Key Parameters for the Rational Design, Synthesis, and Functionalization of Biocompatible Mesoporous Silica Nanoparticles
Abstract
:1. Introduction
2. Silica Nanoparticles
2.1. Strategies for the Preparation of Silica NPs
2.1.1. The Sol-Gel Method
2.1.2. Other Methods
2.2. Mesoporous Silica Nanoparticles
2.2.1. Synthesis of Mesoporous Silica NPs
Sol-Gel Process through Template-Assisted Technique
2.2.2. Factors Influencing the Size and Shape of Mesoporous Materials
pH
Surfactant
Silica Source
Other Factors
2.3. Hollow Silica Nanoparticles
2.4. Other Silica Nanoparticles
3. Applications of MSNs
3.1. MSNs in Biomedical Applications
3.1.1. MSNs as Drug Delivery Systems
3.1.2. MSNs in Biomedical Imaging and as Theranostic Agents
Aimed Disease or Condition | Sample Name | Size | Targeting and/or Triggered Release | Surface Modification (s) | Therapeutic Agent (s) | Biological Model (s) | In Vivo Administration Route | Reference |
---|---|---|---|---|---|---|---|---|
Gastrointestinal oral absorption efficiency | FFB-MSNs | Diameter: 130 nm | Passive targeting | - | Fenofibrate (FFB) | In vitro drug release In vivo rats (Sprague Dawley strain): pharmacokinetics and intestine uptake and retention | Oral (water) | [130] |
W: 65 nm; L: 185 nm | ||||||||
W: 50 nm; L: 23 nm | ||||||||
Gastrointestinal oral absorption efficiency | IMC–MSNs@HPMC | ~60 nm | Passive targeting | - | Indomethacin | In vivo rats (Sprague-Dawley): pharmacokinetics and biodistribution | Oral | [131] |
IMC–MSNs@Kollicoat IR | ||||||||
Amyotrophic Lateral Sclerosis (ALS) | MSN-LEP-PIO | ~94 ± 15 nm. | Passive targeting | (3-Aminopropyl)triethoxysilane (AP), leptin and pioglitazone | Drug cocktail: Leptin (LEP) and Pioglitazone (PIO) | In vitro drug release | Intraperitoneal | [125] |
In vivo mice (transgenic, TDP-43 proteinopathy (TDP-43A315T mice): functional evaluation biodistribution. | ||||||||
Alzheimer | MSN-CCM | 60 nm | Thermo-responsiveness | - | Curcumin (CCM) | In vitro ex vivo mucoadhesion and permeation studies, cytotoxicity | Hydrogel: oral; intranasal | [126] |
In vivo mice (Swiss albino): behavioral assessment | ||||||||
Blood–brain-barrier crossing | MSN-TQ | 90 nm | Passive targeting | - | Thymoquinone (TQ) | In vitro drug release | Intraperitoneal | [132] |
In vivo rats (SD): biodistribution, oxidative and non-oxidative stress parameters (GST, GSH, NO) | ||||||||
Miocardium infarction | MSN-NGR1-CD11b | 83 nm | Active targeting (CD11b) | - | Notoginsenoside R1 (NGR1) | In vitro cytotoxicity assay, ROS generation, oxidative DNA damage assessment, apoptosis assessment | Intragastric, intravenous. | [121] |
In vivo mice (BALB/c nude, C57BL/6J; Zsgreen transgenic), myocardium infarction model: biodistribution, toxicity | ||||||||
Liver fibrosis | IMB16-4-MSNs | ~60 nm | Passive targeting | - | IMB16-4 (N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamide) benzamide) | In vitro drug release, cytotoxicity, antifibrotic effect evaluation | Oral | [133] |
In vivo rats (Sprague-Dawley); pharmacokinetics | ||||||||
Bone regeneration in osteoporosis | NaLuF4:Yb,Tm@NaLuF4@mSiO2-EDTA-E2 | 20 nm | Active targeting (EDTA) | EDTA | 17β-estradiol (E2) | In vitro cytotoxicity, cellular uptake, alkaline phosphatase and alizarin red S staining | Intravenous | [133] |
