Review on Synthesis of Colloidal Hollow Particles and Their

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A Review on Synthesis of Colloidal Hollow Particles and Their Applications Waraporn Wichaita, Duangporn Polpanich, and Pramuan Tangboriboonrat Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.9b02330 • Publication Date (Web): 16 Jul 2019 Downloaded from pubs.acs.org on July 20, 2019

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Industrial & Engineering Chemistry Research

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A Review on Synthesis of Colloidal Hollow Particles and Their

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Applications

3 Waraporn Wichaita1, Duangporn Polpanich2 and Pramuan Tangboriboonrat1*

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1Department

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of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Phyathai, Bangkok 10400, Thailand

2NANOTEC,

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National Science and Technology Development Agency, 111 Thailand Science

Park, Phahonyothin Road, Khlong Luang, Pathum Thani 12120, Thailand

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*Corresponding author: [email protected]

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Tel.: +66-2-2015135, Fax: +66-2-3457151

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Abstract Hollow latex (HL) particles of polymers or hybrid polymer/inorganic materials have

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advantages in efficient encapsulation of active ingredients, ability to improve opacity or

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hiding power and low density. Due to the flexible design for achieving the desired

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functionality, polymeric HL particles serve as stimuli-responsive capsules for drug delivery

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and cosmetics, white pigment for coatings as well as nanoreactors for the confined reactions.

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Among numerous studies on the synthesis of HL particles for specific applications, this

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review article summarizes the recent works on the HL particles prepared from both synthetic

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and natural polymers. The template-based methods using sacrificial hard or soft template,

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self-templating and non-sacrificial techniques are described. Various factors affecting

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morphologies and properties of HL particles are discussed in details. Their applications in

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coatings, cosmetics, biomedicines, electronics and others are also presented.

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KEYWORDS: hollow latex particle, nanocapsule, sacrificial template, drug delivery, opaque

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polymer

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Industrial & Engineering Chemistry Research 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Contents

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1. Introduction

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1. Introduction ………….………………………………………………………………….….2 2. Synthesis of polymeric HL particles ……………..………………………………………...4 2.1. Hard-templating method ………………….……………………………….…………4 2.2. Soft-templating method……………………………………………………………..17 2.3. Self-templating method……………………………………………………………..23 2.3.1. Osmotic swelling…………………………………………………………..….23 2.3.2. Seeeded emulsion polymerization……...….………..………...…….….……..26 2.4. Non-sacrificial templating method………….………….………………………..…31 3. Applications of polymeric HL particles………………………………………...……...…36 3.1. Coatings ……………...….…………………………….………………...……….…36 3.2. Cosmetics……………………………......………..…….……………..……….....…38 3.3. Biomedicines...………………………......…………..………………..……….....…39 3.4. Electronics……....………....……………………………………………………..…41 3.5. Others…………...………….…………………………………………………….…42 4. Conclusion…………………………………………………………………………….….44

Hollow latex (HL) or void-containing particles have unique properties in terms of

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light weight, high opacity and high volume fraction for encapsulation.1,2 The polymeric HL

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particles are of technological interest due to their remarkable properties including

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controllable size, shape and shell thickness, tunable chemical functionality, robust shell and

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porosity as well as facile processibility.3,4 Such particles offer numerous applications

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especially in coatings, electronics, catalysis, cosmetics and biomedical fields. The most

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common procedure used to prepare polymeric HL particles is the template-based strategy.5,6

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The sacrified core or template, which can be hard colloidal particle or soft matter, is coated

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by the desired shell and, after template removal, HL particle is produced. This method has

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benefited a variety choice of components including biodegradable and biobased polymers as

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well as inorganic/organic substances. However, several steps are required and the core-

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removal step might damage the structural integrity of shell. The self-templating method is,

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therefore, introduced. Based on this technique, the void inside polymer particle can be

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generated by either the osmotic swelling process during neutralization step or the phase

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separation during the seeded emulsion polymerization (SEP).2,7,8 Thermodynamically, the

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osmotic swelling method is limited to spherical structure and requires the hydrophilic coreACS Paragon Plus Environment

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hydrophobic shell particle.9,10 Whereas the SEP generates polymeric HL particle in one-pot

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through the migration of seed polymer toward the shell region without core removal.11,12 The

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other technique, non-sacrificial templating, also omits this step because polymerization

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occurs in the bilayer of surfactant-based hollow vesicle.13,14 However, the control of void size

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and shell thickness of HL particles is still a great challenge. In addition, non-spherical HL

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particles with anisotropic properties are particularly attractive, although the deviation from

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spherical shape is rather untypical and requires multi-step procedure.15,16

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In this review, the syntheses of polymeric HL particles based on hard-templating, soft-templating, self-templating and non-sacrificial templating methods are systematically

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presented. The recent published works relating to a variety of morphologies and properties of

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HL particles prepared from several synthetic pathways are discussed in details. The

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applications, especially in industry, of polymeric and hybrid inorganic/polymeric HL

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particles are summarized. A comprehensive list of abbreviations for common polymers and

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chemicals are listed in Table S1.

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2. Synthesis of polymeric HL particles The polymeric HL particles can be synthesized typically by means of the hard/soft

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templating, self-templating and non-sacrificial templating methods. For the template-based

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strategy, polymer shell is formed by coating, polymerization or self-assembly onto a hard or

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soft template. The hollow structure is generated after template removal. This step is tedious

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and possibly damages the shell. Later, the self-templating method, via the osmotic swelling or

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the seeded emulsion polymerization (SEP), and the non-sacrificial templating method are

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introduced. These methods produce an internal void without the need of template removal.

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By using the self-template based technique, the core material transforms to the inner wall of

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the muti-layer shell, which surrounds the void of HL particle. The non-sacrificial technique is

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more straightforward and involves a surfactant-based vesicles for HL particle formation.

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Various shapes of polymeric HL particles prepared from each method are mentioned.

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2.1. Hard-templating method.

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The hard template-based method, widely used to synthesize HL particles with

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predictable cavity size, involves three major steps: (i) preparation of sacrificial template, (ii)

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formation of core-shell particle and (iii) selective removal of core by calcination or

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dissolution with solvent or acid. This method allows to prepare HL particles with different

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shapes, e.g., simple sphere, complex sphere and non-sphere, and compositions, e.g.,

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polymeric and hybrid polymeric/inorganic HL particles.

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To prepare spherical HL particle with single void and mono- or multi-layer polymer

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shells, silica nanoparticles (SiNPs), magnetic nanoparticles (MNPs) or polymer latex particles

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are generally used as templates. The shell can be made from one or more polymers via the

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emulsion polymerization (EP),17-19 atom transfer radical polymerization (ATRP),20,21

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dispersion polymerization22,23 and Layer-by-Layer (LbL) techniques.24-26 The hollow

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structure is formed after dissolving the template by strong inorganic acids, e.g., hydrofluoric


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acid (HF) and hydrochloric acid (HCl), or organic solvents, e.g., tetrahydrofuran (THF) and

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N,N-dimethylformamide (DMF). Prior to fabricating polymeric shell, the surface of SiNPs

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must be grafted by polymerizable silane coupling agents. To prepare monodisperse hollow

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microporous PS nanospheres (MHMPNSs), SiO2 template was first functionalized with 3-

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methacryloxypropyltrimethoxysilane (MPS) and then coated with PS, via emulsion

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polymerization, as schematically presented in Figure 1A.19 Figure 1B shows SiO2@xPS core-

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shell particles after intrasphere hypercrosslinking performed by the Friedel–Crafts reaction,

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whereas Figure 1C displays the robust MHMPNSs after etching SiO2 core with HF.

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Similarly, by immobilizing SiNP surface with an ATRP initiator, the surface-confined living

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radical polymerization of benzyl methacrylate (BMA) allowed the formation of core-shell

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structure which was then transformed to PBMA HL particles after core elimination.20 This

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technique offers HL particles with uniform shell thickness and high monodispersity. HL

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particles constructed by acetylenic polymers led to a shell with unique helical molecular

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architecture.17 The chirally substituted polyacetylene HL particles were acquired for chiral-

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related applications, e.g., asymmetric catalysis, chiral recognition, controlled release and

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enantioselective crystallization. In addition, electrical conductive HL particles were obtained

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by polymerization of conjugated polymer, i.e., polyaniline (PAni), on polystyrene sulfonate

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(PSS) core induced by charge interaction between the sulfonate and anilinium ions.27



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Figure 1. (A) Preparation of monodisperse hollow microporous PS nanospheres

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(MHMPNSs) via emulsion polymerization of styrene/divinyl benzene (St/DVB) on MPS

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modified SiO2 nanospheres, followed by the hypercrosslinking and etching by HF, and TEM

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micrographs of (B) SiO2@xPS core–shell particles and (C) MHMPNSs. Adapted from Ref.

