Synthesis and characterization of poly (n isopropylacrylamide co acrylamide) core silica shell particles

Overview

Hybrid materials featuring a poly(N-isopropylacrylamide) (PNIPAM) core and silica shell have garnered significant interest among researchers due to their unique properties derived from both organic and inorganic components PNIPAM is recognized as a thermosensitive polymer, yet its high softness in the hydrated state limits its mechanical stability In contrast, silica exhibits excellent physicochemical properties, including superior mechanical strength, colloidal stability, biocompatibility, low toxicity, and cost-effectiveness, which help prevent particle aggregation The synthesis of silica directly on the surfaces of PNIPAM particles enables the formation of PNIPAM core-silica shell particles, representing an ideal combination for various applications, particularly in drug delivery systems.

PNIPAM is a prominent thermo-responsive polymer known for its lower critical solution temperature (LCST) of approximately 32 ºC, which is close to human physiological temperature When an aqueous solution of PNIPAM is heated above its LCST, the hydrophobic segments of the polymer attract each other, causing a conformational change that results in the contraction of the swollen polymer chains In very dilute solutions, this can lead to a transition from a coil to a globule, as shown by Wu et al However, rather than forming single chain globules, the contraction of polymer chains typically results in inter-polymeric aggregation and subsequent precipitation Recent observations indicate that heating aqueous PNIPAM solutions does not always lead to the formation of single chain globules.

2 to macroscopic phase separation If the polymer concentration is 0.1 to 1.0 g/l, the polymer chains tend to form stable aggregates upon heating These aggregates are termed

Mesoglobules are distinct from single chain globules, representing collapsed aggregate particles Research by Pelton et al highlights the mechanisms behind the stability of mesoglobules, particularly in colloidally dispersed phase-separated PNIPAM solutions They identified electrostatic repulsion as a key factor in maintaining dispersion stability, noting that the particles possess a weak negative charge This charge is attributed to polymer chains with negatively charged end groups, which are introduced by the persulfate salt used during the polymerization of NIPAM.

In 1986, the synthesis of PNIPAM microgel particles through surfactant-free emulsion polymerization at 70°C using a cross-linker (MBA) was first reported, leading to significant interest in these particles across various scientific fields While "hydrogel" and "microgel" are often used interchangeably, they refer to different physical structures; microgels are discrete gel-like particles, unlike the continuous networks of hydrogels Microgels consist of intermolecular cross-linked polymers created through heterogeneous polymerization techniques, and they are sometimes referred to as nanogels or intramolecular cross-linked macromolecules These superabsorbent polymers possess unique physicochemical properties, combining characteristics of both solids and liquids Microgels are classified as colloidal dispersions, consisting of discrete polymeric gel particles ranging from 1 nm to 1 µm, uniformly dispersed in a solvent medium and swollen by a good solvent.

3 entropy driven demixing of linear PNIPAM chains upon heating takes place by a structural

The "coil-to-globule" transition occurs above the lower critical solution temperature (LCST) of 31-32 °C Chemically cross-linked PNIPAM microgels undergo a volume phase transition (VPT) at approximately 34 °C, slightly above the LCST, attributed to the presence of more hydrophilic cross-links within the network.

PNIPAM microgels are synthesized through precipitation polymerization in aqueous solutions using the cross-linker N,N´-methylenbisacrylamide (MBA) At elevated temperatures, the NIPAM monomer becomes water-soluble, and upon the addition of a radical initiator like potassium peroxodisulfate (KPS), the monomers polymerize into oligomers that eventually become insoluble in water These oligomers are colloidally unstable and aggregate to form precursors, allowing further oligoradicals to attach until the monomer is depleted The typical synthesis temperature for PNIPAM microgels is 70 °C, which is above the lower critical solution temperature (LCST), resulting in the formation of microgels in a collapsed state.

Sodium dodecylsulfate (SDS) is commonly used as a surfactant to stabilize dispersions and regulate particle size during NIPAM polymerization However, conventional surfactants can negatively impact product properties because they may desorb from the surfaces of colloidal particles due to weak hydrophobic interactions To address these issues, the use of reactive surfactants has emerged as a promising solution Reactive surfactants are amphiphilic molecules that possess additional functionalities, granting them chemical reactivity and enhancing stability in polymer systems.

The primary concept involves designing surfactants to engage in hetero-phase polymerizations as polymerizable surfactants (surfmers), surface-active initiators (inisurfs), or surface-active transfer agents (transurfs), ultimately ensuring they are covalently bonded to the polymer chains However, optimizing the polymerization process with inisurfs and transurfs is more challenging than with surfmers, as the concentration of transurfs significantly influences the molar mass.

The concentration of inisurf significantly impacts the polymerization rate, while the cage effect contributes to the low efficiency of inisurfs As a result, surfmers have become the preferred choice among commercially available reactive surfactants This thesis explores the use of an anionic polymerizable surfactant, polyoxyethylene alkylphenyl ether ammonium sulfate with 10 units of ethylene oxide (HS10), as a replacement for conventional surfactants in stabilizing dispersions and controlling particle size during the polymerization of NIPAM.

The process of silica encapsulation involves the formation of silica nuclei on polymeric cores through the sol-gel method using tetraethyl orthosilicate (TEOS) and 3-glycidyloxypropyltrimethoxy silane (GLYMO) At elevated pH levels, alkoxysilanes primarily undergo hydrolysis rather than condensation The initial primary particles that emerge from oligomerization are stabilized by silanolate (R3SiO-) groups on their surfaces With careful control, these primary particles can capture additional particles, resulting in a gradual increase in the average diameter of the relatively monodisperse hybrid particles.

Objectives

1.2.1 Synthesis and characterization of poly(N-isopropylacrylamide-co-acrylamide) mesoglobule core - silica shell nanoparticles

This study focuses on reducing the size of poly(N-isopropylacrylamide-co-acrylamide) (PNIPAM/AM) core-silica shell particles by utilizing mesoglobule cores as nucleating agents for silica encapsulation These mesoglobule cores form at the nanoscale through the separation of liquid and solid phases, leading to the collapse of swollen polymer coils above the lower critical solution temperature (LCST) in a dilute solution without surfactants To achieve effective silica encapsulation, 3-glycidyloxypropyltrimethoxysilane (GLYMO) is employed as a coupling agent, which features one epoxide group and three methoxysilyl groups to improve the interaction between the organic and inorganic components The amide group of AM reacts with the epoxide group of GLYMO, while the ethoxysilyl groups of TEOS and the methoxysilyl groups of GLYMO participate in simultaneous sol-gel reactions, enhancing the encapsulation process.

