ice/acetone bath in which Flask 1 is submerged using a scoop and plastic cup. Replace with room temperature acetone to raise the bath to -40 °C and allow Flask 1 to continue stirring for 2 h while monitoring the temperature. If the temperature increases above -40 °C, add a few pieces of dry ice to cool the acetone.
    2. Warm to -10 °C by removing the cold acetone and dry ice and replace with room temperature acetone.
  8. Remove the septum from Flask 1 and quench the reaction with a 150 mL saturated ammonium chloride solution while stirring via a magnetic stir bar. Place Flask 1 in a freezer at -20 °C overnight for storage.
  9. Remove Flask 1 from the freezer and allow to warm to room temperature. Pour the solution from Flask 1 into a 500 mL separatory funnel.
  10. Add 50 mL dichloromethane (DCM), cap the separatory funnel, and rock gently to mix the DCM and aqueous/THF mixture to extract the product into the organic layer. Collect the organic layer into a 500 mL beaker containing an appropriately sized magnetic stir bar by opening the separatory funnel stopcock and set aside. Repeat two times.
  11. Collect all the organics into the same beaker and stir over magnesium sulfate (to remove any residual water) using a magnetic stir plate until the magnesium sulfate no longer clumps when added to solution. Discard the aqueous waste.
  12. Remove the magnesium sulfate solid from the organic product solution by using a filter paper inside a glass funnel and collect the organics in a 250 mL round bottom flask. Rinse the filter paper and solid magnesium sulfate with excess DCM to ensure that all the product is collected.
  13. Remove the solvent from the product by rotary evaporation while heating at 30 °C and using a water aspirator as the vacuum source.
  14. Purify the crude product by column chromatography10 using a silica gel as the stationary phase and eluting beginning with 3% ethyl acetate/hexanes for 1 column volume (CV), increasing the gradient to 29% ethyl acetate/hexanes over 5 CVs. Collect the fractions in 16 x 150 mm2 borosilicate glass tubes.
  15. Perform thin layer chromatography using 20% ethyl acetate/hexanes as eluent to determine the product fractions.
  16. Combine all product fractions into an appropriately sized round bottom flask and remove the solvent using rotary evaporation at 40 °C. Transfer to a pre-weighed product vial and place under a high vacuum at 0.05 torr to obtain pure AVL. Characterize the product by 1H NMR11 (CDCl3, 400 MHz): δ 5.75 (m, 1H), 5.06 (m, 2H), 4.26 (m, 2H), 2.54 (m, 3H), 2.28 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.54 (m, 1H). Yield: 2.07 g (70.56%).

2. Synthesis and Characterization of VL- co- AVL

  1. Flame dry and purge with nitrogen gas a 25 mL round bottom flask equipped with a magnetic stir bar and septum.
    1. Flame dry the flask to remove moisture by purging with nitrogen gas connected through an inlet needle and open outlet needle in the septum, while using a butane flame torch to gently heat the outside of the flask by moving the flame along the surface.
    2. Continue heating the entire flask by running the flame across the surface until moisture clouding the inside of the flask is not seen. Remove the flame and let the flask cool to room temperature while continuing the nitrogen flow throughout the reaction.
  2. Quickly remove the septum from the round bottom and add tin(II) triflate (2.5 mg, 5.9  x 10-6 mol) to the very bottom of the flask using a spatula. Replace the septum.
  3. Add 3-methyl-1-butanol (72.6 µL, 6.6 x 10-3 mol) via a 100 µL microsyringe and 1.33 mL anhydrous DCM via a 2 mL syringe sequentially. Stir via a magnetic stir plate for 10 min.
  4. Add AVL (0.48 mL, 3.7 x 10-3 mol) and VL (1.37 mL, 1.4 x 10-2 mol) sequentially via a syringe. Allow to continue stirring for 18 – 20 h.
    NOTE: The AVL and VL percentage in the final copolymer can be altered by stoichiometry in this step.
  5. Quench the reaction by adding ~5 mL methanol (MeOH). Add ~100 mg solid-support tin scavenger and stir for 2 h. Filter by gravity filtration to remove the solid.
  6. Remove the solvent under rotary evaporation with a water aspirator as the vacuum source while heating at 30 °C until the solution is viscous. Precipitate the solution dropwise into 500 mL cold MeOH (chilled with dry ice for at least 1 h) to produce flakes of white solid. Filter the solution by vacuum filtration into a funnel containing a fritted glass disc with filter paper to collect the solid.
    NOTE: If precipitation produces a cloudy supernatant or fine powder which goes through the filter paper, then the product solution is too dilute. All supernatant solvent should be removed by rotary evaporation with a water aspirator as the vacuum source while heating at 30 °C until the solution is viscous and then precipitation should be performed again.
  7. Transfer the solid product to a pre-weighed vial via a spatula and dry overnight via high vacuum pressure of 0.05 torr to collect the white, flaky solid.
  8. Characterize the polymer by 1H NMR11 (CDCl3, 400 MHz): δ 5.71 (m, 1H), 5.03 (t, 2H), 4.08 (m, 4H), 3.65 (t, 2H), 2.15 – 2.50 (m, 5H), 1.47-1.78 (m, 9H), 0.91 (d, 6H). 81.42% VL, 18.58% AVL, 2,940 g/mol, 578 g/mol repeat unit of AVL. Yield: 1.43 g, (73.43%).