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19 with permission from The Royal Society of Chemistry, Copyright 2014.

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Caruso et al. prepared biodegradable polymer capsules of poly(L-glutamic acid) (PGA) by coating the dopamine modified PGA on SiO2 particles.28 Before removing the core,

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the shell was strengthened by mediated crosslinking between dopamine units via oxidative

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polymerization. The coordination complexes of natural polyphenol tannins and Fe(III) ions

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were also employed to assemble a shell of metal-phenolic networks (MPNs) on PS template

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in one-step, facilitating relatively low-cost and ease of scaling process.29 The fully green

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technique was developed using lignin core particle because it was easily removed with water

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or mild organic solvent under ambient conditions as schematically presented in Figure 2.30


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Figure 2. Formation of metal-organic network-based HL particle on colloidal lignin using

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Fe(III) and tannins as building blocks for a shell formation. Reproduced from Ref. 30 with

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permission from The Royal Society of Chemistry, Copyright 2018.

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Formation of multi-layer HL particles via the LbL assembly, governed by electrostatic

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or hydrogen-bond donor/acceptor, offers the ability to exert the control over shell thickness at

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nanoscale regime and a range choice of shell materials.31 Hong et al. assemblied protonated

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PS-block-poly(4-vinylpyridine) (PS-b-P4VP) and anionic PS-block-poly(acrylic acid) (PS-b-

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PAA) on a PS core.24 Without additional crosslink, HL particles retained their well-defined

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structure after dissolving core by THF. Many sacrificial colloidal templates, e.g., PS-based



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polymer, melamine formaldehyde, AuNPs, SiO2 or CaCO3, were employed in the syntheses

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of HL particles of polycation/polyanion, e.g., fluorescein isothiocyanate (FITC) modified

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chitosan (CS)/sodium hyaluronate,25 poly(urethane-amine) (PUA)/PSS,26

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poly(diallyldimethylammonium chloride) (polyDADMAC)/PSS,32-35 poly-L-arginine/dextran

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sulfate,32,36 poly(amidoamine) dendrimer/PSS,37 diazoresin/PSS38 and Fe(II) metallo-

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supramolecular polyelectrolyte/PSS.39 Recently, Richardson et al. have developed the facile

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technique to form HL particles with multi-layer of poly(allylamine) hydrochloride (PAH).40

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Since positive charges of PAH become negative after heating, the LbL coating of PAH on

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SiO2 template was conducted through the alternating heat/deposition steps. This technique

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provides the precise HL structure at molecular level through the simple operation, which is

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suitable for industrial use.

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Furthermore, Caruso et al. fabricated the hydrogen-bonded capsules possessing

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stimuli-responsive properties under physiologically-relevant conditions.41 The fundamental is

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based on the alternate deposition of polymers containing hydrogen bond acceptor/donor on

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SiO2 core prior to crosslinking. As shown in Figure 3, the pH-responsive capsules were

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obtained from the assembly of thiol-modifed poly(methacrylic acid) (PMA)/poly(vinyl

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pyrolidone) (PVPON), which were further crosslinked by oxidation of thiols into disulfide

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bonds.42,43 These capsules were stable in oxidizing conditions and disassembled in reducing

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conditions, which facilitated the in vivo degradation specifically. Sukhishvili et al. has

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extensively studied the multi-layer capsules of PVPON-NH2/PMA.44-46 The carbodiimide-

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assisted amide crosslinks between amine modified PVPON and carboxylic groups of the

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polyacid afforded capsule stability. These capsules could reversibly respond to pH, leading to

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the variation in swelling, permeability and stiffness. However, compared to the electrostatic-

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based capsules, interaction of hydrogen-bonding polymers is confined by pH of the

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environment, depending on pKa of the components as well as the strength of the bonding

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interaction between the pairs.


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Figure 3. Formation of hydrogen-bonded multi-layer crosslinked capsule of thiol-modified

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PMA/PVPON via the LbL technique. The capsule is deconstructed through the addition of a

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thiol−disulfide exchange reagent, dithiothreitol (DTT). Reprinted with permission from Ref.

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43. Copyright 2006 American Chemical Society.

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In case of sophisticated HL morphologies, e.g., yolk-shell or rattle-type, the multi-

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step synthesis of template/polymeric shell and the selective removal of specific layer inside

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the particle are required. Due to an interstitial space or hollow layer between core and shell,

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the core particle can move freely within the hollow sphere. This provides great benefits over

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the simple structure, e.g., large active sites for catalysis and high loading capacity. In

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addition, an interior core or external shell can be selectively functionalized or tuned for

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stimuli-responsive materials.47 Figure 4A shows the scheme of PS@PS-co-polyacrylamide

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(PAM) yolk-shell particle prepared via the hard template-based approach. The sandwich-like

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structure of PS/PS-co-poly(methacrylic acid) (PMAA)/PS-co-PAM (core/template/shell) was

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fabricated via the two-stage emulsion polymerization.48 PS-co-PMAA core-shell particle was

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firstly prepared (Figure 4B) and was then swelled by St/DVB monomers. As the forimg P(St-

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co-DVB) was incompatible with the core polymer, the phase separation within the seed

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occurred and the coated particle then assembled into sandwich-like structure (Figure 4C). The

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selectively etching the uncrosslinked template with DMF resulted in the yolk-shell particles

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(Figure 4D).



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Figure 4. (A) PS@PS-co-PAM yolk-shell particles prepared via the emulsion polymerization

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of St, DVB and AM onto a PS-co-PMAA core-shell particle. The PS@PS-co-PAM yolk-shell

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particles were obtained after etching the template by DMF. TEM micrographs of (B) PS-co-

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PMAA core-shell seed particles, (C) the sandwich-like PS/PS-co-PMAA/PS-co-PAM

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particles and (D) PS@PS-co-PAM yolk-shell particles. Reprinted with permission from Ref.

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48. Copyright 2011 American Chemical Society.

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Polymeric HL particle bearing a controllable hole in its external surface is another

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attractive design, which plays an important role in loading and controlled-releasing of active

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ingredients. Figure 5A displays a hole formed in each PS particle as a result of the

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evaporation of swollen toluene.49 MNPs, fluorescent species or small polymer particles could

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be loaded into the hollow interior, as respectively shown in Figures 5B-D, and the hole was

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then closed by thermal annealing or solvent treatment. The double-shell hollow micro-

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/nanostructured materials were expected to have better performance in many applications,

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e.g., carriers, sensors and drug delivery agents. ACS Paragon Plus Environment

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Figure 5. (A) SEM and TEM (inset) images of PS HL particles with a hole on its surface, (B)

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SEM and TEM (right inset) images of these particles loaded with MNPs, (C) fluorescence

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optical micrograph of PS beads containing dinitrophenol-conjugated bovine serum albumin

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as a fluorescence protein and (D) SEM image demonstrating the possibility to load the bowl-

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shaped PS HL particles with small PS beads. Adapted by permission from Springer Nature

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Customer Service Centre GmbH: Nature Publishing Group Nature Materials, Ref. 49,

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Copyright 2005.

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To install additional recognition function to HL, hollow molecularly imprinted

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polymer (HMIP) particle, which has template-shaped cavity on a shell matrix, has been

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attracting an increasing interest. Single-hole HMIPs, developed to accelerate the binding

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kinetics of target molecules, could be prepared by multi-step seed swelling polymerization

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using PS as a sacrificed template as shown in Figure 6A.50,51 This involved the dynamic

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swelling of PS core (Figure 6B) by DVB/MAA monomers, toluene and dibutyl phthalate as

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good solvent and template molecules, i.e., bisphenol A and Sudan-I, and subsequently

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polymerization. Figure 6C reveals HMIPs with a thick imprint porous shell containing single



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hole, after removing the solid core and imprinted molecules. Due to the open architecture of

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HMIPs, the binding capacity and mass transfer of desired molecules were enhanced.

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Figure 6. (A) Preparation process of a single-hole HMIP particle by seed swelling

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polymerization, followed by dissolution of a PS core and TEM images of (B) PS seeds and

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(C) single-hole HMIPs. Adapted with permission from Ref. 51. Copyright 2012 American

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Chemical Society.

