One-Step Synthesis of Hydrogen-Bonded Microcapsules for pH-Triggered Protein Release

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One-Step Synthesis of Hydrogen-Bonded Microcapsules

for pH-Triggered Protein Release

Leekang Jeon, Yurim Kim, Jongsun Yoon, Hanjin Seo, and Hyomin Lee*

1. Introduction

Smart microcapsules are core–shell-structured microparticles

with a membrane that effectively protects the sensitive and valu-

able actives loaded in the inner aqueous core from the surround-

ing environment and allow on-demand release of these actives by

responding to diverse external stimuli including temperature,

[1]

salt,

[2]

chemical agents,

[3]

and mechanical stress.

[4]

These

stimuli–responsive nature of microcapsules and the ability to

precisely tune the release behavior have great potential in various

ﬁelds such as food, medicine, and pharmaceutics. Among vari-

ous stimuli explored, pH is one of the most widely investigated

cues in the oral delivery of nutrients and therapeutics due to the

distinctive pH environments in the gastrointestinal (GI) tract,

[5]

which enables localized delivery of the encapsulated active by

appropriate design of the capsule shell

membrane.

[6]

Moreover, the local pH is

often affected by infection, inﬂammation,

and cancer development, all of which make

pH-responsive microcapsules suitable for

the targeted release of actives in therapeutic

applications.

[7]

pH-responsive microcapsules are

commonly prepared by photo- or thermally

initiated polymerization of monomers that

leads to the formation of a polymeric net-

work consisting of charged functional

groups such as acrylamide and carboxylic

acids in which the degree of ionization

and thus charge density is sensitive to a

local change in pH.

[8]

However, due to

the polar and water-soluble nature of the

monomers, it is often challenging to

directly prepare microcapsules with an

aqueous core. While hydrophobic anhy-

dride monomer and subsequent posthy-

drolysis of the shell membrane were

recently exploited to fabricate pH-responsive poly(acid)-based

microcapsules with an aqueous core, the additional hydrolysis

procedure limits the usage of sensitive bioactive and thus

demands postloading.

[9]

Alternatively, pH-responsive microcap-

sules with a membrane that forms through the complexation

of two oppositely charged polyelectrolytes, polycation and polyan-

ion, have been presented.

[10]

Depending on the nature of the

polyelectrolyte used, whether they are strong or weak, they either

completely dissociate within a reasonable pH ranging from 2 to

10 or exhibit fractional charge depending on the dissociation con-

stant (pK

or pK

) as well as the solution pH, ionic strength,

counterion, and concentration, respectively.

[11]

As a result, the

net electrostatic interaction among the polyelectrolytes can be

altered by tuning these parameters, especially the solution pH,

to modulate the pore size and thus the permeability of the shell

membrane. While the effect of solution pH and ionic strength

have been thoroughly explored to reversibly adjust the release

proﬁle, postload, and trap actives, the interdigitated structure

of the resulting membrane limits the rapid response of the

microcapsule to the local pH environment. Moreover, the net

interaction among polyelectrolytes in electrostatic interaction-

driven complexation depends not only on pH but also ionic

strength of the media which make it difﬁcult to precisely tune

the pH condition at which the capsule releases the encapsulated

actives.

These limitations can be mitigated to some extent by utilizing

hydrogen bonding polymers in microcapsules. Unlike

electrostatic interaction between oppositely charged polycation

L. Jeon, Y. Kim, J. Yoon, H. Seo, H. Lee

Department of Chemical Engineering

Pohang University of Science and Technology (POSTECH)

77 Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk 37673, Korea

E-mail: hyomin@postech.ac.kr

The ORCID identiﬁcation number(s) for the author(s) of this article

can be found under https://doi.org/10.1002/sstr.202300200.

This is an open access article under the terms of the Creative

Commons Attribution License, which permits use, distribution and

reproduction in any medium, provided the original work is properly cited.