3. Post-polymerization Epoxidation to Produce Epoxy-valerolactone (EVL) Copolymer Units

  1. Add VL-co-AVL copolymer (500 mg, 1.7  x 10-4 mol, 2,940 g/mol) to a 6-dram vial with a magnetic stir bar. Add 6.15 mL anhydrous DCM to the vial and vortex to solubilize the polymer.
  2. Add meta-chloroperoxybenzoic acid (mCPBA) (74.53 mg, 4.3 x 10-4 mol) to a second 6-dram vial. Add 6.15 mL anhydrous DCM and vortex until the mCPBA is solubilized completely.
    NOTE: The conversion ratio of allyls to epoxides can be varied by altering the stoichiometry in this step. The final allyl concentration in the solvent should be 0.065 M.
  3. Transfer the mCPBA solution to the VL-AVL solution. Cap the reaction and cover with a plastic paraffin film. Allow to stir for 48 h.
  4. Transfer the reaction mixture to a 50 mL separatory funnel. Add 15 mL saturated sodium bicarbonate, cap the separatory funnel, and rock gently to mix. Collect the organic layer containing the product into a 50 mL Erlenmeyer flask with an appropriate sized magnetic stir bar (product flask).
    1. Add 5 mL DCM to the aqueous layer that is still in the separatory funnel, cap, and then rock gently. Collect the organics into the product flask. Discard the aqueous waste. Transfer the organic layer back into a separatory funnel. Repeat this aqueous wash two times.
  5. Add magnesium sulfate (to remove any residual water) to the product flask while stirring over a magnetic stir plate. Continue adding small scoops of magnesium sulfate until it no longer clumps when added. Use a glass funnel fitted with a filter paper to remove the solid magnesium sulfate while transferring the mixture to a 50 mL round bottom flask.
  6. Remove the solvent by rotary evaporation with a water aspirator as the vacuum source and heating at 25 °C. Transfer the contents of the round bottom flask to a pre-weighed product vial and remove the solvent by rotary evaporation. Place on high vacuum at 0.05 torr overnight to produce a white, waxy solid.
  7. Characterize by 1H NMR11 (CDCl3, 400 MHz): δ 5.71 (m, 1H), 5.03 (t, 2H), 4.08 (m, 4H), 3.65 (t, 2H), 2.94 (d, 1H), 2.90 (s, 1H), 2.74 (s, 1H), 2.15-2.50 (m, 5H), 1.47-1.78 (m, 9H), 0.92 (d, 6H). 84.53% VL, 9.65% AVL, 5.82% EVL, 2,855 g/mol, 1,841 g/mol repeat unit of EVL. Yield: 417.3 mg, (83.46%).