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Similarly, the hybrid polymeric/inorganic HL particle that composes of polymeric

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shell and inorganic components are prepared via the hard-templating method. There are

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typical four locations of inorganic material in hybrid HL particle, i.e., at the external wall, in

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the shell matrix, dispersing in the hollow cavity and acting as a movable core. Fabrication of

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gold-decorated polypyrrole (PPy/PPyNH2@AuNPs) HL particle is the example of the

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attachment of inorganic substance at the external wall.52 In Figure 7, a core-shell

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PS@PPy/PPyNH2 particle consisting of reactive N-amino functional groups on its surface

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was firstly prepared by copolymerizing Py and amino-functionalized Py on PS particle. This

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particle was then decorated with citrate stabilized AuNPs via an electrostatic interaction and

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the PS core was finally etched using THF. This hybrid material combines the benefits of

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conducting polymer shell of PPy with localized surface plasmon property of AuNPs for the

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development of drug delivery systems with photothermal therapeutic capabilities. Similarly, ACS Paragon Plus Environment

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SiNPs, offering good mechanical properties, high catalytic reactivity and favorable

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nontoxicity, have been embedded in the shell matrix of hybrid HL particles.3 Leng et al.

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presented the one-pot synthesis of PS@SiO2 hybrid HL particles by in situ formation of SiO2

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layer on PS particle via the sol-gel reaction under acidic medium.53

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Figure 7. (A) Preparation of PS@PPy/PPyNH2@AuNPs particle by assembly of AuNPs on

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PS@PPy/PPyNH2 core-shell particle and then etched with THF. TEM micrographs of (B) PS

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particle, (C) core-shell PS@PPy/PPyNH2 particle, (D) hybrid core-shell

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PS@PPy/PPyNH2@AuNPs particle and (E) hybrid PPy/PPyNH2@AuNPs HL particle.

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Adapted with permission from Ref. 52. Copyright 2006 American Chemical Society.

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Hybrid HL particle that contains the dispersed inorganic substances in the hollow

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cavity offers a novel route for preparation of “nanoreactor”. This miniature hybrid reactor can

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confine the reaction within the hollow particle. Poly(maleic anhydride-co-DVB) HL particle

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with nanoporous shell and carboxyl groups could encapsulate Ag precursor as well as

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reductant and, hence, allowed the production of AgNPs inside the cavity.54 Likewise,

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monodisperse P(St-co-DVB) HL particle was used as the confined microreactor for the

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synthesis of MNPs, resulting in the hybrid P(St-co-DVB)/Fe2CoO4 HL particle with magnetic

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loading of ca. 27%w/w.22 Recently, hybrid yolk–shell structure possessing a movable gold

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core and a periodic mesoporous shell (highly ordered pore structure) has been prepared using

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aldehyde-functionalized AuNPs@SiO2 as a template.55 As displayed in Figure 8, the reactive

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aldehyde groups assisted the self-assembly of resol (a one-stage phenolic resin) and triblock ACS Paragon Plus Environment


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copolymer pluronic F127 onto AuNPs@SiO2 core, driving by covalent bonds. Finally, a

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highly periodic mesoporous HL shell was generated after removal of F127 and SiO2 core by

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thermal decomposition and acid etching, respectively. The AuNPs@amorphous SiO2 core-

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shell particles were synthesized via sol−gel method and then encapsulated with a poly(benzyl

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methacrylate) (PBzMA) shell via the ATRP technique.56 These hybrid HL particles would

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provide a unique system to investigate the transport property of small molecules associated

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with hollow particles, in which AuNP core acts as an optical probe to follow the diffusion

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kinetics of chemical reagents across the polymeric shell.

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Figure 8. Preparation of yolk–shell structured Au@periodic mesoporous polymer

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nanoparticle by developing an approach of reactive interface-guided co-assembly. Adapted

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from Ref. 55 with permission from The Royal Society of Chemistry, Copyright 2016.

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Besides spherical particles, non-spherical (NS) HL particles, e.g., ellipsoid,

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dumbbell and snowman shapes, are encountered in numerous fields of science and

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engineering. The key features of NS HL particles are their high packing density from ordered

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array, optical anisotropy and amphiphilic properties. These can facilitate their use in broad

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domains, e.g., photonic materials, nanoreactors for catalysis and emulsifers for oil/water

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immiscible mixture.16,57,58 Due to the unfavorable morphology in term of surface tension, the

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fabrication of NS particles is challenging. Both symmetric and asymmetric solid

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nanoparticles can be served as templates.58 The synthesis is based on the elimination of core

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in hybrid seed simultaneously with the formation of new lateral bulge via the protrusion and ACS Paragon Plus Environment

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precipitation of new forming polymer. The formation mechanism involves two types of seed,

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i.e., PS@SiO2 and MPS modified PS@SiO2 (PS@MPS-SiO2) and is schematically illustrated

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in Figures 9A,B. After swelling the hybrid core-shell template with toluene, DVB, glycidyl

4

methacrylate (GMA) and St monomers, PS was gradually dissolved. P(DVB-GMA-St) shell

5

was generated at the interface between the inner wall of silica shell and dissolving PS core.

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As toluene was evaporated, PS clinged at the inner wall of silica, resulting in the hollow

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structure. Meanwhile, the elastic stress of the crosslinked polymers forced out the particle to

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form a new lateral bulge where P(DVB-GMA-St) precursor outside the SiO2 shell

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precipitated, condensed and nucleated on the outer wall asymmetrically. Due to the different

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polarity of seed surface, the spreading coefficient of the new lobe from each hybrid spheres

11

was discreted resulting in elephant trunk-like (Figure 9C) from hydrophilic PS@SiO2 seed

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and acorn-like (Figure 9D) from hydrophobic PS@MPS-SiO2 seed.

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Figure 9. Preparation of (A) elephant trunk-like and (B) acorn-like HL particles in which the

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P(DVB-GMA-St) lateral bulges were formed in different shapes due to the distinct polarity of

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the hybrid seed surfaces and SEM images of (C) elephant trunk-like and (D) acorn-like HL

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particles. Adapted with permission from Ref. 58. Copyright 2014 American Chemical

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Society.

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The ellipsoidal PDVB HL particle was successfully prepared by using MPS-modified

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hematite@silica particle as a sacrificial template where PDVB shell was formed by

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distillation-precipitation polymerization.59 In this case, two types of void character, i.e., a full

4

void and a void with a movable inorganic core, were obtained upon adjusting concentration

5

of HF solution as an etching agent. In addition, the Janus dumbbell HL particle consisting of

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two partially fused poly(N-isopropylacrylamide) (PNIPAM) spheres, i.e., partial hollow in

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one sphere of a copolymer of PS-co-PMPS@PNIPAM and the other one of clear hollow

8

sphere of pure PNIPAM, was fabricated by the mechanism shown in Figure 10A.16 In the

9

procedure, an asymmetric template of crosslinked PNIPAM coated-asymmetrical doublet of

10

PS sphere and one bulge of PS-co-PMPS coated PS was used. After dissolving non-

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crosslinked PS part in the anisotropic dumbell by THF, Janus HL particle with a clear void in

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one side was confirmed by scanning force microscopy (SFM) height and TEM images in

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Figures 10B,C, respectively.

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Figure 10. (A) Preparation of thermosensitive Janus HL particle from dumbbell-shaped

16

polymer particle template covered with crosslinked PNIPAM, (B) SFM height image and (C) ACS Paragon Plus Environment

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17 1

TEM image of thermosensitive Janus HL particles. The inset shows the particle at higher

2

magnification. Reprinted by permission from Springer Nature Customer Service Centre

3

GmbH: Springer Colloid and Polymer Science, Ref. 16, Copyright 2014.

4 5

Despite much success in the synthesis of controllable morphologies and properties of

6

polymeric HL particles, the hard template-based method has the limitations for industrial

7

outlook due to the multi-step synthetic process, especially in the case of HL particles with

8

complex structure.5,6 Moreover, the template removal step may influence capsule integrity,

9

wall properties and the safety for their usage in medical and food applications.60

10 11 12

2.2. Soft-templating method. The concept of soft-templating method is widely applied for the syntheses of both

13

nano- and micro-sized polymeric HL particle by means of liquid droplets or gas bubbles as

14

templates. A range of materials, for instance, copolymer, polymer composite or hybrid

15

components, can be used as coating shell. Compared to the hard-templating method, this

16

approach requires fewer synthetic steps to achieve the hollow structure and the template

17

removal step is more practical by ways of extraction with mild solvent, e.g., water, ethanol

18

and acetone, and/or drying in vacuo.6

19

Among the three convenient processes, i.e., (1) emulsion polymerization (EP) or

20

miniemulsion polymerization (mini-EP), (2) reversible addition−fragmentation chain transfer

21

(RAFT) polymerization and (3) self-assembly of the pre-formed polymer, EP or mini-EP has

22

advantages on facile tuning of nanostructure, void diameter and void fraction of HL particles.