This study demonstrates the formation of tiny silica nanoparticles on the surfaces of PNIPAM/AM mesoglobule cores, resulting in optimized particle morphology The findings are valuable for the development of thermo-responsive PNIPAM/AM mesoglobule core-silica shell nanoparticles, allowing for controlled particle morphology and tailored physicochemical properties.

1.2.2 Synthesis and characterization of PNIPAM microgel core - silica shell particles

This study presents a straightforward method for synthesizing poly(N-isopropylacrylamide-co-acrylamide-co-N,N′-methylenebisacrylamide) (PNIPAM/AM/MBA) microgel core-silica shell particles at temperatures significantly above the lower critical solution temperature (LCST) The microgel particles are formed through homogeneous nucleation without surfactants or organic solvents, stabilized by electrostatic repulsion from the sulfate groups of PNIPAM/AM/MBA, which are generated by a persulfate initiator during surfactant-free emulsion copolymerization These microgel cores serve as templates for silica encapsulation, utilizing 3-glycidyloxypropyltrimethoxysilane (GLYMO) as a coupling agent to improve the interaction between the organic core and inorganic silica shell The amide groups in AM react with GLYMO's epoxide group, while TEOS and GLYMO undergo sol-gel reactions, resulting in silica nanoparticles forming on the microgel surfaces and achieving an ideal core-shell structure The findings of this research are significant for developing thermo-responsive PNIPAM/MBA/AM microgel core-silica shell submicron particles with tailored morphology and physicochemical properties for drug delivery applications.

1.2.3 Synthesis and characterization of poly(N-isopropylacrylamide-co-N,N′- methylenebisacrylamide-co-acrylamide) core - silica shell nanoparticles by using reactive surfactant polyoxyethylene alkylphenyl ether ammonium sulfate

This study aims to assess the impact of the anionic polymerizable surfactant polyoxyethylene alkylphenyl ether ammonium sulfate with 10 ethylene oxide units (HS10) on the properties of P(NIPAM/AM) core and hybrid core-shell particles HS10 exhibits a low critical micellar concentration (CMC) of 0.09 mM, significantly lower than the 8.28 mM CMC of sodium dodecyl sulfate (SDS) A series of hybrid particles were synthesized from P(NIPAM/AM) cores with varying HS10 concentrations (ranging from zero to over 0.5 wt%) and silica shells, followed by characterization of their morphology, particle size, and size distribution using FE-SEM, TEM, FTIR, and TGA The lower critical solution temperature (LCST) was analyzed using DLS and DSC, and optimal conditions for achieving the desired particle size of the polymeric core-silica shell particles were explored Additionally, the biocompatibility of a representative sample was confirmed through cytotoxicity assays.

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Introduction

N-isopropylacrylamide (PNIPAM) stands out among thermo-sensitive polymers for biomedical applications due to its biocompatibility and a lower critical solution temperature (LCST) of approximately 32 ºC, which is close to human body temperature PNIPAM is characterized by its hydrophilic amide and hydrophobic isopropyl groups Below the LCST, the amide group forms strong hydrogen bonds with water molecules, resulting in expanded polymer coils that retain significant water content Conversely, when the temperature exceeds the LCST, these hydrogen bonds are disrupted, leading to a more compact polymer structure, phase separation, and the collapse of swollen polymer coils, known as mesoglobules.

PNIPAM exhibits significant softness in its hydrated state, which limits its mechanical stability To address this limitation, researchers have proposed the development of interpenetrating networks that combine PNIPAM with polymers that have superior mechanical properties, or the incorporation of inorganic nanoparticles into PNIPAM Inorganic silica has been highlighted for its excellent physicochemical properties, including mechanical strength, chemical and thermal stability, biocompatibility, low toxicity, and cost-effectiveness A promising method involves synthesizing silica directly on the surfaces of PNIPAM particle cores to create PNIPAM core-silica shell particles, enhancing their overall performance For instance, PNIPAM particles can be filled with colloidal silica of similar particle sizes, further improving their characteristics.

The in situ sol-gel process successfully produced thermo-sensitive raspberry-like hybrid particles, approximately 500 nm in diameter, featuring PNIPAM microgel cores adorned with silica particles Additionally, Wang and Asher developed PNIPAM cores encased in shells made of silica particles around 400 nm in diameter, along with poly(NIPAM-co-acrylic acid) core-silica shell particles.

Hu and colleagues successfully synthesized PNIPAM/silica composite microspheres with a diameter of 250 nm, while Duan et al proposed a method for their synthesis using Pickering emulsion polymerization However, most reported PNIPAM/silica composite particles are micron-sized, limiting their effectiveness in drug delivery due to difficulties in penetrating tissues and entering cells, which results in inefficient drug delivery to target sites Research indicates that nanoparticles have a significantly higher uptake (15-250 times) compared to microparticles in the 1-10 µm size range Therefore, controlling the size of PNIPAM/silica composite particles within the nanoscale is essential, which can be achieved by minimizing the core particle size Various methods to adjust the size of cross-linked PNIPAM core particles have been explored, including the use of surfactants, electrolytes, and highly charged co-monomers; however, optimal control of microgel particle size has not been consistently achieved in these studies.

This study introduces a novel method for controlling the size of poly(NIPAM-co-acrylamide) (PNIPAM/AM) mesoglobule core-silica shell nanoparticles, synthesized at temperatures above the lower critical solution temperature (LCST) The formation of nanoscale mesoglobule cores occurs through the separation of liquid and solid phases, leading to the collapse of swollen polymer coils without surfactants in dilute solutions These mesoglobule cores serve as nucleating agents for silica encapsulation, resulting in an ideal core-shell nanostructure To enhance the silica encapsulation process, 3-glycidyloxypropyltrimethoxysilane (GLYMO) is utilized as a coupling agent, featuring one epoxide group and three methoxysilyl groups to improve the interaction between organic and inorganic components This allows the amide group of acrylamide to react with the epoxide group of GLYMO, while the ethoxysilyl groups of tetraethyl orthosilicate (TEOS) and the methoxysilyl groups of GLYMO undergo simultaneous sol-gel reactions, facilitating the formation of silica nanoparticles directly on the mesoglobule cores.

The study highlights the successful design of thermo-responsive PNIPAM/AM mesoglobule core-silica shell nanoparticles, which exhibit controlled particle morphology and tailored physicochemical properties These findings are instrumental in achieving the desired particle characteristics for various applications.