4. Nanosponge Synthesis and Characterization

  1. Dissolve the VL-co-AVL-co-EVL polymer (200 mg, 7.0 x 10-5 mol, 2,855 g/mol) in 20.01 mL anhydrous DCM for an epoxide concentration of 0.0054 M. Transfer to a 100 mL round bottom flask with a 14/20 neck.
    NOTE: To catalyze the reaction, 100 µL aqueous saturated sodium bicarbonate can be added in this step.
  2. Place the reaction flask in an oil bath at 50 °C. Stir the solution with a fast vortex and add 2,2'-(ethylenedioxy)bis(ethylamine) (21.45 µL, 2.9 10-4 mol) via a microsyringe dropwise. Fit the neck of the flask with a water-jacketed condenser with cool water flowing through it, fitted with a 14/20 neck adapter, and reflux the solution for 12 h. Ensure a very tight seal between the neck of the flask and the condenser to avoid solvent evaporation.
  3. Remove excess solvent from the reaction flask by rotary evaporation at 25 °C until a viscous solution is obtained.
  4. Place a large magnetic stir bar into a 2 L beaker. Cut an approximately six-inch section of 10 K molecular weight cut-off (MWCO) dialysis tubing and fold one end then close with a dialysis clip.
    1. Transfer the product to 10 K MWCO dialysis tubing. Rinse the flask with excess DCM and transfer it to the tubing.Fold the top of the tubing and close with a dialysis clip that has a wire for hanging. Hang the dialysis tubing on the side of the beaker using the wire and fill the beaker with DCM until the dialysis tubing is completely submerged.
    2. Place on a magnetic stir plate and stir gently. Cover the beaker with aluminum foil to prevent solvent evaporation. Remove the solvent by pouring into a waste container and replace with fresh DCM three times daily for 48 h to remove the unreacted polymer and crosslinker.
  5. Remove all solvent from the beaker and transfer the contents of the dialysis tubing to a 10 mL syringe fitted with a 0.45 µm polytetrafluoroethylene (PTFE) syringe filter. Push the solution through the filter directly into a pre-weighed product vial to remove any remaining impurities. Remove the solvent by rotary evaporation at 25 °C, then place on high vacuum at 0.05 torr overnight to collect the light yellow, waxy solid.
  6. Characterize by 1H NMR11 (CDCl3, 400 MHz): δ 5.71 (m, 1H), 5.03 (t, 2H), 4.08 (m, 4H), 3.60-3.67 (t, 14H), 2.94 (d, 1H), 2.90 (s, 1H), 2.74 (s, 1H), 2.15-2.50 (m, 5H), 1.47-1.78 (m, 9H), 0.92 (d, 6H). Yield: 176.9 mg (88.45%).

5. TEM Imaging of Nanosponge Morphology and Size

  1. Filter 5 mL cell culture water through a 0.2 µm PTFE syringe filter.
  2. Place 0.5 mg nanosponges into a 1.5 mL centrifuge tube. Add 1 mL filtered cell culture water. Use a probe sonicator (20 kHz, 40 a) to sonicate the solution with 2 s bursts 4 – 5 times at room temperature until the particles have developed a fine suspension. Do not use prolonged sonication or let the solution heat up as this will cause aggregation.
  3. Add 30 mg phosphotungstic acid hydrate (PTA) to 1 mL filtered cell culture water in a 1.5 mL centrifuge tube. Vortex on the highest setting for 10 s or until the PTA is completely solubilized to produce 3% PTA solution.
  4. Use a 1 mL syringe with 22 G needle to draw up 0.5 mL 3% PTA solution. Add 4 drops of the 3% PTA solution to the particles and vortex on the highest setting for 10 s. Use a pair of self-closing tweezers to pick up a TEM grid then dip it into the particles solution quickly, three times. Let the grid dry for 5 h under a cover to reduce dust collection on the grid.
  5. Perform TEM imaging12 of the sample using high contrast and 40 µm objective.

Representative Results

Para evaluar la relación entre los parámetros de síntesis de la nanosponge y su tamaño resultante, es importante la concentración y colgante de funcionalidad de cada precursor de polímero. En la figura 1, se lleva a cabo un esquema de successfulsynthetic de nanosponges bajo condiciones de reflujo tras incorporar ambos crosslinker de diamina y el polímero precursor en DCM de 12 h. La concentración de epóxidos en la solución también es fundamental a …

Discussion

Obtener medidas reproducibles nanosponge es vital en aplicaciones de suministro de drogas. Varios parámetros en la síntesis de polimerización y nanosponge afectan el tamaño y reticulación de la densidad de la partícula resultante. Tres parámetros importantes fueron identificados en nuestro análisis: peso molecular de polímero, epóxido colgante funcionalidad y crosslinker equivalentes. Para producir una gama de pesos moleculares y funciones epóxido para síntesis de nanosponge, debe modificarse la estequiometr?…

Divulgaciones

The authors have nothing to disclose.

