Safety and Toxicity Issues of Therapeutically Used Nanoparticles from the Oral Route

The emerging science of nanotechnology sparked a research attention in its potential benefits in comparison to the conventional materials used. Oral products prepared via nanoparticles (NPs) have garnered great interest worldwide. They are used commonly to incorporate nutrients and provide antimicrobial activity. Formulation into NPs can offer opportunities for targeted drug delivery, improve drug stability in the harsh environment of the gastrointestinal (GI) tract, increase drug solubility and bioavailability, and provide sustained release in the GI tract. However, some issues like the management of toxicity and safe handling of NPs are still debated and should be well concerned before their application in oral preparations. This article will help the reader to understand safety issues of NPs in oral drug delivery and provides some recommendations to the use of NPs in the drug industry.

[1]  Lanze Liu,et al.  Research on the fate of polymeric nanoparticles in the process of the intestinal absorption based on model nanoparticles with various characteristics: size, surface charge and pro-hydrophobics , 2021, Journal of Nanobiotechnology.

[2]  P. Opanasopit,et al.  Mucoadhesive chitosan and thiolated chitosan nanoparticles containing alpha mangostin for possible Colon-targeted delivery , 2021, Pharmaceutical development and technology.

[3]  Stephen Kennedy,et al.  Carbon Nanotube–Liposome Complexes in Hydrogels for Controlled Drug Delivery via Near-Infrared Laser Stimulation , 2020, ACS Applied Nano Materials.

[4]  Zhuge Xi,et al.  Toxic effects of the food additives titanium dioxide and silica on the murine intestinal tract: Mechanisms related to intestinal barrier dysfunction involved by gut microbiota. , 2020, Environmental toxicology and pharmacology.

[5]  P. Leng,et al.  Oral drug delivery with nanoparticles into the gastrointestinal mucosa , 2020, Fundamental & clinical pharmacology.

[6]  Yuanyuan Wang,et al.  The Influence of Nanoparticle Properties on Oral Bioavailability of Drugs , 2020, International journal of nanomedicine.

[7]  E. Muñoz,et al.  Toxicity of Carbon Nanomaterials and Their Potential Application as Drug Delivery Systems: In Vitro Studies in Caco-2 and MCF-7 Cell Lines , 2020, Nanomaterials.

[8]  A. Mohammad,et al.  The Potential of Silver Nanoparticles for Antiviral and Antibacterial Applications: A Mechanism of Action , 2020, Nanomaterials.

[9]  Å. Keita,et al.  The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability , 2020, Cells.

[10]  Junbo Xie,et al.  Mechanism of the Intestinal Absorption of Six Flavonoids from Zizyphi Spinosi Semen Across Caco-2 Cell Monolayer Model. , 2020, Current drug metabolism.

[11]  K. C. Sekhar,et al.  Green Synthesized Ag Nanoparticles for Bio-Sensing and Photocatalytic Applications , 2020, ACS omega.

[12]  S. Hua Advances in Oral Drug Delivery for Regional Targeting in the Gastrointestinal Tract - Influence of Physiological, Pathophysiological and Pharmaceutical Factors , 2020, Frontiers in Pharmacology.

[13]  Maryam Rameshrad,et al.  Monitoring of drug resistance towards reducing the toxicity of pharmaceutical compounds: Past, present and future. , 2020, Journal of pharmaceutical and biomedical analysis.

[14]  Y. Pellequer,et al.  Small silica nanoparticles transiently modulate the intestinal permeability by actin cytoskeleton disruption in both Caco-2 and Caco-2/HT29-MTX models , 2020, Archives of Toxicology.

[15]  Mi-Kyung Lee Liposomes for Enhanced Bioavailability of Water-Insoluble Drugs: In Vivo Evidence and Recent Approaches , 2020, Pharmaceutics.

[16]  V. K. Venuganti,et al.  Effect of particle size and surface charge of nanoparticles in penetration through intestinal mucus barrier , 2020, Journal of Nanoparticle Research.

[17]  Shik Nie Kong,et al.  Oral administration of protein nanoparticles: An emerging route to disease treatment. , 2020, Pharmacological research.

[18]  Hongbo Zhang,et al.  Fabrication of a pH/Redox-Triggered Mesoporous Silica-Based Nanoparticle with Microfluidics for Anticancer Drugs Doxorubicin and Paclitaxel Codelivery. , 2020, ACS applied bio materials.

[19]  D. Drucker Advances in oral peptide therapeutics , 2019, Nature Reviews Drug Discovery.