Experimental

The chemicals utilized in this study include high-purity N-isopropylacrylamide (NIPAM), acrylamide (AM), potassium persulfate (KPS), 3-glycidyloxypropyltrimethoxysilane (GLYMO), tetraethyl orthosilicate (TEOS), potassium bromide (KBr), tetrahydrofuran (THF), and ethanol, all sourced from reputable suppliers such as Acros, Sigma-Aldrich, and Evonik Deionized water with a specific conductance of less than 0.057 µS cm⁻¹ was employed in all experiments, ensuring the use of reagent-grade chemicals as received for optimal results.

The samples PNIPAM, PNIPAM/5AM, and PNIPAM/10AM were synthesized through free radical polymerization, utilizing 1 g of NIPAM and varying amounts of AM (0, 0.05, and 0.1 g) with 0.04 g of KPS as the initiator in 10 g of water The reaction took place at 70 °C for 24 hours under a nitrogen atmosphere, and the resulting crude polymer solution was subsequently washed with hot water.

To eliminate any residual monomers and initiators, the resultant polymer (PNIPAM, PNIPAM/5AM, or PNIPAM/10AM) was heated to 50 °C Afterward, the polymer was dissolved in cold water and stored as a stock solution for subsequent experiments.

2.2.3 Synthesis of hybrid core - shell particles

The encapsulation of polymeric cores with silica shells was achieved through a sol-gel reaction involving GLYMO as a coupling agent and tetraethyl orthosilicate (TEOS) as a silica precursor Initially, a 0.5 wt% aqueous polymer solution was adjusted to pH 12 using 0.5 M sodium hydroxide and heated to 50 °C Following this, GLYMO was introduced to the polymer dispersion, and TEOS was added to the mixture, with the entire reaction maintained at 50 °C.

The final product was obtained through a process involving centrifugation at 25,000 rpm for 30 minutes, followed by washing with alcohol and water three times Table 2.1 outlines the recipes utilized for the preparation of hybrid organic-inorganic (core-shell) colloidal particles in this study.

The average molecular weight (Mw) of the polymer was determined using gel permeation chromatography (GPC) with Waters Styragel HR2, HR4, and HR6, utilizing a calibration curve established from polystyrene standards Tetrahydrofuran (THF) served as the eluent solvent, with a flow rate of 1 mL/min at 40 °C for GPC measurements Dynamic light scattering (DLS) was employed to measure the average hydrodynamic diameter of colloidal particles and the lower critical solution temperature (LCST) across a temperature range of 26-50 °C in 2 °C intervals, with concentrations varying from 0.1 to 1 wt% The thermal behavior of both the polymer and core-shell particles, with a total solids content of 10%, was analyzed using Differential Scanning Calorimetry (DSC) from 25 °C.

The dried particle size and morphology were characterized using field emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM), with a scanning rate of 2 °C min -1 at 60 °C A sample with approximately 0.5% total solids was prepared by diluting in water, then deposited on carbon tapes or polymer-coated copper grids and dried at room temperature Particle diameters, including the number average (dn), weight average (dw), and polydispersity index (PDI = dw/dn), were measured by SEM or TEM, analyzing at least 150 particles The chemical incorporation of acrylamide (AM) into N-isopropylacrylamide (NIPAM) chains was confirmed through proton nuclear magnetic resonance spectroscopy (1H-NMR) The NIPAM/AM sample was prepared by washing with hot water and drying in a vacuum oven, followed by dissolution in DMSO-d6 for NMR analysis Fourier transform infrared (FTIR) spectra were obtained using an FTS-3500 instrument, covering a wavenumber range of 4000-400 cm −1 with a resolution of 4 and a total of 32 scans.

Thermogravimetric analysis (TGA) was performed using a Perkin-Elmer Diamond TG/DTA instrument, with a heating rate of 10 °C/min and an air flow rate of 200 ml/min, within a temperature range of 100 °C to 15 cm −1 under nitrogen flow to eliminate any moisture present.

Results and discussion

2.3.1 The approach used to synthesize PNIPAM based mesoglobule core - silica shell nanoparticles

The formation of PNIPAM core-silica shell nanoparticles is illustrated in Scheme 2.1, where mesoglobule cores are encapsulated by silica nanoparticles using GLYMO as the coupling agent GLYMO contains an epoxy group that can react with the amino group of the AM unit, if present, or with the amide group of the NIPAM unit through ring-opening reactions The primary hydrogen of the -NH2 group in the AM unit exhibits significantly higher reactivity towards GLYMO compared to the secondary hydrogen of the >NH group in the PNIPAM chain This difference in reactivity is attributed to the steric effects associated with N-isopropylacrylamide, as supported by existing literature on the competitive reactions of primary and secondary amines with epoxy resins.

The formation of silica nuclei on polymeric cores is essential during the initial stages of the sol-gel process to achieve the desired morphology of organic core-inorganic shell particles Following this, hydrolyzed TEOS, or silicic acid, along with oligomeric silica, diffuses from the bulk aqueous phase to the interfacial layer between the continuous and disperse phases, facilitating sol-gel reactions that promote the growth of the silica shell Ultimately, this process results in the creation of hybrid nanoparticles featuring a PNIPAM core and a silica shell.

2.3.2 Preparation and characterization of PNIPAM based mesoglobule cores

Mesoglobule cores based on PNIPAM were synthesized through free radical polymerization of NIPAM, incorporating varying amounts of AM (0 wt%, 5 wt%, and 10 wt%) at a temperature of 70 °C The characterization of these cores was conducted using Dynamic Light Scattering (DLS) and Gel Permeation Chromatography (GPC), with the findings summarized in the results section.

Above the Lower Critical Solution Temperature (LCST), PNIPAM exhibits hydrophobic interactions that lead to the precipitation of polymer chains, forming particle embryos in the aqueous phase These nuclei grow as PNIPAM molecules diffuse from the bulk solution to the particle surfaces, reducing interfacial free energy through deposition or aggregation At a constant acrylamide (AM) concentration, the average hydrodynamic diameter of particles increases with higher PNIPAM concentration, resulting in a broad particle size distribution (PDI > 0.1) Research by Yan et al indicates that PNIPAM particle size is influenced by both concentration and molecular weight, with lower concentrations yielding smaller particles Additionally, particle embryos in the aqueous phase often aggregate into multi-chain structures, which typically cease growth upon reaching a certain size during nucleation.