(E2-csUCNP@MSN-EDTA, UCHRT) | In vivo mice (Kunming mice): biodistribution, mechanical assessment, bone turnover assessment | |||||||
Periodontal bone regeneration in diabetes mellitus | PPP-MM-S | ~ 50 nm | Thermo-responsiveness (PDLLA-PEG-PDLLA) | PDLLA-PEG-PDLLA | SDF-1 | In vitro osteogenesis assessment, ROS generation, alkaline phosphatase and alizarin red S staining, migration assay, cytotoxicity, protein profile assessment | Hydrogel | [123] |
(PDLLA-PEG-PDLLA-Met@MSN-SDF-1 ) | In vivo rats (Sprague-Dawley): degradation assessment, toxicity, bone regeneration assessment | |||||||
Vascularization for bone repair | S1P@MSNs/ALG/NOOC | ~150 nm | Passive targeting | Alginate (ALG) and chitosan (CHI) | aldehyde hyaluronic acid (AHA) and N,O-carboxymethyl chitosan (NOCC) | In vitro degradation, drug release, cytotoxicity, migration assay, chorioallantoic membrane assay | Topic | [134] |
In vivo mice (ICR): vascularization assessment | ||||||||
Antiangiogenic therapy | Bevacizumab-MSN | 140 ± 18 nm | Active targeting (vascular endothelial growth factor receptor, VEGFR) | PEG | Bevacizumab | In vitro drug release, cytotoxicity, tube formation assay | Intravitreal | [135] |
MSN-encapsulated bevacizumab | In vivo mice (C57BL/6J): pharmacokinetic evaluation, neovascularization assay | |||||||
Hepatitis C infection | VLP-MSNs | 186 nm | Passive targeting | - | Velpatasvir | In vitro drug release, cytotoxicity | Oral (food) | [136] |
In vivo rats (Sprague-Dawley): pharmacokinetics, toxicity | ||||||||
Hemorrhage | MSN–GACS | ~60 nm | - | - | glycerol-modified N-alkylated chitosan sponge (GACS) | In vitro hemostatic efficiency assays, hemolytic test, cytotoxicity | Topic (gauze) | [137] |
In vivo rats (Sprague-Dawley), liver injury model and prognosis; rabbits (New Zealand), femoral artery injury model | ||||||||
Wound infection | AMPC@siTNF-α | ~100 nm | - | PEG, CFL, siTNF-α | Silver (Ag+), Ciprofloxacin (CFL) and Tumor Necrosis Factor-α (TNF-α) small interfering RNA (siTNF-α) | In vitro drug release, cytotoxicity, hemolysis, anti-inflammatory assay, anti-bacterial activity assessment In vivo mice (BALB/c): wound healing assessment, safety | Topic | [138] |
Infections and cancers | MSNs@Cy7-PA-C1b@FA-GO | 100–120 nm | Active targeting (folic acid) | Graphene oxide (GO), folic acid (FA) | Antimicrobial peptide PA-C1b (chensinin-1b conjugated with palmitic acid) | In vitro drug release, intracellular localization assessment | Intratumor | [139] |
Light-mediated peptide release | In vivo mice (nude): biodistribution; anticancer activity | |||||||
Cancer (melanoma) | CP/CQ@MSN−HtB/Cu2+ | 160 nm | Active targeting (HtB) | Histidine-tagged targeting peptide (HtB) and Cu2 (pore sealing) | Cisplatin (CP) and chloroquine (CQ) | In vitro drug release assay, cytotoxicity, cellular uptake, intracellular ROS generation | Intravenous | [116] |
pH-responsiveness | In vivo mice (C57BL/6), subcutaneous model: biodistribution, antitumor efficacy and biosafety | |||||||
Cancer (pancreas) | CyP-MSNs | 252 ± 40 nm | Passive targeting | PEG | Cyclopamine (CyP), gemcytabine (Gem), cisplatin (cisPt) | In vitro cytotoxicity, pathway inhibition assay | Intratumor, intravenous | [117] |