23

McDonald et al. prepared HL particles with 33-50% void fraction from an emulsion of

24

St/MAA/isooctane dispersed in water/alcohol.61 Hollow mesoporous organic polymer was

25

formed by the polymerization of tris(4-bromophenyl)amine and benzene-diboric acid using

26

palladium (Pd) catalyst in aqueous phase dispersed in DMF.62 Hollow poly(methyl



Page 18 of 86

18 1

methacrylate) (PMMA) particles with finely tuned size were synthesized by acoustic

2

emulsification and photopolymerization of MMA on the surface of the

3

perfluoromethylcyclohexane emulsion droplets.63 Landfester et al. synthesized HL particles

4

of polyurea, polythiourea, and polyurethane using polyaddition reaction or polycondensation

5

of 2,4-toluene diisocyanate (TDI) and various amine components at the interface of inverse

6

miniemulsion droplets.64-67 The same technique was also employed to prepare biodegradable

7

nanocapsules constructed from naturally occurring substances or drugs.68-71 The shell of these

8

capsules entirely composed of proteins, antigen or heparin drug crosslinked via the interfacial

9

polyaddition of TDI with –OH or –NH groups of the respective compounds.

10

In the case of RAFT polymerization, the amphiphilic RAFT agent acts as a surfactant

11

of monomers emulsion and confines polymerization at the interface. The polymer chains

12

would gradually grow inwards in the controlled manner, leading to the formation of a

13

polymeric shell around liquid droplet. HL particles of crosslinked PS or PMMA shell have

14

been developed by Utama et al. via the inverse miniemulsion periphery RAFT

15

polymerization.72 As a template, water droplet dispersed in toluene was stabilized by

16

amphiphilic diblock copolymer of macro RAFT agents, which further mediated the

17

controlled/living radical polymerization of St/DVB or MMA/ethylene glycol dimethacrylate

18

(EGDMA) at the droplet surface. However, the preparation of amphiphilic block copolymer

19

as RAFT agent requires several steps and the unwanted solid or collapsed particles are often

20

formed.

21

The self-assembly is also applicable for synthesis of HL capsule from a spontaneous

22

organization of polymer chains/nanoparticles at the liquid/liquid interface. The control of

23

void size, shell thickness and size distribution are still a challenge. Crosslinking or

24

assembling with solid nanoparticles can lock the structure to ensure that the final architecture

25

of capsule remains intact after removal of liquid core. Self-assembly of graft copolymers

26

composing of AA/2-methacryloylethyl acrylate (MEA) backbone and PNIPAM/PEG


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19 1

segments yielded polymeric micelles in an aqueous solution.73 Hollow nanogel was produced

2

by crosslinking with radical polymerization of MEA moieties. Likewise, the crosslinked

3

CS/PAA HL particles were prepared from CS/AA micelles using glutaraldehyde as a

4

crosslinker.74 Recently, HL particles have been prepared by assembling poly(methyl

5

methacrylate-co-cinnamoylethyl methacrylate) in o/w emulsion in association with photo-

6

induced crosslinking of cinnamoyl groups.75 Poly(lactic-co-glycolic acid) (PLGA) HL

7

particles were synthesized using n-octanol/water emulsion as soft templates. The surface of

8

n-octanol/water was further stabilized by PS particles, Pickering stabilizer.76 These assembled

9

PS particles were locked through the precipitation of PLGA at the o/w interface, leaving a

10

composite PS/PLGA shell surrounding the oil droplet. Similarly, hollow capsules were

11

obtained by organization of PDADMAC coated PS particles on a soft template of olive oil,

12

liquid paraffin or toluene droplets, followed by the LbL coating of PSS/PDADMAC to

13

support the shell rigidity.77 The more complicated system was polysulfone (PSF) HL particles

14

synthesized by the water-in-oil-in-water (w/o/w) double emulsion-solvent evaporation

15

method.78 As schematically shown in Figure 11A, the w/o pre-emulsion of oleic acid (OA)

16

stabilized PSF dispersed in dichloromethane (DCM) was added into poly(vinyl alcohol)

17

(PVA) solution to produce the w/o/w system. Upon solvent evaporation, PSF layer shrunk

18

and a hollow core was formed, leaving behind the PSF HL particle with porous shell as

19

observed in SEM image (Figure 11B).

20 ACS Paragon Plus Environment


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20 1

Figure 11. (A) Formation of PSF microsphere with a hollow core/porous shell structure by

2

self-assembly of PSF in w/o/w double emulsion-solvent evaporation technique and (B) SEM

3

image of PSF microspheres (inset: a broken capsule). Adapted with permission from Ref. 78.

4

Copyright 2012 John Wiley and Sons.

5 11 18 25 10 13 15 17 20 22 24 27 14 21 12 19 26 16 23 8769 28

Hollow Free TemplateorePreparing Core*for Nanospheres Strategy

29

shell surrounding liquid droplet template, hybrid HL particles can be also prepared. Figure

30

12A shows the scheme representing the preparation of hybrid P(St-co-DVB)@SiO2 HL

31

particle via Pickering emulsion polymerization of St/DVB using MPS modified SiO2 as

32

Pickering stabilizer.79 The void was formed after phase separation between poly(St-co-DVB)

33

and dodecanol (C12H25OH) and etching with ethanol. Photographs or optical micrographs of

34

the particles in each step are shown in Figures 12B-F.

By immobilization of inorganic materials, e.g., TiO2, MNPs and SiNPs, into polymeric

35 36

Figure 12. (A) Preparation of hybrid P(St-co-DVB)@SiO2 HL particle via Pickering

37

emulsion polymerization of St/DVB using MPS modified SiO2 as Pickering stabilizer,

38

photographs of (B) mixture before emulsification and (C) emulsion for 30 min and optical

39

micrographs of (D) emulsion droplets by transmission model, (E) microcapsules with

40

dodecanol core and (F) P(St-co-DVB)@SiO2 HL particles by reflective model. Scale bar: 100

41

mm. Reproduced with permission from Ref. 79. Copyright 2011 John Wiley & Sons.


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21 1 2

Hybrid PS/MNPs shell of HL particles with superparamagnetic behavior fabricated by

3

inverse miniemulsion polymerization were also reported.80 Under -ray, the amphipathic

4

MNPs favorably generated free radicals (OH) at the interface of w/o emulsion (St-kerosine

5

stabilized by OA coated MNPs and Span 80) for interfacial polymerization of St. Chiang et

6

al. reported the preparation of self-assembled micelle of citric acid-coated MNPs and

7

copolymer comprising AA/2-methacryloylethyl acrylate (MEA) units as the backbone and

8

PEG/PNIPAM as the grafts.81 The hybrid hollow nanogels were then covalently stabilized by

9

photoinitiated polymerization of MEA residues within vesicles, forming the well-defined HL

10

particles having MNPs embedded in the shell layer. These multifunctional particles would

11

play the roles for magnetic guidance, imaging and thermotherapy of MNPs as well as the

12

advantages of polymers, e.g., good mechanical property, protective oxidation of MNPs and

13

stimuli-triggered release of active substances.

14

An alternative soft template of HL particles is gas bubble which is not widely utilized

15

because it is difficult to achieve the thermodynamic conditions necessary for bubble

16

formation in such small size.82 The scheme representing the formation of hierarchical

17

polyimide (PI) HL microspheres using gas bubble as template is presented in Figure 13A.83

18

As the transimidation-induced crystallization process between blocked dianhydride

19

(pyromellitic dianhydride-2-aminopyridine) and diamine (3,5-diamino-1,2,4-triazole)

20

occurred, primary fine crystalline nanoparticles of PI were formed. The small molecule of 2-

21

aminopyridine as a by-product was volatized and gas bubbles in the reaction solution were

22

generated in situ. PI nanoparticles was attached at the gas/liquid interface of the in situ

23

formed gas bubbles to minimize the surface energy. SEM and TEM images in Figures 13B,C

24

show the hierarchical hollow spheres.



Page 22 of 86

22 (A)

(B)

(C)

1 2

Figure 13. (A) Preparation of PI hollow microspheres via gas bubble template assisted

3

transimidization induced crystallization process (when  = gas bubble and

4

nanoparticle), (B) SEM and (C) TEM images of the prepared PI HL particles. Reprinted by

5

permission from Springer Nature Customer Service Centre GmbH: Springer Nature Polymer

6

Bulletin, Ref. 83, Copyright 2012.



= PI

7 8 9

Orsi et al. reported the new method for the fabrication of polymeric HL particles by gas foaming technology.82 Air void inside the pre-formed polymeric particle was directly

10

generated, which produced PS and PLGA HL particles with various shapes, e.g., spherical,

11

ellipsoidal and discoidal. The procedure involved the embedding of PS and PLGA particles in

12

the deformable and soft glycerol-plasticized PVA film used as a barrier film. Then, the

13

foaming process by pressurizing the vessel containing a film with the blowing agent at 14.0

14

MPa and 100 °C allowed the bubble growth in spherical particle without gas loss in the free

15

surface. Size, shape and dimension of HL particles obtained after dissolving PVA could be

16

modulated by tuning the foaming condition and viscoelastic properties of the film.