[20]  K. Adibkia,et al.  Formulation and Evaluation of Eudragit RL-100 Nanoparticles Loaded In-Situ Forming Gel for Intranasal Delivery of Rivastigmine , 2019, Advanced pharmaceutical bulletin.

[21]  F. Lotfipour,et al.  A brief overview on nano-sized materials used in the topical treatment of skin and soft tissue bacterial infections , 2019, Expert opinion on drug delivery.

[22]  H. M. Nielsen,et al.  The distribution of cell-penetrating peptides on polymeric nanoparticles prepared using microfluidics and elucidated with small angle X-ray scattering. , 2019, Journal of colloid and interface science.

[23]  Simin Sharifi,et al.  The Application of Nanomaterials in Cardiovascular Diseases: A Review on Drugs and Devices , 2019, Journal of Pharmacy & Pharmaceutical Sciences.

[24]  T. Orsière,et al.  Toxicological Assessment of ITER-Like Tungsten Nanoparticles Using an In Vitro 3D Human Airway Epithelium Model , 2019, Nanomaterials.

[25]  Jun‐Seok Oh,et al.  How membrane lipids influence plasma delivery of reactive oxygen species into cells and subsequent DNA damage: an experimental and computational study. , 2019, Physical chemistry chemical physics : PCCP.

[26]  J. Lazniewska,et al.  Cytotoxicity of Dendrimers , 2019, Biomolecules.

[27]  Mohammad Hasanzadeh,et al.  Current analytical approaches in diagnosis of melanoma , 2019, TrAC Trends in Analytical Chemistry.

[28]  M. Tyska,et al.  PACSIN2-dependent apical endocytosis regulates the morphology of epithelial microvilli , 2019, bioRxiv.

[29]  Clive G. Wilson,et al.  Impact of regional differences along the gastrointestinal tract of healthy adults on oral drug absorption: An UNGAP review. , 2019, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[30]  C. Drummond,et al.  Encapsulation in egg white protein nanoparticles protects anti-oxidant activity of curcumin. , 2019, Food chemistry.

[31]  Haitao Huang,et al.  Multi-walled carbon nanotube-based systems for improving the controlled release of insoluble drug dipyridamole , 2019, Experimental and therapeutic medicine.

[32]  Oral delivery of proteins and peptides by mucoadhesive nanoparticles , 2019, Biointerface Research in Applied Chemistry.

[33]  H. Valizadeh,et al.  Evaluation of anti-inflammatory impact of dexamethasone-loaded PCL-PEG-PCL micelles on endotoxin-induced uveitis in rabbits , 2019, Pharmaceutical development and technology.

[34]  F. Lotfipour,et al.  Freeze-thaw-induced cross-linked PVA/chitosan for oxytetracycline-loaded wound dressing: the experimental design and optimization , 2019, Research in pharmaceutical sciences.

[35]  W. Parak,et al.  Investigating Possible Enzymatic Degradation on Polymer Shells around Inorganic Nanoparticles , 2019, International journal of molecular sciences.

[36]  M. Neek,et al.  Protein-based nanoparticles in cancer vaccine development. , 2019, Nanomedicine : nanotechnology, biology, and medicine.

[37]  K. Adibkia,et al.  An Alternative Approach for Improved Entrapment Efficiency of Hydrophilic Drug Substance in PLGA Nanoparticles by Interfacial Polymer Deposition Following Solvent Displacement , 2018, Jundishapur Journal of Natural Pharmaceutical Products.

[38]  F. Cassee,et al.  Toxicity of copper oxide and basic copper carbonate nanoparticles after short-term oral exposure in rats , 2018, Nanotoxicology.

[39]  M. Tyska,et al.  IRTKS (BAIAP2L1) Elongates Epithelial Microvilli Using EPS8-Dependent and Independent Mechanisms , 2018, Current Biology.

[40]  S. Salatin,et al.  Box–Behnken experimental design for preparation and optimization of the intranasal gels of selegiline hydrochloride , 2018, Drug development and industrial pharmacy.

[41]  Huajian Gao,et al.  Rapid transport of deformation-tuned nanoparticles across biological hydrogels and cellular barriers , 2018, Nature Communications.

[42]  S. Salatin,et al.  Natural low- and high-density lipoproteins as mighty bio-nanocarriers for anticancer drug delivery , 2018, Cancer Chemotherapy and Pharmacology.

[43]  D. Vllasaliu,et al.  Intestinal uptake and transport of albumin nanoparticles: potential for oral delivery. , 2018, Nanomedicine.