DOI: 10.1002/sstr.202300200

One-step microﬂuidic approach in which interfacial complexation of hydrogen

bonding polymers is utilized to prepare pH-responsive microcapsules is

presented. Using water-in-oil-in-oil-in-water (W

) triple-emulsion

droplets as templates, it is shown that polymeric microcapsules with an aqueous

core and a shell that consists of two complementary hydrogen bonding polymers,

poly(propylene oxide)(PPO) and poly(methacrylic acid)(PMAA), can be prepared

in a robust manner. The presence of a buffer layer enables controlled interfacial

complexation of PMAA and PPO at the water/oil interface, followed by spon-

taneous dewetting of the oil droplet to result in hydrogen-bonded microcapsules

dispersed in aqueous media. In addition, it is demonstrated that the permeability

of the PPO/PMAA membrane can be readily tuned by varying the molecular

weight of PMAA. Furthermore, it is shown that the resulting PPO/PMAA

microcapsules are stable at a high salt concentration (>1

NaCl) unlike

analogous capsules prepared through electrostatic complexation while they

release the encapsulated protein above the critical pH of which the PMAA ionizes

and results in disassembly of the shell membrane.

RESEARCH ARTICLE

www.small-structures.com

and polyanion, hydrogen bonding polymer pairs comprise hydro-

gen acceptors and donors. For instance, poly(vinyl pyrrolidone)

(PVPON) and poly(propylene oxide) (PPO) serve as hydrogen

acceptors as they each have carbonyl and ether groups with lone

electron pairs on electronegative atoms. On the other hand, weak

polyacids such as poly(acrylic acid) (PAA) and poly(methacrylic

acid) (PMAA) act as hydrogen acceptors at acidic pH where

the acid groups are protonated. While the complementary inter-

action among these hydrogen bonding polymers at acidic pH

leads to complex formation, the acid groups in hydrogen donor

deprotonate and ionize at distinctive pH conditions above the

, resulting in rapid disassembly of the shell membrane.

Moreover, the hydrogen-bonded complex is stable at high salt

concentrations,

[12]

which makes this an ideal shell membrane

that primarily depends on the solution pH.

These microcapsules based on hydrogen bonding polymers

are conventionally prepared using layer-by-layer (LbL) assembly

on colloidal substrates.

[13]

As LbL assembly allows precisely tun-

ing the composition and the shell thickness by simply varying the

type and number of cycles that the complementarily interacting

polyelectrolytes are sequentially assembled, LbL assembly of

hydrogen bonding polymers and subsequent dissolution and

removal of the colloidal template yield hollow polyelectrolyte

microcapsules comprising a shell with known composition

and thickness.

[14]

However, LbL assembly requires a large num-

ber of repeated cycles with multiple rinsing steps in between,

especially to acquire a thick and conformal shell. Moreover,

the usage of sacriﬁcial templates and removal implies the need

for additional postloading of the desired actives after fabrication,

limiting the broad applicability of such an approach. We note that

while interfacial complexation of electrostatically interacting

polymers, as well as nanoparticles at water/oil interface of a

water-in-oil-in-water (W/O/W) double-emulsion droplet, has

been recently exploited for the one-step synthesis of polyelectro-

lyte microcapsules with an aqueous core, these are based on

electrostatic interactions.

[2b,15]

In a separate work, a similar con-

ceptual idea was extended to hydrogen bonding polymers but the

demonstration was limited to microcapsules with an oil core,

mandating additional oil core removal, resuspension in aqueous

media, and postloading of actives for practical use.

[16]

Therefore,

there is an unmet need for a new method that allows reliable and

facile preparation of polyelectrolyte microcapsules with an

aqueous core based on hydrogen bonding polymers.