17

Conducting of the foaming process in a stress field allowed the non-isotropic deformation of

18

the particles, which could result in the formation of NS HL particles.


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23 1

Although the soft-templating method is an effective way to produce HL particles

2

since it is relatively easier compared to the solid template, the core removal step is still

3

required in some cases. Furthermore, particle morphology is difficult to control.6,84 Most of

4

polymeric and hybrid polymeric/inorganic HL particles possess only spherical shape with a

5

single void and a mono- or multi-layer shell due to the effect of interfacial tension of the two

6

immiscible phases.

7 8

2.3. Self-templating method.

9

The self-templating method is used for the formation of HL particle without the

10

core/template removal. In general, a void is generated from the migration of polymer from

11

the central part of particle toward the outer shell layer during the chemical treatment or

12

polymerization at the seed surface. Beside shortening the HL preparation step, the core

13

material, which later becomes the component in the shell part, can strengthen the particle.

14

This method could produce high product uniformity and ease of scaling up. In this section,

15

the self-templating synthesis of polymeric HL particles based on the method for expanding a

16

void is divided into 2 categories, i.e., osmotic swelling and seeded emulsion polymerization

17

(SEP).

18 19

2.3.1. Osmotic swelling.

20

The osmotic swelling method is one of the earliest commercial process for synthesis

21

of spherical polymeric HL particles. It involves the preparation of hydrophilic electrolyte

22

core and one or more hydrophobic outer shells by multi-stage emulsion polymerization. The

23

core is generally made of alkali-swellable carboxylic acid monomers and contains 10-30% wt

24

of ionizable compound,9 whereas the shell composes of styrene and acrylate polymers.2,10,85

25

The ionization of the carboxylated core under basic pH at temperature above the softening

26

point of polymer shell allows imbibing of water to the center of the particle by osmotic



Page 24 of 86

24 1

process, giving rise to the voided particles after water evaporation. In order to gradually

2

decrease the hydrophilicity of core surface and form hydrophobic polymer shell, the

3

core/intermediate layer/shell particle was fabricated via semi-continuous SEP. Yuan et al.

4

prepared P(MMA/MAA) core coated with interlayer of poly(butyl acrylate

5

(BA)/MMA/MAA) and PS outer shell as schematically shown in Figure 14A.10 HL structure

6

was obtained after treating the particle with ammonia solution at 90C as shown in Figure

7

14B. The well-defined HL particles with high opacity could be tuned by controlling the

8

intermediate layer:core ratio. At high ratio (8:1), the stiffer particles suffered from the

9

expansion tension during alkali-swelling. As the intermediate layer became a part of an inner

10

shell, the ratio of hydrophobic shell layer was not much concerned and the

11

core/intermediate:shell ratio was generally fixed at 1:1. Karakaya et al. fabricated

12

P(MMA/MAA/EGDMA)/PS HL particles for use as opaque pigment. Upon tuning of copper

13

phthalocyanine ratio in the monomer mixture during shell forming step, the color of resulted

14

HL particles varied from blue-green to blue.86 Although the osmotic swelling technique

15

produces monodispersed HL particles with controllable void and particle sizes,2 its time

16

consuming process and particle shape constraint are the major disadvantages of this

17

approach.6

18


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25 1

Figure 14. (A) Preparation of core-multi-layer shell HL particles via multi-stage emulsion

2

polymerization and alkali swelling process and (B) TEM image of the obtained

3

P(St/BA/MMA/MAA) HL particles. Reproduced with permission from Ref. 10. Copyright

4

2015 John Wiley and Sons.

5

Compared to a single void particle, multi-hollow particle offers several advantages.

6

Its high specific surface area and abundant inner void provides good accessibility for

7

reactants and facilitates the transport of adsorptive molecules from the bulk solution to the

8

interior. Okubo et al. reported the stepwise alkali/acid87 and acid/alkali methods88 for the

9

preparation of P(St-co-MAA) particles and P(St-co-BA-co-DMAEMA) multi-hollow

10

particles, respectively, based on the osmotic swelling strategy. In this case, seed particles

11

were totally made of copolymer containing carboxyl or amino groups which allowed the

12

formation of small water vesicles throughout the structure. The multi-voided particles were

13

generated by a consecutive addition of KOH and HCl solution leading to the formation of

14

polyelectrolyte or salt inside particle, which allowed the water swelling due to the osmotic

15

effect. By consecutive deionization of core polymer, the shrinkage and precipitation of

16

polymer segments occurred in water domains, which were distributed throughout the polymer

17

matrix.

18

In the similar way, while monomer was diffusing into the polymer particles,

19

surfactant inside these particle induces water imbibing to form small water pools and, hence,

20

multi-void particle. The voids were expanded due to the water absorption and this structure is

21

then locked during the polymerization. The proposed mechanism of PS multi-hollow

22

structure formation is presented in Figure 15A.11 PS seed particles, containing numerous

23

amount of small water pools, were formed from the absorption of water during

24

polymerization. To minimize interfacial free energy, these pools coalesced until the particles

25

solidify, and then a clear hollow structure was formed. The incorporation of nonionic

26

surfactant (Emulgen 911) in PS seed greatly improved water swelling and coalescence of



Page 26 of 86

26 1

water domains in the particle and, thus, increased the void size (Figures 15B-D and E-G).

2

Similarly, multi-hollow particles were prepared using poly(St-co-sodium 4-

3

vinylbenzenesulfonate) (P(St-NaSS)) particles as seeds.89,90 The mechanical strength of the

4

particles was obtained by crosslinking with DVB and GMA. By further generating inorganic

5

nanocrystals, i.e., Ag and Au, on multi-hollow particle surface by way of in situ reduction,

6

hybrid HL particles were fabricated.91

7 8

Figure 15. (A) Formation mechanism of multi-hollow structure during polymerization and

9

TEM micrographs of PS seed employing various Emulgen 911 concentrations (wt% based on

10

St): (B) 0.4; (C) 2.0; (D) 4.1 and multi-hollow PS particles (E, F, G) prepared by

11

polymerization with various PS seed particles. Adapted with permission from Ref. 11.

12

Copyright 2007 American Chemical Society.

13

2.3.2. Seeded emulsion polymerization (SEP).

14

SEP is a convenient method to prepare polymeric or hybrid double-layer HL particles

15

without the requirement of seed removal step as schematically shown in Figure 16.

16

Polymerization preferentially takes place on the seed surface leading to the formation of

17

polymer shell. In association with the seed polymer, the swollen monomers gradually move

18

from the center to the polymerization locus and the small void is then generated. The


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27 1

incompatibility between seed and existing crosslinked polymer, the polymerization shrinkage

2

and the osmotic pressure are responsible for the void enlargement.7 Since the seed component

3

becomes the inner wall of particles that entrap water inside the void, the double-layer HL

4

particle is formed without any post-treatment step.92,93

5 6

Figure 16 Formation of a hollow particle by the one-pot SEP involves monomer-swelled

7

seed particle and the polymerization confined at the seed surface. The polymerization occurs

8

simultaneously with the migration of polymer chains to the shell region, resulting in the

9

imbibing of water by osmotic pressure to create a void.

10 11

There are 3 key success factors to produce the well-defined hollow structure via the

12

SEP method, i.e., initiation system, hydrophobic/hydrophilic pair monomers and phase

13

separation. First, the use of proper initiation system is the important parameter to control the

14

polymerization locus at the seed surface. Second is to select the hydrophobic/hydrophilic pair

15

monomers which are responsible for “dissolution” of seed and adsorption of oligoradicals on

16

the surface of swollen seed. The last factor is the fast and efficient phase separation between

17

seed and shell polymers. The different architectures of HL particles with tailored shape and

18

shell composition can be prepared from both synthetic and natural polymeric seed particles.