PEG-Gem-cisPt-MSNs | In vivo mice, subcutaneous model: antitumor effect | |||||||
Cancer (bladder) | c(RGDfK)-MSN NPs | 100–200 nm | Active targeting (RGDfK) | PLGA-PEG decorated with c(RGDfK) | miR-34a and siPD-L1 | In vitro siRNA/miRNA release, cellular uptake, cytotoxicity, migration and invasion assays, target inhibition, protein expression | Intravenous | [118] |
In vivo mice, intraperitoneal model: antitumor effect, toxicity assay | ||||||||
Cancer (breast) | MSN-Res | ~60 nm | Passive targeting | - | Resveratrol (Res) | In vitro cytotoxicity, cell migration and invasion assays, annexin-V assay | NA | [119] |
In vivo mice (BALB/c nude), subcutaneous model: antitumor effect, toxicity assay | ||||||||
Cancer (osteosarcoma) | MPCT@Li-R NPs | 95 nm | Active targeting (RGD) | Liposome shell; RGD | Photosensitizer chlorin e6 (Ce6) and MTH1 inhibitor TH588 | In vitro drug release assay, cytotoxicity, hemolysis assay, cellular uptake, ROS generation assay | Intravenous | [120] |
MSN-Pt NPs | In vivo mice (BALB/c nude), subcutaneous model: biodistribution, antitumor therapy, toxicity | |||||||
Cancer (lung) | MSN@OHA-Ce6/BSO/Pt | ∼211.4 nm | pH-responsiveness | Oxidized hyaluronic acid (OHA) as pore-blocking agent. + Cisplatin (Pt), Chlorin e6 (Ce6) | Buthionine-sulfoximine (BSO), chlorin e6 (Ce6) and Cisplatin (Pt) | In vitro drug release assay, cellular uptake, ROS generation, cytotoxicity | Intravenous | [140] |
In vivo mice (nude), subcutaneous model: biodistribution, biocompatibility, antitumor | ||||||||
Cancer (gastric) | MSN/Res-PEI-FA | 100 nm | Passive targeting | Polyethylenimine (PEI), folic acid (FA) | Resveratrol (Res) | In vitro cytototoxicity, apoptosis assay, migration and invasion assays | NA | [141] |
In vivo mice (BALB/c nude) SC: antitumor effect and toxicity | ||||||||
Solid tumors | 1j@-MSN-PBA-GN | ~86 nm | Active targeting (phenyl boronic acid, PBA) | PBA | 1j (synthetic compound) | In vitro intracellular drug release and uptake, cytotoxicity; ROS generation and mitochondrial membrane potential | Intravenous | [142] |
Redox-responsiveness | In vivo mice (Swiss albino mice): biodistribution, antitumor effect | |||||||
Cancer (breast) | DOX@MSN-CHI-RGD-PEG | ~155 nm | Active targeting: adamantane-glycine-arginine-glycine-aspartic acid-serine (Ad-GRGDS) | mPEG | Doxorubicin hydrochloride (DOX) | In vitro stability, drug release, cytotoxicity, antitumor assays, cellular uptake | Intravenous | [143] |
pH-responsiveness | In vivo mice (BALB/c), orthotopic model: antitumor, toxicity | |||||||
Cancer | DOX-loaded MSN@M | ~ 90 nm | Active targeting (mesenchymal stem cells membrane) | Mesenchymal stem cells membrane (M) | Doxorrubicine (DOX) | In vitro drug release, cellular uptake, cytotoxicity, immune escape capacity | Intravenous | [144] |
In vivo mice (BALB/c nude; ICR), subcutaneous model: parmacokinetics, biodistribution, antitumor effect, biocompatibility | ||||||||
Cancer (melanoma) | MSN(Mn)-ICG/DTIC | 125.57 ± 5.96 nm | Photothermal activation | - | Dacarbazine (DTIC) and indocyanine green (ICG) | In vitro cytotoxicity, chemo-phototherapy, apoptosis assay | Intratumor | [145] |