At a constant concentration of 0.5 wt%, the weight-average molecular weight (Mw) decreases with increasing acrylamide (AM) concentration, highlighting the influence of polymerization methods Free radical polymerization in heterogeneous systems, such as emulsion polymerization, typically yields higher molecular weights compared to solution polymerization In the copolymerization of N-isopropylacrylamide (NIPAM) and AM using potassium persulfate (KPS) as an initiator at 70 °C, the significance of solution polymerization leads to the formation of lower molecular weight polymer chains However, the molecular weight distribution (PDI ranging from 1.7 to 2.0) remains relatively stable despite increasing AM concentrations For further silica encapsulation, PNIPAM, PNIPAM/5AM, and PNIPAM/10AM at 0.5 wt% were selected to achieve a balance between small particle size and high total solids content.

2.3.3 Encapsulation of PNIPAM based mesoglobule cores with silica shells

2.3.3.1 Effects of reaction temperature and time

The study investigates the encapsulation of PNIPAM/5AM mesoglobules with silica shells through a sol-gel reaction using TEOS, performed above its lower critical solution temperature (LCST) of 34.7 °C The reaction's transparency at room temperature (around 25 °C) transitions to a milky white appearance after being maintained at elevated temperatures for varying durations (1, 3, 5, and 7 hours) At 40 °C, a stable milky dispersion is achieved after approximately 5 hours, resulting in hybrid organic core-inorganic shell particles with a diameter of 132 nm and a polydispersity index (PDI) of 1.09, characterized by a spherical shape and rough surface as observed in SEM images Similarly, at 50 °C, the reaction mixture turns milky white after 3 hours, yielding smaller particles (92 nm, PDI 1.06) after 5 hours, followed by significant agglomeration into a network structure over 7 hours This reduction in particle size at higher temperatures is attributed to enhanced hydrophobic interactions of PNIPAM/5AM, which facilitate water expulsion and result in a more compact particle structure.

1 h, the reaction mixture rapidly turned to a milky white dispersion (observed at room temperature), followed by fast particle aggregation to form the network structure, as shown in Fig 2.1D

2.3.3.2 Effects of GLYMO and TEOS concentrations

In this series of experiments, the reaction temperature and time were kept constant at 50 °C and 5 h, respectively, and the weight percentage of PNIPAM based mesoglobule cores was also

The study examined the effects of varying the weight ratio of GLYMO, a coupling agent, to TEOS while maintaining a constant GLYMO concentration of 0.5 wt% Initial compositions for the experimental runs PNIPAM/5AM-111, PNIPAM/5AM-121, PNIPAM/5AM-112, and PNIPAM/5AM-122 are detailed in Table 2.1 Notably, the last three digits in PNIPAM/5AM-111 indicate a weight ratio of PNIPAM/5AM:GLYMO:TEOS of 1:1:1 For comparative analysis, PNIPAM/5AM-101 was included in the study as a control without the coupling agent.

In the run PNIPAM/5AM-101, the reaction system involving TEOS with PNIPAM/5AM mesoglobules remained transparent at room temperature, suggesting that silica nucleation primarily occurred in the aqueous phase, with minimal encapsulation of mesoglobules affecting the sol-gel reaction This transparency contrasts with the translucent nature of PNIPAM/5AM-111, indicating a different interaction with TEOS The presence of GLYMO, which has one reactive epoxide group and three methoxysilyl groups, facilitates the sol-gel reaction; the epoxide can react with the amide group of AM under basic conditions, while the methoxysilyl groups hydrolyze to form reactive silanol groups that enhance the sol-gel process Consequently, the PNIPAM/5AM-111 mesoglobule cores grow effectively during this reaction, achieving an average particle diameter of 92 nm as confirmed by SEM and TEM analyses Similar silica encapsulation behaviors were observed in experiments with other compositions, as illustrated in the provided figures and particle size data.

The diameter of weight-average PNIPAM/5AM core-silica shell particles (dw) increases with higher concentrations of GLYMO or TEOS For instance, at a constant TEOS concentration, comparing PNIPAM/5AM-111 with PNIPAM/5AM-121 reveals a significant dw increase of approximately 57%, indicating that doubling GLYMO concentration enhances the nucleation and growth of silica embryos around the PNIPAM/5AM cores, resulting in thicker silica shells and greater surface roughness However, at elevated TEOS concentrations, the impact of increased GLYMO concentration on particle size is less pronounced, with a dw increase of only about 29% This is due to the abundance of silica precursors available for encapsulating the PNIPAM/5AM cores, which mitigates the effects of the higher GLYMO concentration Additionally, visual evidence shows that PNIPAM is encapsulated by small silica nanoparticles.

We have developed an effective method for silica encapsulation of PNIPAM-based mesoglobule cores by incorporating comonomer units, such as AM, into the PNIPAM structure This process utilizes a coupling agent, like GLYMO, which reacts with both the amide group of the AM unit and silica precursors from TEOS This technique facilitates the nucleation and growth of silica on the surfaces of PNIPAM mesoglobule cores, resulting in hybrid nanoparticles Additionally, it enables precise control over the particle size, shell thickness, and morphology, including the permeability of the PNIPAM-silica shell particles.

The effects of acrylamide (AM) content in PNIPAM-based mesoglobule core-silica shell particles are detailed in Table 2.3 and Figures 2.3A, 2.4A, 2.5, and 2.6 PNIPAM/5AM-111 exhibits a similar particle size and distribution to PNIPAM-111 without AM, both showcasing a relatively spherical shape and raspberry-like morphology In contrast, PNIPAM/10AM-111 displays a mixed morphology of oblong and spherical particles with smoother surfaces The transition from spherical to oblong shapes in PNIPAM/10AM-111 resembles changes observed in surfactant systems, likely due to enhanced nucleation and silica growth on AM-rich mesoglobule surfaces This promotes the sol-gel reaction between methoxysilyl and ethoxysilyl groups, increasing the likelihood of forming oblong nanoparticles The presence of AM-rich chain segments in PNIPAM/10AM may significantly influence particle morphology by minimizing interfacial free energy Additionally, TEM images reveal a contrast between the core and shell phases, confirming the formation of PNIPAM-based mesoglobule core-silica shell structures.

The unclear distinction between the core and shell phases hindered the estimation of shell thickness Additionally, Figure 2.6B depicts both oblong and spherical particles containing the core phase within PNIPAM/10AM-111.

The incorporation of acrylamide (AM) into poly(N-isopropylacrylamide) (PNIPAM) chains was confirmed through 1 H-NMR spectroscopy for the copolymerization sample of NIPAM and AM in water, with a ratio of [10/0.5 (w/w)] or [12.6/1 (mol/mol)] The 1 H-NMR spectrum of PNIPAM served as a reference, revealing all proton signals related to the polymer structure Notably, a new shoulder peak at a chemical shift of 6.8 ppm in the P(NIPAM/5AM) spectrum corresponds to the protons of the –NH2 units from AM Before polymerization, the theoretical integral area ratio of the -NH2 protons from AM to the -NH protons from NIPAM was calculated to be 1/12.6 After polymerization, this ratio was estimated at 0.11/1, indicating a molar ratio of AM to NIPAM of 0.11/1 in the copolymerization process.