In this work, we present a one-step microﬂuidic approach to

prepare pH-responsive microcapsules. The interfacial complexa-

tion of hydrogen bonding polymers at water/oil interface of

water-in-oil-in-oil-in-water (W

) triple-emulsion drop-

lets prevents uncontrollable complexation and subsequent device

clogging. The complementarily interacting hydrogen bonding

polymer pair, PMAA and PPO, each dissolved in the aqueous

core (W

) and the outer oil phase (O

), respectively, forms the

shell membrane upon mixing of the two oil phases followed

by interfacial complexation at the W

/O interface. Fluorescent

dye permeability study on sets of PPO/PMAA microcapsules

revealed that the permeability of the shell membrane can be read-

ily tuned by varying the molecular weight of PMAA. Moreover,

we show that the resulting microcapsules remain stable at

high salt concentrations unlike the conventional polyelectrolyte

microcapsules assembled through electrostatic interactions.

Furthermore, we show that the PPO/PMAA microcapsules rap-

idly disassemble above the critical pH of 5, thereby releasing

the encapsulated protein. We envision that the strategy outlined

in this work can be further extended to other hydrogen bonding

polymer pairs to design smart microcapsules with tunable pH

stability, offering new opportunities in microencapsulation

technologies.

2. Results and Discussion

2.1. Synthesis of PPO/PMAA Microcapsules via Interfacial

Complexation of Polymers

For reliable and facile preparation of hydrogen-bonded microcap-

sules, we utilized water-in-oil-in-oil-in-water(W

)

triple-emulsion droplets as templates, as schematically illustrated

in Figure 1a,b. To prepare these triple-emulsion droplets, we

used a glass capillary microﬂuidic device, as described in our pre-

vious works,

[17]

and the details are in the Experimental Section.

We injected pH 2-adjusted aqueous solution containing 1 wt% of

PMAA (hydrogen donor) as the innermost aqueous phase (W

)

through the small tapered capillary in this device. Isopropyl myr-

istate (IPM) containing 2 wt% Span 80 (surfactant) is supplied as

the inner oil phase (O

) through the hydrophobically modiﬁed

injection capillary (left) to form a periodic stream of aqueous

droplets dispersed in the oil phase due to preferential wetting

of the oil on the injection capillary surface.

[18]

Next, IPM with

the identical surfactant composition (2 wt% Span 80) but with

an additional 1 wt% PPO (hydrogen acceptor) is supplied as

the outer oil phase (O

) through the interstices between the injec-

tion capillary and the square capillary. We note that due to the

identical solvent used for both oil phases (O

and O

), they mix

immediately upon contact. Here, the inner oil phase (O

) serves

as a buffer layer, delaying the complexation between PMAA and

PPO during emulsiﬁcation, which often leads to clogging of the

device. The triphasic coaxial ﬂow is simultaneously emulsiﬁed at

the entrance of the collection capillary (right) by shearing of the

pH 2-adjusted outer aqueous phase (W

) containing 10 wt% of

poly(vinyl alcohol)(PVA, surfactant), yielding monodisperse

triple-emulsion droplets that eventually become double-

emulsion droplets by mixing of the two oil phases. This leads

to the diffusion of PPO to the W

/O interface followed by inter-

facial complexation of the two complementarily interacting

hydrogen bonding polymers, PMAA and PPO. Due to the acidic

aqueous environment, the carboxylic acid group of PMAA

remains nonionized and hydrogen bonds with the ether group

of PPO, leading to formation of the microcapsule shell mem-

brane. Indeed, collection of the resulting emulsion droplets in

a bath containing aqueous solution with a composition identical

to the outer aqueous phase and monitoring the behavior of these

droplets over time reveal that a polymeric membrane forms at the

/O interface. This is followed by dewetting of the IPM droplet

within a few minutes, resulting in hydrogen-bonded microcap-

sules, as shown in the scheme of Figure 1c. Interestingly, storage

of the resulting microcapsules in an isotonic collection bath con-

taining 10 wt% PVA leads to shrinkage of the microcapsules due

to consumption of the PMAA through complexation at the W

interface. This results in a decrease in concentration of PMAA,

www.advancedsciencenews.com www.small-structures.com

26884062, 2023, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/sstr.202300200 by Southwest University, Wiley Online Library on [03/07/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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One-Step Synthesis of Hydrogen-Bonded Microcapsules for pH-Triggered Protein Release

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