Acknowledgements

LK es agradecido para la financiación del programa nacional de ciencia Fundación postgrado investigación beca (DGE-1445197) y Departamento de química de la Universidad de Vanderbilt. LK y EH quisiera agradecer la financiación para el instrumento Osiris TEM (NSF EPS 1004083).

Materials

2,2'-(Ethylenedioxy)bis(ethylamine) Sigma-Aldrich 385506-100ML
3-methyl-1-butanol Sigma-Aldrich 309435-100ML anhydrous, ≥99%
Acetone Sigma-Aldrich 179124-4L
Allyl bromide Sigma-Aldrich A29585-5G ≥99%
Ammonium chloride Fisher Scientific A661-500 saturated solution in DI water
Cell culture water Sigma-Aldrich W3500-500ML Filtered through 0.45 μm syringe filter
Dichloromethane (DCM) Sigma-Aldrich 270997-100ML anhydrous, ≥99%, contains 40-150 ppm amylene as stabilizer
Ethyl Acetate Fisher Scientific E145SK-4
EZFlow 0.2 μm Syringe Filter Foxx Life Sciences 386-2116-OEM Hydrophillic PTFE, 13 mm
EZFlow 0.45 μm Syringe Filter Foxx Life Sciences 386-3126-OEM Hydrophillic PTFE, 25 mm
Fisherbrand Disposable Borosilicate Glass Test Tubes with Plain End Fisher Scientific 14-961-31
Fisherbrand Microcentrifuge Tubes Fisher Scientific 14-666-318 1.5 mL
Hamilton Microliter Syringe, 100 μL Hamilton Company 80600 Model 710 N SYR, Cemented NDL, 22s ga, 2 in, point style 2
Hexamethylphosphoramide Sigma-Aldrich H11602-100G ≥99%, contains ≤1000 ppm propylene oxide as stabilizer
Hexanes Fisher Scientific H292-4
Magnesium sulfate anhydrous Fisher Scientific M65-500
Meta-chloroperoxybenzoic acid Sigma-Aldrich 273031-100G Purified to ≥99% by buffer wash
Methanol (MeOH) Sigma-Aldrich 322415-100ML anhydrous, ≥99%
N-butyllithium solution Sigma-Aldrich 230707-100ML 2.5 M in hexanes
N,N-diisopropylethylamine Sigma-Aldrich 550043-500ML ≥99%
Parafilm M Sigma-Aldrich P7793-1EA
PELCO Pro Reverse (Self-Closing) Tweezers Ted Pella, Inc. 5375-NM
Phosphotungstic acid hydrate Alfa Aesar 40116
Q55 Sonicator Qsonica Q55-110 55 Watts, 20 kHz
SiliaMetS Cysteine Silicycle R80530B-10g
SnakeSkin Dialysis Clips Thermo Scientific 68011
SnakeSkin Dialysis Tubing, 10K MWCO Thermo Scientific 68100
Sodium bicarbonate Fisher Scientific 5233-500 saturated solution in DI water
TEM grid Ted Pella, Inc. 01822-F Ultrathin Carbon Type-A, 400 mesh, Copper, approx. grid hole size: 42µm
Tetrahydrofuran (THF) Sigma-Aldrich 401757-1L Anhydrous, ≥99.9%, inhibitor-free
Tin(II) trifluoromethanesulfonate Sigma-Aldrich 388122-1G
Vortex-Genie 2 Scientific Industries SI-0236
Whatman Filter Paper, Grade 1 Fisher Scientific 09-805H Circles, 185 mm
δ-valerolactone Sigma-Aldrich 389579-100ML Purified by vacuum distillation
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Referencias

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Tags

NanospongeSizeCrosslinking DensityDrug DeliveryPolymer NetworksHydrogelsMicroparticlesTin Triflate3-methyl-1-butanolAnhydrous DCMAVLVLMethanolSolid Support ScavengerRotary EvaporationVLAVL Co-polymer

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Kendrick-Williams, L. L., Harth, E. Nanosponge Tunability in Size and Crosslinking Density. J. Vis. Exp. (126), e56073, doi:10.3791/56073 (2017).
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