2.3.4 Characterization of PNIPAM-based core - silica shell particles

Figure 2.8A illustrates the hydrodynamic hybrid particle diameter (d) measured by dynamic light scattering (DLS) as a function of temperature (T) The lower critical solution temperature (LCST) was identified by analyzing the first derivative of the d vs T curve, pinpointing the temperature at which a minimum occurs in the dd/dT plot.

T curve, as shown in Fig 2.8B

Figure 2.8A illustrates that hybrid particles, similar to PNIPAM-based mesoglobules, contract significantly with rising temperatures, primarily due to the silica layer's permeability It is anticipated that the shell layers consist of numerous small silica clusters, which display a relatively discrete distribution on the surface of the P(NIPAM/AM) core as a result of reactions between amino groups from AM and NIPAM and epoxy groups from GLYMO This shell structure, containing various slots or channels, permits water molecules to pass through, enabling the PNIPAM-based mesoglobule cores to either shrink or swell with temperature changes Consequently, the stress caused by the thermo-responsive PNIPAM core's shrinking or swelling results in the displacement of the silica clusters, allowing PNIPAM-based mesoglobule core-silica shell particles to demonstrate a distinct LCST phase transition.

22 behavior The LCST determined by DLS shifts slightly to higher temperature with increasing

Conclusions

The way to encapsulate PNIPAM mesoglobule cores by silica shells significantly affects the resultant hybrid nanoparticle structures and their physicochemical properties This work

A novel technique for creating thermo-responsive PNIPAM-based mesoglobule core-silica shell nanoparticles with a narrow particle size distribution has been introduced This method involves integrating acrylamide (AM) units into the PNIPAM chain, alongside 3-glycidyloxypropyltrimethoxysilane (GLYMO) as a coupling agent The reaction between the -NH2 group of the AM unit in the mesoglobule core and the epoxide group of GLYMO, along with the sol-gel reaction of TEOS and GLYMO, enhances the nucleation and growth of silica particles on the PNIPAM-based core surfaces Consequently, this results in a desirable hybrid organic-inorganic particle morphology The morphology, including shape, core size, shell thickness, and surface roughness, can be controlled by adjusting the AM content and the weight ratio of PNIPAM/AM:GLYMO:TEOS For instance, the PNIPAM/5AM core, containing 5 wt% AM, exhibits an increase in particle size with higher concentrations of GLYMO or TEOS during silica encapsulation Experiments with a weight ratio of PNIPAM/nAM:GLYMO:TEOS = 1:1:1, where n equals 0, 5, and 10 wt%, reveal that PNIPAM/5AM-111 achieves a comparable particle size (dw = 92 nm) and particle size distribution (PDI = 1.13) to its counterparts.

The study reveals that PNIPAM/10AM-111 exhibits a mixed morphology of oblong and spherical particles, characterized by a smooth surface The lower critical solution temperature (LCST) of PNIPAM-based mesoglobules increases with higher acrylamide (AM) content, as the hydrophilic nature of AM makes the polymer less temperature-sensitive Additionally, encapsulating PNIPAM-based mesoglobules with silica further reduces the thermo-sensitivity of the resulting core-shell nanoparticles.

PNIPAM core-silica shell particles were synthesized through the encapsulation of silica onto crosslinked PNIPAM microgel particles in the presence of a surfactant The resulting hybrid particles exhibit sizes approximately 2.5 to 5 times larger than the original microgel particles.

This study presents the development of PNIPAM-based mesoglobule core-silica shell nanoparticles However, the unique dimensions of the crosslinked PNIPAM microgel core and silica shell restrict their effectiveness as drug carriers, despite efforts to enhance colloidal stability and minimize particle size through surfactant use.

Fine-tuning the lower critical solution temperature (LCST) of PNIPAM-based core-silica shell nanoparticles is crucial for maintaining their thermo-sensitivity while ensuring a well-defined pore structure in the silica shell, especially for biomedical applications The integration of organic and inorganic materials, along with the associated colloidal and interfacial phenomena, presents significant challenges for future research in this area.

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Introduction

Thermo-sensitive N-isopropylacrylamide (PNIPAM) stands out as a leading candidate for biomedical applications due to its excellent biocompatibility and a lower critical solution temperature (LCST) of approximately 32 ºC, closely aligning with human physiological temperature The unique structure of PNIPAM includes both hydrophilic amide groups and hydrophobic isopropyl groups, enhancing its versatility in various applications.

Microgel particles exhibit strong interactions with water molecules through hydrogen bonding when temperatures are below the Lower Critical Solution Temperature (LCST), leading to significant water retention within their expanded structure However, as the temperature exceeds the LCST, the hydrogen bonds between the amide groups of PNIPAM and water molecules are disrupted, causing the microgel particles to become more compact This transition results in the separation of liquid and solid phases, ultimately leading to the collapse of the swollen microgel particles.

PNIPAM is known to be quite soft in its hydrated state, which limits its mechanical stability (Nun et al [16]) To address this issue, researchers have proposed the use of interpenetrating networks that combine PNIPAM with other polymers that possess better mechanical properties or the incorporation of inorganic nanoparticles into PNIPAM (Nun et al [16]) Byun et al [17] highlighted that inorganic silica offers excellent physicochemical properties, including mechanical strength, chemical and thermal stability, biocompatibility, low toxicity, and low permeability, making it a cost-effective option Additionally, synthesizing silica directly on the surfaces of PNIPAM particles to create PNIPAM core-silica shell particles is considered a highly advantageous method (Nun et al [16]).

Duan et al synthesized PNIPAM/silica composite microspheres through inverse Pickering suspension polymerization, achieving particle diameters between 4-100 µm In this process, PNIPAM droplets were dispersed in toluene and stabilized by silica particles before polymerization Byun et al developed PNIPAM particles filled with colloidal silica, approximately 1 µm in diameter, using an in situ sol-gel process Dechezelles et al reported thermos-sensitive raspberry-like hybrid particles, with PNIPAM microgel cores decorated by silica particles, measuring around 500 nm in diameter Additionally, Wang and Asher prepared PNIPAM cores enveloped by a shell of very small silica particles, with diameters of about 100 nm.

Hu and colleagues successfully synthesized 400 nm PNIPAM/AA core-silica shell particles, approximately 250 nm in diameter, using a self-assembly approach However, the study noted that without a coupling agent, the encapsulation of PNIPAM microgel core-silica shell particles was incomplete.

