Particles without a Box: Brush-first Synthesis of Photodegradable PEG Star Polymers under Ambient Conditions

Summary

Poly(ethylene glycol) (PEG) brush-arm star polymers (BASPs) with narrow mass distributions and tunable nanoscopic sizes are synthesized in via ring opening metathesis polymerization (ROMP) of a PEG-norbornene macromonomer followed by transfer of portions of the resulting living brush initiator to vials containing varied amounts of a rigid, photo-cleavable bis-norbornene crosslinker.

Abstract

Convenient methods for the rapid, parallel synthesis of diversely functionalized nanoparticles will enable discovery of novel formulations for drug delivery, biological imaging, and supported catalysis. In this report, we demonstrate parallel synthesis of brush-arm star polymer (BASP) nanoparticles by the "brush-first" method. In this method, a norbornene-terminated poly(ethylene glycol) (PEG) macromonomer (PEG-MM) is first polymerized via ring-opening metathesis polymerization (ROMP) to generate a living brush macroinitiator. Aliquots of this initiator stock solution are added to vials that contain varied amounts of a photodegradable bis-norbornene crosslinker. Exposure to crosslinker initiates a series of kinetically-controlled brush+brush and star+star coupling reactions that ultimately yields BASPs with cores comprised of the crosslinker and coronas comprised of PEG. The final BASP size depends on the amount of crosslinker added. We carry out the synthesis of three BASPs on the benchtop with no special precautions to remove air and moisture. The samples are characterized by gel permeation chromatography (GPC); results agreed closely with our previous report that utilized inert (glovebox) conditions. Key practical features, advantages, and potential disadvantages of the brush-first method are discussed.

Introduction

Polymeric nanoparticles have been widely studied for their potential use as platforms for drug delivery, supported catalysis, biological imaging, and self-assembly^1-3. Modern applications require that nanoparticle syntheses be facile, reproducible, compatible with chemical functionalities, and amenable to diversification^4,5. Ring-opening metathesis polymerization (ROMP) of strained olefins is a powerful methodology for the synthesis of functional polymeric nanostructures with controlled sizes and narrow mass distributions^1,6-8. For example, norbornene-functionalized poly(ethylene glycol) (PEG) macromonomers (MMs) can be efficiently pol....

Protocol

We first describe the synthesis and purification of PEG-MM B from 3 kDa O-(2-aminoethyl)polyethylene glycol (PEG-NH₂) and norbornene-N-hydroxysuccinimidyl (NHS) ester. The former compound can be purchased from Sigma Aldrich Inc., or prepared via anionic polymerization according to literature procedures^22,23. The latter compound can be prepared in two steps according to a published procedure²¹. Next we describe a synthesis of catalyst A from commercially available Grubbs 2^nd generation catalyst. We then demonstrate the use of this complex for brush-first BASP synthe....

Results

Figure 2 shows GPC traces for a variety of BASPs prepared from B1, B2, and B3. In all cases, the data illustrate that increasing the equivalents of crosslinker (N) leads to an increase in the size of the BASP. As was observed in our previous report, 10 equivalents of crosslinker is not sufficient to achieve uniform BASPs; the N = 10 sample shows a clearly multi-modal GPC trace with a large amount of residual b.......

Discussion

The key advantage of brush-first BASP synthesis is the unique ability to rapidly synthesize nanostructures of diverse size and composition in parallel without need for specialized equipment. In this study, we demonstrate the brush-first synthetic method using a norbornene functionalized PEG macromonomer (B, Figure 1) and a bis-norbornene nitrobenzyl ester crosslinker (C, Figure 1). The PEG chains from B impart .......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Grubbs Second Generation Catalyst	Materia (or Sigma Aldrich)	C848 (Sigma Aldrich: 569747)	Used as purchased from manufacturer. *Provided as a generous gift.
Pyridine	Sigma Aldrich	270970	Used as purchased from manufacturer
O-(2-aminoethyl)polyethylene glycol 3000	Sigma Aldrich	07969	Used as purchased from manufacturer
PEG-MM	N/A	N/A	Synthesized following reported procedures (Ref. 21, protocol 1)
norbornene-N-hydroxysuccinimidyl (NHS) ester	N/A	N/A	Synthesized following reported procedures (Ref. 21)
Bis-norb-NBOC Crosslinker	N/A	N/A	Synthesized following reported procedures (Ref. 21)
Pentane	Sigma Aldrich	158941	Used as purchased from manufacturer
Tetrahydrofuran (HPLC grade)	Sigma Aldrich	34865	Dried and purified over a solvent purification columns
Dichloromethane	VWR	BDH1113-4LG	Used as purchased from manufacturer
Acetonitrile (HPLC grade)	Sigma Aldrich	34998	Used as purchased from manufacturer
Acetic Acid	Sigma Aldrich	A6283	Used as purchased from manufacturer
Sodium sulfate	Sigma Aldrich	239313	Used as purchased from manufacturer
Diethyl ether	Sigma Aldrich	673811	Used as purchased from manufacturer
Dimethylformamide (HPLC grade)	Sigma Aldrich	270547	Used as purchased from manufacturer
Lithium Bromide	Sigma Aldrich	213225	Used as purchased from manufacturer
MillQ Biocel A10	Millipore
Beckmann Coulter HPLC (127p solvent module, 166p detector)	Beckmann Coulter
Zorbax 300SB-C18 PrepHT reverse phase column	Agilent
1260 Infinity Liquid Chromatography	Agilent
GPC KD-806M column	Shodex
Dawn Heleos II Light Scatterer	Wyatt
Optilab T-rEX Refractive Index Detector	Wyatt
Glass Scintillation Vials - 40 ml	Chemglass	CG-4909-05
Glass Scintillation Vials - 4 ml	Chemglass	CG-4904-06
Glass Scintillation Vials (PTFE-lined cap) - 2 ml	Agilent	5183-4518
Stir-bars	VWR	5894x	various sizes
13 mm 0.45 µm Nylon Syringe filter	PerkinElmer	02542903
13 mm 0.45 µm polytetrafluoroethylene syringe filter	PerkinElmer	02542909
1 ml disposable syringes	VWR	53548-001
Swing bucket centrifuge or similar			Should be able to reach approximately 4,000 rpm
Round bottom flask
Fritted glass filter assembly
Rotary Evaporator
Balance