19

Itou et al. synthesized spherical HL particles with 30-70% of void space from PS seeds,

20

DVB/MMA monomers and sodium persulfate (SPS) initiator.93 The stress concentration

21

during polymerization at the seed surface played a role on the void development, which can

22

be tuned by varying the ratio of monomer/seed and the hydrophilicity of monomers. Mixing

23

HL particles in the coating boosted up the opacity twice compared to the use of solid ACS Paragon Plus Environment


Page 28 of 86

28 1

particles. Park et al. simplified the SEP technique by means of one-step dispersion

2

polymerization. Nevertheless, a dimple on the particle surface was observed due to the

3

collapse of non-crosslinked shell.94 Highly charged non-collapse P(St/DVB/MMA/AA) HL

4

particle (430 nm) with a void (280 nm) was obtained when Nuasean et al. used spherical

5

P(St/AA) as seed, KPS as initiator and DVB/MMA/AA as monomers.95,96 The double-layer

6

shell composing of P(St/AA) as inner and P(DVB/MMA/AA) as the outer layers was

7

responsible for the rigid wall of HL particle and high opacity caused from multiple light

8

scattering. By further functionalized with chitosan (CS), these carboxylated HL particles with

9

high surface charge density of 1210 ± 38 µC/cm2 could effectively adsorb formaldehyde

10

gas.97

11

The study of the preparation of HL particles via the one-pot SEP using NR latex, tapped

12

from Hevea Brasiliensis tree, as seeds was initiated by Tangboriboonrat et al.12 As shown in

13

Figure 17A, NR particles consisting of cis-1,4-polyisoprene stabilized by indegenous proteins

14

and phospholipids are polydisperse in size (0.02-3 m) and, hence, the synthesis and

15

characterization of NR-based hybrid particles are tedious.98-103 Schneider et al. reported the

16

NR-based

17

Heterocoagulation of large NR core particle with small polychloroprene (CR) shell particles

18

was proved to be an efficient method for the preparation of composite core-shell particle.100

19

The extension of the heterocoagulation by replacing the CR with epoxidized NR (ENR),

20

crosslinked ENR, skim NR or sulphur-prevulcanized skim NR latex particles was also

21

examined.99,102,103 Recently, Wichaita et al. have fabricated HL-NR via the one-pot SEP whose

22

proposed mechanism is shown in Figure 17C.12 The polymerization of MMA/DVB/AA

23

monomers occurred when t-BuHP/TEPA redox initiator was used to generate free radicals at

24

the NR seed surface. A void was formed when swollen DVB moved along with polyisoprene

25

chains of NR in order to compensate the co-polymerization at the outermost layer. The

26

void/particle size was tuned by adjusting the ratios of MMA/DVB and monomers/seed.

nanocomposites

with

core-shell

and

subinclusion


morphologies.104-106

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29 1

Polydispersed HL-NR particles (298 ± 58 nm) with 52% void volume and raspberry-like

2

surface were obtained as shown in Figure 17B. Besides omitting the seed fabrication and

3

removal steps, the non-collapse HL particle with double-layer shell having high molecular

4

weight (ca.106 g/mol) polyisoprene as an inner layer would be beneficial.

5

6 7

Figure 17. TEM images of (A) NR and (B) HL-NR particles and (C) schematic diagram

8

representing the formation of HL-NR particle via the one-pot SEP using NR latex seed, t-

9

BuHP/TEPA redox initiator and MMA/DVB/AA monomers. Adapted from Ref. 12,

10

Copyright (2016), with permission from Elsevier.

11 12

Later, Sudjaipraparat et al. employed the one-pot SEP method to fabricate non-

13

spherical (NS) HL particles with a void located only in one side of the dumbbell particle as

14

summarized in Figure 18A.15 Starting from crosslinked spherical seed (Figure 18B),

15

anisotropic or NS seeds with two separated domains (Figure 18C), i.e., semi-interpenetrating

16

network (semi-IPN) P(St/DVB/AA) and linear PS, were prepared. During the polymerization

17

of PS, the elastic stress built up in crosslinked spherical seed and the incompatibility between ACS Paragon Plus Environment


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30 1

PAA and swollen PS allowed PS to protrude out of the seed in long axis, i.e., the generation of

2

a new lateral bulge. The completion of hollow structure was continuously formed in NS seed

3

by incorporating MMA/DVB/AA monomers with the proper MMA/DVB ratio of 1/2. After

4

polymerization, the cavity occurred in non-crosslinked PS bulge due to an ease of phase

5

separation, which produced the non-collapsed anisotropic hollow structure with double shell

6

(Figure 18D). Besides the multiple light scattering, the %opacity of coatings that contained NS

7

HL particles as white pigment was significantly higher compared to the use of NS solid and

8

spherical HL particles. The opacity enhancement stems from the highly effective packing

9

density of NS HL particles.

10 11

Figure 18. (A) Proposed mechanism of the formation of anisotropic NS particles and TEM

12

images of (B) spherical P(St/AA) seeds, (C) NS P(St/DVB/AA)-PS seeds and (D) NS HL

13

particles. Adapted from Ref. 15, Copyright (2017), with permission from Elsevier.

14 15

The one-pot SEP method is also practical for the synthesis of hybrid organic/inorganic

16

HL particles. Narongthong et al. successfully fabricated hybrid P(St/AA/DVB)@SiNPs HL

17

particles using P(St/AA) seed, DVB monomer, 2,2′-azobis(isobutylamidine hydrochloride)

18

(AIBA) initiator and SiNPs Pickering stabilizer.107 The proposed mechanism of hybrid particle


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31 1

formation and its morphology are, respectively, presented in Figure 19A,B. In this case, the

2

strong capillary force from the space between neighboring SiNPs drove the diffusion of PS into

3

the small cavities of SiNPs shell and hence facilitated the void formation.

4

5 6

Figure 19. (A) Formation mechanism of hybrid HL-P(St/AA/DVB)@SiNPs particle from

7

P(St/AA) seed and SiNPs Pickering stabilizer and (B) TEM image of hybrid HL-

8

P(St/AA/DVB)@SiNPs particles. Adapted by permission from Springer Nature Customer

9

Service Centre GmbH: Springer Nature Colloid and Polymer Science, Ref. 107, Copyright

10

2015.

11 12

2.4. Non-sacrificial templating method.

13

The non-sacrificial templating method employs a surfactant-based vesicle as a

14

template for the formation of HL particle. This vesicle stabilizes the monomers in the interior

15

of their bilayer but does not end up as a part of the capsule wall.108 Kaler et al. polymerized

16

hydrophobic monomers within a hydrophobic vesicle bilayer formed from the mixture of

17

cationic surfactant (cetyltrimethylammonium toluenesulfonate (CTAT) or

18

dodecyltrimethylammonium bromide (DTAB)) and branched chain anionic surfactant

19

(sodium dodecylbenzene sulfate (SDBS)).109 These vesicles served for the polymerization of

20

St and DVB initiated by a cationic water soluble initiator. Meier et al. further polymerized

21

methacrylate monomers, i.e., 1-methacryloyloxybutane (MAOB) and BMA with EGDMA, ACS Paragon Plus Environment


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32 1

in the interior of dimethyldioctadecylammonium chloride (DODAC) vesicles using

2

azobis(isobutyronitrile) (AIBN) initiator, which resulted in HL particles ranging from several

3

nanometers to hundred micrometers.13,108 A fascinating discovery reported by Jung and van

4

Herk et al. confirmed that polymerization of St in dioctadecyldimethylammonium bromide

5

(DODAB) vesicle caused the phase separation between PS and surfactant bilayer matrix.110

6

Clumps of the polymer shell in the vesicle bilayer led to the undesirable parachute

7

morphology.

8 9

To avoid the parachute morphology, van Herk et al. developed a RAFT-based vesicle templated polymerization as shown in Figure 20.111 The anionic ‘living’ RAFT P(BAx-co-

10

AAy) oligomers were electrostatically adsorbed onto the surface of a cationic DODAB

11

vesicle which subsequently mediated the synthesis of P(MMA-co-BA) wall to prevent phase

12

separation. Furthermore, pH-responsive monomer, i.e., tertiary butyl acrylate (TBA), in the

13

crosslinked PMMA shell was produced.112 The acid hydrolysis of tertiary butyl ester groups

14

led to the thermo-responsive behavior of the shell which influenced the swelling degree and

15

wall permeability of drug. Cuomo and Lindman et al. reported the synthesis of pH-responsive

16

nanocapsules via the LbL of alginate/chitosan on a template of didodecyldimethylammonium

17

bromide (DDAB) or phosphatidylcholine/DDAB liposome.113,114 Although the removal of

18

surfactant or lipid template was carried out, it is not mandatory and the process is benign

19

compared to the other techniques.

20


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33 1

Figure 20. Formation of HL particle via the RAFT-based vesicle templated polymerization

2

using anionic RAFT P(BAx-co-AAy) oligomers adsorbed on a cationic DODAB vesicle for

3

copolymerization of MMA and BA monomers. Reprinted with permission from Ref. 111.

4

Copyright 2010 American Chemical Society.

5 6

The four methods for the preparation of HL particles with different structures already

7

discussed are summarized in Table 1. The comparison of advantages and drawbacks of

8

various strategies is presented in Table 2.