In vivo mice (BALB/c nude), subcutaneous model: antitumor effect | ||||||||
Cancer (liver) | TLS11a-LB@TATp-MSN/DOX | 100 nm | Active targeting: Liver cancer-specific aptamer (TLS11a-LB) and nuclear targeting (TATp) | Lipid bilayer, PEG. | Doxorrubicine (DOX) | In vitro drug release, intracellular localization, cytotoxicity | Intravenous | [146] |
In vivo mice (BALB/c), subcutaneous model: biodistribution, antitumor effect | ||||||||
Cancer (colon) | PEG@MSNR-CPT PEG@MSNR-CPT/Sur Apt-PEG@MSNR-CPT/Sur | ~250 nm ~150 nm ~150 nm | Active targeting (nucleolin) | APTES, PEG | Camptothecin and survivin shRNA | In vitro drug release, cytotoxicity, apoptosis assay | Intravenous | [147] |
In vivo: C26 tumor bearing mice: biodistribution, antitumor effect | ||||||||
Cancer (breast) | Umbe@MSN-PAA-FA | 40–50 nm | Active targeting (folic acid) | Polyacrylic acid (PAA), folic acid (FA) | Umbelliferone (Umbe) | In vitro drug release and intracellular uptake; cytotoxicity, ROS generation, MMP determination | Intravenous | [148] |
pH responsiveness (PAA) | In vivo mice (Swiss albino): biodistribution, antitumor effect, toxicity systemic evaluation | |||||||
Solid tumors | CMSN-PEG | 150 nm | Passive targeting | PEG | Celastrol (mitochondrial targeting) | In vitro drug release, cytotoxicity, cellular uptake, apoptosis assessment | Intravenous | [149] |
In vivo mice (BALB/s nude), subcutaneous model: antitumor effect and toxicity |
Imaging Modality | Aimed Disease or Condition | Sample Name | Size | Targeting and/or Triggered Release | Surface Modification (s) | Imaging (and Therapeutic) Agent | Biological Model (s) | In Vivo Administration Route | Reference |
---|---|---|---|---|---|---|---|---|---|
MRI | Cancer | SA-Gd2O3@MSN | 83.2 ± 8.7 nm | pH-responsiveness | Sodium alginate | Gadolidium (Gd) for MRI | In vitro hemolysis assays, cellular uptake | Intravenous | [150] |
Rhodamine B | In vivo mice (BALB/c): biodistribution | ||||||||
MRI | Cancer | HA-MnO@MSN | 50 nm | Active targeting (CD44) | Hyaluronic acid (HA) | Mn2+ for MRI | In vitro MRI imaging | Intratumor | [151] |
In vivo mice, subcutaneous model: MRI imaging, tumor uptake | |||||||||
MRI | Atherosclerosis | cRGD-platelet@MnO/MSN@PPARα/LXRα | ~150 nm (DLS) | Active targeting (cRGD to integrin αvβ3) | cRGD-platelets | MnO for MRI PPAR and LXRα as therapeutic agent | In vitro cytotoxicity, ROS generation, | Intravenous | [152] |
In vivo rats (Sprague Dawley): MRI imaging, apoptosis assessment, ROS generation, biodistribution, toxicity | |||||||||
MRI | Inflamation | Fe/Ce-MSN-PEG | 190 ± 1.2 nm (DLS) | Passive targeting | PEG | Mn, Fe for MRI | In vitro MRI assay, cytotoxicity, cellular uptake, anti-apoptotic activity assay, ROS scavenging assay, anti-inflammation assessment | - | [153] |
pH responsiveness | |||||||||
MRI | Cancer | MN@MS@CS@ABE | 131 ± 18 nm | Passive targeting | Chitosan (CS) | Abemaciclib (ABE) as therapeutic agent Magnetite Nanoparticles (MN) for MRI | In vitro MRI assay, drug release, cytotoxicity, cell cycle and apoptosis assessment | - | [154] |
MRI | Cancer (breast) | MSN-Ce6@PDA (Mn) | 139 ± 1.70 nm | PDA as photothermal agent | Polydopamine (PDA) | Mn2+ for MRI | In vitro biocompatibility, cytotoxicity, cellular uptake, in vitro MRI, ROS generation | Intravenous | [155] |