The use of less effective coupling agents can lead to undesirable fast drug release kinetics in PNIPAM/silica composite particles Conversely, employing surfactants to create smaller PNIPAM/AA core-silica shell particles may introduce biocompatibility issues for biomedical applications However, the modified PNIPAM/silica composite particles documented in the literature typically exhibit enhanced long-term stability and good dispersity, making them valuable for a range of applications.

This study presents an effective method for synthesizing poly(N-isopropylacrylamide-co-acrylamide-co-N,N′-methylenebisacrylamide) (PNIPAM/AM/MBA) microgel core-silica shell particles at temperatures exceeding the lower critical solution temperature (LCST) The microgel particles are formed through homogeneous nucleation without surfactants or organic solvents, stabilized by electrostatic repulsion from the terminal sulfate groups of PNIPAM/AM/MBA, which are derived from the persulfate initiator during surfactant-free emulsion copolymerization These microgel cores serve as templates for silica encapsulation, utilizing 3-glycidyloxypropyltrimethoxysilane (GLYMO) as a coupling agent to enhance the interaction between the organic core and the inorganic silica shell The amide group of AM reacts with GLYMO's epoxide group, while the ethoxysilyl groups from tetraethyl orthosilicate (TEOS) and GLYMO undergo sol-gel reactions, resulting in silica nanoparticles forming on the microgel surfaces This approach yields thermo-responsive PNIPAM/MBA/AM microgel core-silica shell submicron particles with tailored morphology and physicochemical properties, suitable for drug delivery applications.

Experimental

This study utilized a variety of high-purity chemicals, including N-isopropylacrylamide (NIPAM), acrylamide (AM), and N,N′-methylenebisacrylamide (MBA) from Acros, as well as potassium persulfate (KPS) from Acros and 3-glycidyloxypropyltrimethoxysilane (GLYMO) from Evonik Additional reagents included doxorubicin hydrochloride (DOX) and thiazolyl blue tetrazolium bromide (MTT) from Sigma-Aldrich, phosphate buffered saline (PBS), antibiotic antimycotic solution (AB), fetal bovine serum (FBS), and minimum essential medium alpha modification (MEM) from HyClone Potassium bromide (KBr) was sourced from Acros, while ethanol was obtained from Uni-Onward Corp All experiments were conducted using deionized water from the Barnsted Nanopure Ultrapure Water System, ensuring high purity with a specific conductance of less than 0.057 µS/cm All chemicals were of reagent grade and used as received.

The samples PNIPAM/10MBA and PNIPAM/10AM/10MBA were synthesized through free radical precipitation polymerization of NIPAM, using 10 wt% MBA as a crosslinking agent and 4 wt% KPS as a thermal initiator, with or without the addition of 10 wt% AM The reaction was conducted at 70 °C in a nitrogen atmosphere for 6 hours, maintaining a total solids content of 2 wt% Following polymerization, the microgel particles were isolated via centrifugation and washed three times with water to eliminate unreacted monomers and impurities.

3.2.3 Synthesis of hybrid core - shell particles

The polymeric core template was encapsulated with silica through a sol-gel reaction using tetraethylorthosilicate (TEOS) as a silica precursor, with or without the addition of 3-glycidyloxypropyltrimethoxysilane (GLYMO) as a coupling agent Initially, 200 g of a 0.5 wt% aqueous polymer solution was adjusted to a pH of 12 using a 0.5 M sodium hydroxide solution.

The polymer dispersion was initially heated to 50 °C, after which 1 g of GLYMO and 1 g of TEOS were added The reaction proceeded at this temperature for 5 hours, resulting in a final product that was precipitated through centrifugation at 5000 rpm for 20 minutes The product was then washed three times with alcohol followed by water Table 2.1 provides a summary of the recipes utilized for preparing the hybrid organic-inorganic (core-shell) colloidal particles in this study.

The zeta potential of colloidal particles was measured using a Brookhaven 90 Plus instrument, while the average hydrodynamic diameter and lower critical solution temperature for a sample with 0.5% total solids content were determined through dynamic light scattering (DLS) at temperatures ranging from 26 to 50 °C in 2 °C intervals The thermal behavior of microgel and hybrid organic core-silica shell particles with 10% total solids content was analyzed using differential scanning calorimetry (DSC) from 25 to 60 °C at a scanning rate of 2 °C/min Particle size and morphology were characterized by field emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM), with samples diluted to approximately 0.5% total solids, deposited on carbon tapes or polymer-coated copper grids, and dried at room temperature The number average diameter, weight average diameter, and polydispersity index were calculated from SEM or TEM measurements of at least 150 particles Fourier transform infrared (FTIR) spectra were obtained using a Bio-Rad FTS-3500 instrument, scanning the wavenumber range of 4000-400 cm−1 with 32 scans at a resolution of 4 cm−1 under nitrogen flow to eliminate moisture Additionally, characteristic weight loss data were recorded using a Perkin-Elmer Diamond TG/DTA instrument with a heating rate of 10 °C/min under air flow.

20 mLmin −1 in the temperature range 100-800 °C

DOX was chosen for the drug loading and releasing experiments In brief, the mixture of 5 mL DOX solution (1 mg mL -1 ) and 1 mL dispersion of hybrid polymer core - silica shell

The DOX-loaded particles were prepared by stirring a suspension of 38 particles at a concentration of 15 mg mL -1 at room temperature (approximately 25 °C) overnight, followed by incubation at 4 °C in the dark for 24 hours After centrifugation at 6000 rpm for 10 minutes, the DOX-loaded particles were separated from the supernatant, which contained free DOX molecules To ensure the removal of unabsorbed DOX, the particles were washed three times with deionized water The concentration of free DOX in the supernatant was quantified using absorbance measurements at a wavelength of 486 nm on a UV-Vis spectrophotometer (V-730, Jasco, Japan), with a standard free DOX solution used to create a calibration curve The drug loading efficiency (DLE) and drug loading content (DLC) were calculated using specific equations.

(2) where WL is the weight of loaded drug, Wo the initial weight of drug and WC the weight of the hybrid particle carriers

The release of the drug from hybrid core-shell particles was conducted at 37°C using equilibrium dialysis at two different pH levels (6.0 and 7.4) A sample of 0.75 mL was dialyzed in a 3-mL dialysis tube with a 12 kDa cellulose membrane against 30 mL of PBS at the specified pH At various time intervals, 2 mL of the PBS solution containing the released DOX was extracted for UV-Vis measurements, followed by the addition of 2 mL of fresh PBS to maintain a constant volume of 30 mL in the sink The amount of released DOX was quantified using a calibration curve, and the percentage of drug release was calculated accordingly.