9 10



Page 34 of 86

34 1

Table 1. Summary of HL particles having different structures prepared from four techniques Strategy I. Hardtemplating

Morphology Simple-sphere/ one-component

17, 19, 20, 27-30, 40

PS-b-P4VP/PS-b-PAA, CSFITC/sodium hyaluronate, PUA/PSS, PDADMAC/PSS, poly-L-arginine/dextran sulfate, poly(amidoamine) dendrimer/PSS, diazoresin/PSS, Fe(II) metallosupramolecular polyelectrolyte/PSS, PMA/PVPON, PMA/PVPON—NH2

24-26, 32-39, 42-46

Complex sphere

SEP, Seed swelling/frozen/evaporation

PS@PS-co-PAM, PS, P(MAA-coEGDMA)

47-50

Hybrid sphere

EP, sol-gel reaction/in situ seed diffusion or ATRP, LbL assembly

PPy/PPyNH2@AuNPs, PS@SiO2, Poly(maleic anhydride-co-DVB)@AgNPs, P(St-co-DVB)@Fe2CoO4, Au@resol resin, Au@SiO2/PBzMA

3, 22, 52-54

Sol-gel reaction/SEP, distillation-precipitation polymerization

PS@MPS-SiO2@P(DVB-co-GMA-co-St), PDVB, P(DVB-co-MAA), PNIPAM/PS-coPMPS@PNIPAM

16, 58, 59

EP or mini-EP, polyaddition and polycondensation on inverse miniemulsion

P(St-co-MAA), organic polymer of Tris(4bromophenyl)amine/benzene–diboronic acid, PMM, polyurea, proteins, antigen or heparin P(St-co-DVB), P(MMA-co-EGDMA)

61,62, 64-71, 82,115

poly(AA-co-MEA)-PNIPAM/PEG, CS/PAA, P(MA-co-CEMA), PS/PLGA, PDADMAC/PS/ PSS/PDADMAC, PSF PI, PS and PLGA

73-78

Simple-sphere

self-assembly

Hybrid sphere

Transimidation/in-situ gas forming, gas foaming in latex embedded films Pickering EP, Mini-EP, self-assembly

10, 85, 86

Osmotic swelling

Hybrid sphere

Osmotic swelling/in-situ inorganic formation, SEP

P(DVB-co-GMA)@AuNPs, P(StNaSS)@AgNPs, P(St/AA/DVB)@SiNPs

SEP

P(St/DVB/AA)/P(DVB/MMA/AA)

Vesicle templated radical polymerization, RAFT and LbL

P(St/DVB), P(MAOB/EGDMA), P(BMA/EGDMA), P(MA/EGDMA), P(MMA/EGDMA), PS, P(MMA-co-BA), P(MMA-co-TBA), alginate/CS

Non-sphere

Simple-sphere

82, 83

79-81

Multi-hollow

Osmotic swelling

72

P(St-co-DVB)@SiO2, PS@MNPs, poly(AA-co-MEA)-PNIPAM/PEG@MNPs,

P(MMA/MAA)/P(BA/MMA/MAA)/PS, PA/P(MMA/BA/MAA/EGDMA)/P(MMA/ St), P(MMA/MAA/EGDMA)/PS P(St/DVB/MMA), P(St/DVB/MMA/AA), NR/P(MMA/DVB/AA) PS, P(St-NaSS)

Simple-sphere

SEP

IV. Nonsacrificial templating

References

LbL assembly; via electrostatic and hydrogen bond donor/acceptor

RAFT

III. Selftemplating

Shell component PS, polyacetylene, PAni, PBMA, Dopamine modified PGA, Metal-phenolic networks

Simple-sphere/ multi-component

Non-sphere

II. Softtemplating

Shell formation technique EP, ATRP, monophenolic polymerization, oxidative polymerization


12, 92, 93, 95-97 11, 87, 88, 90

89, 91, 107

15

13, 14, 108-113

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35 1

Table 2. Comparison of four techniques used for preparation of HL particles Technique

Advantages

Drawbacks

Hard-templating

- It is flexible to prepare HL particles with a variety of shape (sphere, non-sphere) and compositions, enable for a complex structure, e.g., HL with a controllable hole, molecular imprint shell, yolkshell, multi-layer and anisotropic structure. - Shell component and its thickness can be finely adjusted via the choice of chemical reactions, processing condition and polymer/inorganic ingredients. - Size and shape of the void can be controlled by the structure of template. - In case of simple-sphere HL, excellent uniformity of particle structure is generally obtained.

- Core-shell structure needs to be initially formed. - Additional step is required for incorporating inorganic substances for hybrid structure. - HL particles with complex structure require the multi-step synthesis and harsh processing. - Core removal process is relatively severe due to the use of organic solvents or strong acid. - Template removal step may influence capsule integrity, wall properties and the safety for their usage in medical and food applications. - The presence of radicals may render the procedure to be unsuitable for the encapsulation of sensitive substances.

Soft-templating

- Shell component and its thickness can be flexibly designed by selecting a variety choice of components. - Making of bio-based or biodegradable capsules with stimuli-responsive behavior is allowed for biomedical applications. - The direct contact of active compounds with the processing chemicals, e.g., monomer and radicals, is minimized allowing the one-pot drug encapsulation during synthesis. - Enable for the facile embedding of inorganic substances in the shell formation stage. - Core removal stage requires milder condition than hard template.

- The technique is limit to spherical shape with a single void and a plain character of shell due to the effect of interfacial tension of the two immiscible phases. - Multi-step procedures in LbL assembly render them difficult to scale-up. - The non-uniformity of particles and shell collapse during synthesis or core elimination can be occurred, which usually require postcrosslinking step to strengthen the shell.

Self-templating

- The technique is mostly used in industrial process to prepare a large amount of HL particles. - It offers good product uniformity, facile control over the void and particle sizes and ease of scaling up due to the absence of core removal step. - The core polymer becomes a part of the shell, hence non-collapse HL particle with double- or multi-layer shell are formed. - Core fabrication is sometimes not required by using NR latex as seed in SEP, allowing the real one-pot synthesis.

- Multiple-step core-interlayer-shell formation in the case of osmotic swelling technique is time consuming. - The technique normally limits to spherical shape, design and synthesis of complex structure HL particles are still not practical. - Type of polymer shell component is restricted, usually based on St/acrylate polymers while stimuli-responsive capsule has not been reported.

Non-sacrificial templating

- It is cost effective and experimentally straightforward from a simple in vesicle template formation. - Polymer shell can be formed by a choice of polymerization or polymer assembly and formation of stimuli-responsive polymer is possible. - The number of synthetic step is reduced due to the unneccessary to fabricate and remove the template. - The surfactant template can help to stabilize the particles after complete synthesis, while its removal, if needed for final uses, is benign compared to the other techniques. - The capsule and void sizes can be determined by the generated vesicle template via a choice of surfactant and concentration.

- The additional step to prepare a vesicle template is needed with a special concern to select the right choice of surfactant and its optimization. - HL particles can be collapsed or form parachute morphology, the controlled radical polymerization is sometime required to provide the well-defined hollow structure. - The collloidal instability may occur during the polymerization. - The control of shell composition, particle uniformity and morphology is still limited.



Page 36 of 86

36 1

3. Applications of polymeric HL particles

2

3.1. Coatings.

3

Polymeric HL particle is appreciated by paper and paint manufacturers as a white

4

pigment or an opacifying agent. Compared to TiO2, a conventional white pigment, HL

5

particle possesses lower density, better UV resistance, lower thermal expansion coefficient

6

and lower cost per gallon.2 In coatings, HL particle with an average diameter of 0.5-1.2 μm

7

and void volume of 40-60% is preferred. Its high hiding power is resulted from the multiple

8

light scattering between its surrounding medium and air void.116,117 Hence, polymeric HL

9

particles can replace 10-20% of TiO2 in paint formulation without sacrificing opacity. The

10

first commercial HL particle as a synthetic opacifier was introduced in the early 1980s as

11

patented by The Rohm and Hass company, which was then licensed and launched to the

12

market by Dow Chemical.118 The HL particles made from acrylic or St-acrylic copolymer,

13

i.e., ROPAQUETM HP 1055, ROPAQUETM Ultra E, ROPAQUETM OP-62 and ROPAQUETM

14

OP-96, are commercially avilable.119,120 BASF supplies acrylic copolymer HL particles under

15

tradename AQACell® HIDE 6299 with low VOC and odor, enable for both interior and

16

exterior architectural coatings.121 Dow Chemical also supplies HL particles of carboxylated

17

St/acrylate copolymer as gloss-enhancing plastic pigments for paper and paperboard coatings

18

with tradename of HS 2000NA, HS 3000NA, HS 3020NA, UCARHIDETM 4001 and

19

UCARHIDETM 98.122,123 Later, Dow creates the unique polymeric pigment plus binder with

20

name HSB 3042NA, which combines HL particles with St/butadiene latex binder.124 The

21

higher solid content of hollow pigment dispersion (ca. 42%) than the typical HL products (ca.