In vivo mice (BALB/c nude), subcutaneous model: biodistribution, MRI imaging, antitumor effect, toxicity | |||||||||
MRI | Cancer | GdBO3 @mSiO2-PG | ~100 nm | Passive targeting | Hydrophilic polyglycerol (PG) | GdBO3 for neutron capture therapy and MRI | In vitro cytotoxicity, cellular uptake | Intravenous | [156] |
In vivo mice (BALB/c): blood circulation assessment, biochemistry examinations, toxicity | |||||||||
MRI | _ | Gd2O3@MSN | 86.85 ± 10.44 nm | Passive targeting | - | Gd2O3 for MRI | In vitro cytotoxicity, MRI | Intravenous | [157] |
In vivo rats (Spraque-Dawley): toxicity, MRI imaging | |||||||||
MRI | Kidney disfunction | Gd@PEG NPs | ~5 nm | Passive targeting | PEG | Gadolinium (Gd) for MRI | In vitro cytotoxicity | Intravenous | [158] |
In vivo mice: imaging, biodistribution, toxicity | |||||||||
MRI and phototermal imaging | Cancer (melanoma) | MSN(Mn)-ICG/DTIC | 125.57 ± 5.96 nm | Photothermal activation | - | Mn2+ ions for MRI Indocyanine green (ICG) for photothermal imaging | In vitro cytotoxicity, chemo-phototherapy, apoptosis assay | Intratumor | [145] |
In vivo mice (BALB/c nude), subcutaneous model: antitumor effect. | |||||||||
MRI Optical imaging | Atherosclerosis | PP1-IO@MS-IR820 | 90 nm | Active targeting (PP1, towards macrophages) | PEG, PP1 | Iron oxide (IO) for MRI IR820 for NIR optical imaging | In vitro MRI and fluorescence imaging, cytotoxicity, target assessment | Intravenous | [159] |
In vivo mice (ApoE−/−); in vivo MRI imaging, ex vivo fluorescence imaging, toxicity | |||||||||
MRI Optical imaging | Cancer (prostate) | PSA-Mn-Msn-Cy7 | 50 nm | Active targeting (PSA) | DSPE-PEG2000-COOH | Cy7 for optical imaging Mn2+ for MRI | In vitro cytotoxicity, in vitro MRI and TEM | Intravenous | [160] |
In vivo mice (nude), subcutaneous model: toxicity, pharmacokinetics, imaging, Mn determination | |||||||||
Optical imaging | Cancer | DCNPs@Si-omSi | ∼255 nm (DLS) | Active targeting (RGD to integrin αvβ3) | DSPE-PEG2000-NH2 | Indocyanine green (ICG) for imaging | In vitro fluorescent dye stability, cellular uptake by flow cytometry and microscopy | Intravenous | [161] |
In vivo: mice (BALB/c) subcutaneous model for imaging guided tumor surgery | |||||||||
Optical imaging | Cancer | PPV@MSN-CP1@FA | ~100 nm | Active targeting (folate acid, FA) | DSPE-PEG2000, folic acid (FA) | PFV-co-MEHPV (CP1) for fluorescent imaging of ROS | In vitro confocal laser scanning microscopy imaging, cellular uptake | Intratumor | [162] |
In vivo mice (BALB/c), subcutaneous model: imaging | |||||||||
Optical imaging PET | Cancer (breast) | NOTA-QD@HMSN(DOX)-PEG-TRC105 | ~ 72 nm | Active targeting (CD105) | SCM-PEG5k-Mal, NOTA, TRC105 | QDs for optical imaging | In vitro targeting assay | Intravenous | [163] |
64Cu-NOTA-QD@HMSN-PEG-TRC105 | 64Cu for PET imaging | In vivo mice (BALB/c), subcutaneous model: biodistribution, toxicity | |||||||
PET | Atherosclerosis | 18F-DBCOT-MSNs | ≈ 60–80 nm | Passive targeting | PEG, azadibenocyclooctyne (DBCO) | 18F for PET imaging | In vitro proliferation, cytokine assay, cell uptake, phagocytic activity assay, macrophage cell labeling | Retro-orbital | [164] |