3.2.6 Cell culture and cytotoxicity MTT assay

Mouse fibroblast cells (i.e., L929) were cultured in MEM alpha modification supplemented with 10% FBS and 1% antibiotics The cells grew on the tissue culture flask in humidified

39 incubator at 37 o C with 5% CO2, and the growth medium was replaced by fresh medium every

The cytotoxic effects of hybrid polymer core-silica shell particles on L929 cells were evaluated using the MTT assay Initially, L929 cells were cultured in a 96-well plate at a density of 10,000 cells per well in 100 µL of medium Subsequently, 100 µL of the hybrid core sample was added to each well for analysis.

Shell particles were introduced into the wells at concentrations ranging from 0.08 to 2.50 mg/mL and incubated at 37°C for 24 hours After incubation, the medium was removed and the wells were washed with PBS Subsequently, 50 µL of MTT solution (0.5 mg/mL in PBS) was added to each well, followed by another incubation at 37°C for 4 hours The unreacted MTT was carefully removed, and 150 µL of DMSO was added to dissolve the formazan crystals, with the plate shaken for 15 minutes Finally, the absorbance of each well was measured at a wavelength of 570 nm using a BioTek microplate reader.

Results and discussion

3.3.1 Characterization of PNIPAM based microgel cores with silica shells

The formation of monodisperse crosslinked PNIPAM-based microgel core-silica shell particles involves encapsulating the microgel core with silica nanoparticles using GLYMO as a coupling agent GLYMO, which contains an epoxy group, reacts with the amino groups of NIPAM and MBA units, or the AM unit if present, through ring-opening reactions The amino group in the AM unit exhibits higher reactivity towards GLYMO compared to the amide group in NIPAM For optimal organic core-inorganic shell particle morphology, it is essential to induce silica nuclei formation on the polymeric core surfaces during the early sol-gel process This is followed by the diffusion of hydrolyzed TEOS, or silicic acid, and oligomeric silica from the bulk aqueous phase to the interfacial layer, where further sol-gel reactions occur.

40 leading to the continuous growth of the silica shell Ultimately, the hybrid submicron particles comprising PNIPAM-based microgel core and silica shell can be achieved

Table 3.2 and Fig 3.1 present the particle size, distribution data, and morphology of crosslinked PNIPAM-based microgel core particles, both before and after silica encapsulation Prior to encapsulation, PNIPAM/10MBA and PNIPAM/10AM/10MBA exhibit a uniform spherical shape, smooth surface, and a nearly monodisperse size distribution, with PNIPAM/10AM/10MBA having a larger particle size (dw1 = 445 nm) compared to PNIPAM/10MBA (dw1 = 356 nm) The incorporation of 10 wt% AM units increases hydrophilicity and particle size Stabilization of the PNIPAM-based microgel cores is primarily due to terminal -SO4- groups from the persulfate initiator, providing electrostatic stability The zeta potential (ζ) for PNIPAM/10MBA is approximately -15.4 mV at pH 4.2, while PNIPAM/10AM/10MBA shows a lower ζ of about -4.8 mV at pH 2.8, indicating increased hydrophilicity due to strong hydrogen bonding with water from AM units This hydrophilic nature leads to the migration of AM-rich segments to the particle surface, forming a hydrated layer that shifts the shear plane toward the aqueous phase, reducing electrostatic repulsion and promoting particle aggregation to minimize interfacial free energy.

The polymeric core particles and hybrid core-shell particles underwent purification before being dispersed in phosphate buffered saline (PBS) at varying pH levels of 5, 7, and 9 for zeta potential (ζ) measurements The pH of the PBS solution was specifically adjusted to 5 and 7.4 for accurate testing.

The zeta potential of polymeric core particles (PNIPAM/10MBA and PNIPAM/10AM/10MBA) shows minimal sensitivity to pH changes when treated with 0.5 M HCl or 0.5 M NaOH In contrast, hybrid core-shell particles (PNIPAM/10MBA-101, PNIPAM/10MBA-111, and PNIPAM/10AM/10MBA-111) exhibit a more negative surface charge across all pH levels due to the ionization of surface silanol groups from the silica shells Additionally, the absolute value of the zeta potential for these hybrid particles increases steadily with rising pH Notably, at a constant pH, the zeta potential of PNIPAM/10AM/10MBA-111 is lower than that of PNIPAM/10MBA-111.

After the silica encapsulation process, the PNIPAM/10MBA-101, PNIPAM/10MBA-111, and PNIPAM/10AM/10MBA-111 formulations resulted in spherical particles, although they exhibited distinct surface morphologies Notably, when GLYMO and AM were not included, the PNIPAM/10MBA particles displayed unique characteristics.

The 101 shows a distorted spherical shape with a heterogeneous particle surface, where some particles have a relatively smooth surface indicating lower silica encapsulation, while others exhibit a rough surface reflecting higher silica encapsulation, as shown in Fig 3.3a This variation is likely attributed to the weak interaction between PNIPAM/10MBA microgel particles and silica nanoparticles Additionally, in the presence of GLYMO but without AM, the behavior of PNIPAM/10MBA is influenced.

The study reveals that microgel particles exhibit incomplete or uneven silica encapsulation due to the lower reactivity of amino groups in NIPAM and MBA compared to those in the AM unit This is evidenced by the well-dispersed sample containing both AM and GLYMO, which showcases an almost perfect hybrid core-shell particle morphology with the microgel core fully covered by numerous tiny silica nanoparticles These findings underscore the importance of incorporating a co-monomer like AM alongside a coupling agent such as GLYMO to effectively facilitate the nucleation and growth of silica on PNIPAM-based microgel cores, resulting in optimal encapsulation.

PNIPAM-based microgel core particles are encased in a silica shell, with estimated shell thicknesses of approximately 63 nm, 57 nm, and 87 nm for the samples PNIPAM/10MBA-101, PNIPAM/10MBA-111, and PNIPAM/10AM/10MBA-111, respectively.

The TEM image in Fig 3.4a reveals that PNIPAM/10MBA-101 lacks a distinct core-shell particle structure, exhibiting non-uniform silica encapsulation with varying shell thickness and small cracks in the thinner silica layer, likely due to stress during the shrinking and swelling of PNIPAM-based microgel cores Notably, insufficient silica deposition on the microgel surfaces is observed, attributed to the generation of extremely small silica nanoparticles in the continuous aqueous phase In contrast, PNIPAM/10MBA-111 and PNIPAM/10AM/10MBA-111, aided by GLYMO and/or AM, display a clear core-silica shell structure with identifiable silica nanoparticles on the microgel surfaces, though the boundary between the core and shell phases remains indistinct The silica shell thickness is estimated at 95±12 nm for PNIPAM/10MBA-111 and 127±14 nm for PNIPAM/10AM/10MBA-111, aligning with SEM measurements Additionally, PNIPAM/10MBA-111 demonstrates a more compact shell with higher silica nanoparticle density, indicating lower permeability compared to PNIPAM/10AM/10MBA-111 in the shrinking state.