22

26-37%) accelerates the drying process after coating.

23

Several research groups have continuously developed HL particles for potential use as

24

pigment in coating with specific purposes. For example, Nuasaen et al. functionalized the

25

highly charge HL-P(St/AA) particles, prepared via the one-pot SEP, with chitosan (CS).96,97

26

The scheme representing the formation of composite HL particle coated with CS and its


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37 1

mechanism of formaldehyde adsorption is displayed in Figure 21A. Figures 21B-D show

2

TEM images of P(St/AA) solid and HL particles while their SEM images and photographs of

3

coating films formulated by these particles are presented in Figures 21E-G and 21H-J,

4

respectively. The high opacity of 23.4% for HL-P(St/AA) and 28.3% for HL-P(St/AA)/CS

5

compared to 3.7% for solid particles (all at 15% latex) were determined from the photographs

6

of black and white charts. Increasing latex amount to 45% could boost up the opacity of

7

coating films to 63.7%. Besides high hiding power, the multi-layer HL-P(St/AA)/CS

8

particles, which can chemically adsorb formaldehyde gas via the reaction of primary (1◦)

9

amines to form azomethine or Schiff base, would be useful in special coating applications.

10

Hybrid particles of light hollow polymer microsphere (LHPM) physically coated with

11

TiO2 nanoparticles were incorporated in the external wall of thermal insulation coatings.125

12

By adding 10%wt of LHPM@TiO2 hybrid particles in the coating recipe, the density of paint

13

was only 0.8554 g/cm3 while maintaining high paint stability. The thermal conductivity of

14

this material (0.1687 W/m.K) reduced ca. nine-fold compared to the conventional coatings

15

(1.4757 W/m.K). The reflectivity of 87.3% to the solar radiation confirmed the superior

16

thermal insulation performance of the LHPM@TiO2 based coatings. In the same way, the

17

robust HL particle made of 2-(N,N-diethylamino)ethyl methacrylate with SiO2 and TiO2

18

Pickering stabilizers was used as self-healing hydrophobic coating.126 The release of

19

encapsulated molecules from enlarged pore on the shell could be influenced by 2 processes,

20

i.e., protonation of pH-dependent amine-containing polymer and shell degradation by the

21

UV-induced photocatalytic activity of TiO2.

22



Page 38 of 86

38

1 2

Figure 21. (A) Scheme showing the preparation of HL-P(St/AA) particle, via the one-pot

3

SEP of P(St/AA) solid particle, coated with CS for formaldehyde adsorption, TEM images of

4

the particles, SEM images and photographs of coating films formulated with (B,E,H)

5

P(St/AA) particles, (C, F, I) HL-P(St/AA) particles and (D, G, J) HL-P(St/AA)/CS particles.

6

Adapted from Ref. 96, Copyright (2015), with permission from Elsevier.

7 8

3.2. Cosmetics.

9

Primasphere® (microcapsules) and Primasys® (nanocapsules) are the registered

10

trademark by Cognis group for commercially available cosmetic delivery systems.127 The

11

capsules based on multi-layer assembly of opposite charge biopolymers, e.g.,

12

CS/carboxymethyl cellulose (CMC), gelatine/CMC and PEG-15/liposomes, are used to


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39 1

encapsulate vitamins, botanical extracts, proteins, antioxidants, biocides and fragances. Their

2

surface charges are designed for specific affinity to the substrates, e.g., skin, hair, fabric,

3

glass and paper. Releasing active compounds can be triggered by scatching, rubbing and skin

4

enzyme induced shell degradation.

5

Due to the efficient light scattering, St/acrylate HL particles (100-500 nm) are used as

6

sun protection factor (SPF) boosters with tradename “SunSpheresTM” supplied by Dow

7

Chemical in the form of aqueous dispersion mixed with PEG-8 Laurate and SDBS.128,129 The

8

HL particles with refractive index of polymer shell of ca. 1.5 can raise the efficacy of

9

UVA/UVB filters in formulation, allowing the recipe to deliver a higher SPF for a given level

10

of UV actives (11-15% boost in SPF per 1% solids of SunSpheresPM). Recently, a novel UV-

11

shielding and transparent polymer film using bioinspired dopamine-melanin HL particles

12

have been reported.130 Besides the intrinsic photo-protection property of dopamine, the

13

hollow structure allowed multiple reflections of UV light within the interior cavity, which

14

enhanced the efficiency of UV-shielding activity. The incorporation of hybrid HL particles

15

comprising of sub-micron TiO2@Al(OH)3 particles embedded in P(MMA-co-EGDMA)

16

matrix in cosmetic formulation provided the NIR shielding and light scattering effects for

17

sunscreen. However, they are still not commercially available.131

18 19

3.3. Biomedicines.

20

HL particles have large void for efficient loading of drug, gene or molecular probes

21

and a tailor-designed shell for medical diagnosis and treatment. Polybead® is an example of

22

commercial product, which has been used in general diagnostic tests. It contains surfactant-

23

stabilized St-based HL particles (400-1000 nm in diameter) with 100 nm shell thickness and

24

is slightly porous with an effective density of ca.1 g/cm3.132 With plain, carboxyl- and amine-

25

modified surface, Polybead® can be loaded with hydrophobic dyes for a wide range of

26

cellular assay and functionalized with recognition molecules, e.g., antibodies, antigens,



Page 40 of 86

40 1

peptides, ligand or nucleic acid probes for specific uses. Several research groups have

2

experimentally developed HL partcles with new features for more specific medical usages.

3

For instance, multi-layer capsules of CS/PAA were prepared for loading amoxiline, a

4

betalactam antibiotic, with tunable entrapment efficiency controlled by the number of

5

electrolyte bilayers.133 Hybrid mesoporous silica (m-SiO2) hollow particles with the

6

assemblied layers of poly(L-lysine) (PLL)/cytosine-phosphodiester-guanine oligodeoxy-

7

nucleotide (CpG ODN), a model gene, were used as an enzyme-responsive carrier for drug

8

and gene codelivery.134 With the enzymatic degradation of PLL by changing concentration of

9

R-chymotrypsin enzyme, the release rate of drug and gene from the HL spheres could be

10

controlled. Shi et al. reported the pH and thermally responsive multi-layer HL particles

11

constituted from aliphatic PUA and PSS for smart doxorubicin (DOX) delivery.26 P(MAA-

12

co-EGDMA)@P(NIPAM-co-MAA) yolk-shell HL particles were also applied to the tumor

13

environment-responsive drug delivery.135 The polymer shell acted as a smart “valve” to

14

rational release behavior for DOX, i.e., very low drug release at pH 7.4 but rapid drug release

15

at reduced pH value (6.5 or 5.0) at 37˚C. The movable P(MAA-co-EGDMA) core also

16

displayed pH responsiveness.

17

The pH-responsive multi-layer HL particles of FITC-modified CS (CSFITC)/sodium

18

hyaluronate were used as smart capsules for DOX delivery. After surface functionalization

19

with galactosylated CS having galactose-specific recognition, the particles displayed

20

fluorescent-targeting for hepatocytes.25 In addition, hybrid HL particles of MNPs/graft

21

copolymer comprising AA/2-methacryloylethyl acrylate units as the backbone and

22

PEG/PNIPAM as the grafts could be employed in the multimodal theranostic system,

23

including magnetically targeting, pH-triggered drug releasing, imaging and hyperthermia

24

systems.81 Similarly, hybrid MNPs/PLGA HL particles containing DOX and 3,3’-

25

dioctadecyloxacarbocyanine perchlorate (DiO) as a fluorescent dye inside the void were

26

reported.136 The MNPs encapsulated in PLGA shell generated heat when induced by


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41 1

switching high-frequency magnetic field. As temperature elevating to the Tg of the shell, the

2

mobility of PLGA molecules allowed the release of DOX and DiO monitored in time-

3

controllable manner.

4

Besides drug delivery systems, micron-size polymeric HL particles, e.g., poly(vinyl

5

silane)/PNIPAM,137 PMMA/methoxy(polyethylene glycol) methacrylate138,139 and

6

polydopamine,140 were used as ultrasound and photoacoustic contrast agents (UCAs and

7

PCAs) for imaging technique. The interesting features of these polymeric UCAs/PCAs is a

8

large density difference between the agent and surrounding tissue, gas aqueous diffusivity

9

and shell mechanical stability. A uniform and large size of polymeric HL particle is preferred

10

because it provides a strong acoustic signal. However, the size must not exceed the blood

11

capillary size (

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