In vivo mice (nude; ApoE−/−); MSNs-labeled macrophage cell tracking, imaging, toxicity | |||||||||
PET | Cancer | *As-MSN | 65 ± 5 nm | Passive targeting | Thiol functional groups, radioarsenic | Radioarsenic for PET imaging | In vitro nanoparticle stability | Intravenous | [165] |
[*As]ATO-MSN | 150 ± 5 nm | Arsenic trioxide (ATO) as therapeutic agent | In vivo mice (BALB/c): nanoparticle stability, biodistribution | ||||||
Multimodal NIR-PL/MR/PET | Cancer | 68Ga /DOX/Si-Pc-Loaded HMNPs | ∼93–98 nm | Passive targeting NIR-PL-sensitized photodynamic therapy | - | 68Ga for PET imaging Ga2O3:Cr3+, Nd3+ for NIR-PL imaging Gd2O3 for MRI Si-Pc as photosensitizer Doxorubicin hydrochloride (DOX) as therapeutic agent | In vitro nanoparticle stability, imaging drug release, cellular uptake, cytotoxicity, hemolysis | Intravenous | [166] |
In vivo mice (BALB/c nude), subcutaneous model: MRI imaging, PET imaging, NIR-PL im aging, chemotherapeutic effect, photodynamic therapy, toxicity | |||||||||
Multimodal: PET and photoacoustic imaging | Cancer | 89Zr-labeled bGNR@MSN(DOX)-PEG | L: 104.6 ± 5.6 nm | Passive targeting | PEG | Doxorubicine (DOX) as therapeutic agent | In vitro drug release, photothermal and chemo-photothermal effect assessments | Intravenous | [167] |
W: 68.6 ± 5.2 nm | 89Zr for PET imaging | In vivo mice: PET and PA imaging; antitumor effect | |||||||
SPECT/CT | PEG-PEI-*In- MSNs PEG-QA-*In- MSNs PEG-TMS-*In- MSNs | 32 ± 1 nm 55 ± 1 nm 93 ± 1 nm 142 ± 1 nm 52 ± 2 nm 56 ± 2 nm | Passive targeting | PEG-polyethylenimine (PEG-PEI) PEG-quaternary amine (PEG-QA) PEG-trimethylsilane (PEG-TMS) | 111Indium for SPECT imaging | In vitro nanoparticle stability | Intravenous Intraperitoneal | [168] | |
In vivo rats (Fischer 344): SPECT/CT imaging, biodistribution, pharmacokinetics |
Optical Imaging
Magnetic Resonance Imaging
Positron Emission Tomography
3.1.3. MSNs in Vaccines
3.1.4. Other Biomedical Applications
4. Coating and Functionalization
4.1. Active and Passive Targeting
4.2. Functionalization in Drug Delivery
4.2.1. PEG Functionalization
4.2.2. Smart Drug Delivery
4.2.3. Other Coatings and Functionalizations
5. Biocompatibility, Degradability and Biodistribution
5.1. Biocompatibility and Toxicity
5.2. Degradability
5.3. Biodistribution
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Florensa, M.; Llenas, M.; Medina-Gutiérrez, E.; Sandoval, S.; Tobías-Rossell, G. Key Parameters for the Rational Design, Synthesis, and Functionalization of Biocompatible Mesoporous Silica Nanoparticles. Pharmaceutics 2022, 14, 2703. https://doi.org/10.3390/pharmaceutics14122703
Florensa M, Llenas M, Medina-Gutiérrez E, Sandoval S, Tobías-Rossell G. Key Parameters for the Rational Design, Synthesis, and Functionalization of Biocompatible Mesoporous Silica Nanoparticles. Pharmaceutics. 2022; 14(12):2703. https://doi.org/10.3390/pharmaceutics14122703
Chicago/Turabian StyleFlorensa, Marta, Marina Llenas, Esperanza Medina-Gutiérrez, Stefania Sandoval, and Gerard Tobías-Rossell. 2022. "Key Parameters for the Rational Design, Synthesis, and Functionalization of Biocompatible Mesoporous Silica Nanoparticles" Pharmaceutics 14, no. 12: 2703. https://doi.org/10.3390/pharmaceutics14122703