The PNIPAM-based microgel core with a silica shell was analyzed through thermogravimetric analysis (TGA) at temperatures up to 800 °C, both in the presence and absence of AM and GLYMO The TGA curve for the PNIPAM/10MBA-101 sample displayed a distinct sharp peak, indicating significant thermal behavior.

Thermal degradation of PNIPAM occurs between 250 - 550 °C, while PNIPAM/10MBA-111 and PNIPAM/10AM/10MBA-111 exhibit multiple degradation stages from 100 - 800 °C The initial weight loss from 250 - 350 °C is attributed to the thermal degradation of PNIPAM and the organic component of GLYMO, followed by the decomposition of AM units from 350 - 550 °C At temperatures between 600 - 800 °C, most organic components decompose, leaving behind inorganic silica The residue percentages for PNIPAM/10MBA-101, PNIPAM/10MBA-111, and PNIPAM/10AM/10MBA-111 are 47.5%, 53.2%, and 56.5%, respectively The thermal stability of these hybrid core-shell particles decreases in the order of PNIPAM/10AM/10MBA-111, PNIPAM/10MBA-111, and PNIPAM/10MBA-101, which aligns with SEM and TEM findings Calcination in a TGA cell, heated from 500 to 800 °C over 30 minutes, effectively decomposes the organic components, resulting in residual inorganic silica All samples maintain a hollow particle structure with minimal damage and comparable sizes to the original particles, confirming the PNIPAM-based microgel core-silica shell structure Additionally, silica nanoparticles on PNIPAM/10MBA surfaces are smaller than those on PNIPAM/10AM/10MBA surfaces, leading to a raspberry-like morphology for PNIPAM/10AM/10MBA-111, while PNIPAM/10MBA-111 has a smoother surface.

The LCST data for PNIPAM-based microgel particles, analyzed through DLS, reveals that the hydrodynamic diameter changes with temperature, as illustrated in Figure 3.7 The LCST is pinpointed at the temperature where the minimum occurs in the derivative curve of diameter versus temperature Similar to PNIPAM microgels, hybrid core-shell particles also exhibit significant shrinkage with rising temperatures, primarily due to the silica layer's permeability The silica shell is likely composed of numerous small silica clusters, which form a discrete distribution on the P(NIPAM/AM) core surface due to reactions between amino and epoxy groups This structure allows water molecules to permeate, enabling the PNIPAM core to shrink or swell with temperature changes Consequently, the thermo-responsive behavior of the PNIPAM core causes displacement of the silica clusters, maintaining the distinct LCST phase transition Notably, the silica shell does not affect the LCST of the PNIPAM core compared to microgels without silica Additionally, incorporating 10 wt% AM and MBA units raises the LCST due to enhanced hydrogen bonding with water molecules The DLS-determined hydrodynamic diameter trends align with SEM and TEM measurements.

Differential Scanning Calorimetry (DSC) was employed to investigate the thermo-responsive characteristics of PNIPAM-based microgel core-silica shell particles within a temperature range of 25-60 °C, using a heating rate of 2 °C/min The temperature at which the minimal endothermic peak occurred, as shown in Fig 3.8, was identified as the Lower Critical Solution Temperature (LCST) phase transition temperature, with results detailed in Table 3.3.

The thermosensitivity of hybrid particles is influenced by the incorporation of 10 wt% AM and 10 wt% MBA units into PNIPAM chains, as well as the encapsulation of PNIPAM-based microgel cores with silica Data from DSC and DLS measurements indicate a consistent trend, with the total heat (ΔH, J g -1) related to the breaking of hydrogen bonds between polymeric units and water molecules Notably, the ΔH of PNIPAM-based microgel particles is significantly higher than that of the PNIPAM-based microgel core-silica shell particles Additionally, when compared to PNIPAM-based mesoglobule core-silica shell particles, the ΔH of PNIPAM-based microgel particles is lower than that of their PNIPAM-111 counterparts.

The lack of significant thermo-sensitivity in the AM and MBA units within the microgel cores, along with the dilution effect of inorganic silica, contributes to the observed phenomena Importantly, the ΔH data for both PNIPAM-based microgel particles and PNIPAM-based core-silica shell particles indicate a decrease in ΔH with higher AM content.

Conclusions

Thermo-responsive PNIPAM-based microgel core-silica shell submicron particles with a narrow size distribution were successfully synthesized using a straightforward method This technique involves integrating acrylamide (AM) units into the PNIPAM/MBA chain along with 3-glycidyloxypropyltrimethoxysilane (GLYMO) as a coupling agent The reaction between the amide group of AM and the epoxide group of GLYMO, combined with the sol-gel reaction of TEOS and GLYMO, enhances silica particle nucleation and growth on the surfaces of PNIPAM-based microgel particles, resulting in improved particle morphology.

The morphology of particles, including shape, core size, shell thickness, and surface roughness, can be effectively controlled by the key ingredients AM and GLYMO The samples PNIPAM/10MBA-101, PNIPAM/10MBA-111, and PNIPAM/10AM/10MBA-111 all exhibit a relatively spherical shape, yet their surface morphologies differ significantly Notably, PNIPAM/10MBA-101, lacking both AM and GLYMO, demonstrates poor silica encapsulation, resulting in an undesirable particle morphology Similarly, PNIPAM/10MBA-111 shows incomplete or non-uniform silica encapsulation despite the presence of GLYMO In contrast, PNIPAM/10AM/10MBA-111 achieves an ideal raspberry-like morphology, where the microgel core is fully covered by numerous tiny silica nanoparticles The incorporation of AM units into PNIPAM/MBA microgel particles plays a crucial role in achieving this enhanced morphology.

The incorporation of hydrophilic AM units in PNIPAM/MBA chains increases the lower critical solution temperature (LCST), making the material less responsive to temperature variations While encapsulating PNIPAM-based microgel particles with silica does not significantly affect the LCST, it notably diminishes the thermo-sensitivity of the resulting core-silica shell particles Furthermore, the potential of these PNIPAM-based core-silica shell particles as effective drug carriers has been successfully demonstrated.

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