[44]  G. Zhu,et al.  Electrochemical sensing of 4-nitrochlorobenzene based on carbon nanohorns/graphene oxide nanohybrids. , 2018, Biosensors & bioelectronics.

[45]  David J Brayden,et al.  Effects of surfactant-based permeation enhancers on mannitol permeability, histology, and electrogenic ion transport responses in excised rat colonic mucosae. , 2018, International journal of pharmaceutics.

[46]  P. Ganesan,et al.  Lipid nanoparticles: Different preparation techniques, characterization, hurdles, and strategies for the production of solid lipid nanoparticles and nanostructured lipid carriers for oral drug delivery , 2017 .

[47]  M. Campagna,et al.  The unrecognized occupational relevance of the interaction between engineered nanomaterials and the gastro-intestinal tract: a consensus paper from a multidisciplinary working group , 2017, Particle and Fibre Toxicology.

[48]  Xincai Xiao,et al.  Natural material-decorated mesoporous silica nanoparticle container for multifunctional membrane-controlled targeted drug delivery , 2017, International journal of nanomedicine.

[49]  R. Chuck,et al.  Safety of Nonporous Silica Nanoparticles in Human Corneal Endothelial Cells , 2017, Scientific Reports.

[50]  Hari Sowrirajan,et al.  Impact of Silver and Iron Nanoparticle Exposure on Cholesterol Uptake by Macrophages , 2017, Journal of nanomaterials.

[51]  F. Reimann,et al.  Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity , 2017, Mucosal Immunology.

[52]  C. Cho,et al.  Surface modification of solid lipid nanoparticles for oral delivery of curcumin: Improvement of bioavailability through enhanced cellular uptake, and lymphatic uptake , 2017, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[53]  H. Bouwmeester,et al.  Effects of food‐borne nanomaterials on gastrointestinal tissues and microbiota , 2017, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[54]  Laura M Ensign,et al.  Nanoparticles for oral delivery: Design, evaluation and state-of-the-art. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[55]  N. N. Belyaeva,et al.  Structural and Functional Analysis of the Small Intestine in Rats After Six-Month-Long Exposure to Multiwalled Carbon Nanotubes , 2016, Bulletin of Experimental Biology and Medicine.

[56]  Mahdieh Rahmani,et al.  Fast Dissolving Sublingual Films Containing Sumatriptan Alone and Combined with Methoclopramide: Evaluation in Vitro Drug Release and Mucosal Permeation , 2016 .

[57]  M. Pumera,et al.  Air-stable superparamagnetic metal nanoparticles entrapped in graphene oxide matrix , 2016, Nature Communications.

[58]  Siqi Zhu,et al.  Enhanced oral bioavailability of insulin using PLGA nanoparticles co-modified with cell-penetrating peptides and Engrailed secretion peptide (Sec) , 2016, Drug delivery.

[59]  D. Jain,et al.  Nanotechnology Based Approaches for Enhancing Oral Bioavailability of Poorly Water Soluble Antihypertensive Drugs , 2016, Scientifica.

[60]  L. Hoffmann,et al.  Effects of silver nanoparticles and ions on a co-culture model for the gastrointestinal epithelium , 2015, Particle and Fibre Toxicology.

[61]  D. Mcclements,et al.  Uptake of Gold Nanoparticles by Intestinal Epithelial Cells: Impact of Particle Size on Their Absorption, Accumulation, and Toxicity. , 2015, Journal of agricultural and food chemistry.

[62]  Xiaoxiao Cai,et al.  Independent effect of polymeric nanoparticle zeta potential/surface charge, on their cytotoxicity and affinity to cells , 2015, Cell proliferation.

[63]  B. Conway,et al.  Modification of drug delivery to improve antibiotic targeting to the stomach. , 2015, Therapeutic delivery.

[64]  Z. Teng,et al.  Solid lipid nanoparticles for oral drug delivery: chitosan coating improves stability, controlled delivery, mucoadhesion and cellular uptake. , 2015, Carbohydrate polymers.

[65]  P. P. Kundu,et al.  Assessment of in vivo chronic toxicity of chitosan and its derivates used as oral insulin carriers , 2015 .

[66]  B. Manshian,et al.  (Intra)cellular stability of inorganic nanoparticles: effects on cytotoxicity, particle functionality, and biomedical applications. , 2015, Chemical reviews.

[67]  Steffen Loft,et al.  In vivo toxicity of cationic micelles and liposomes. , 2015, Nanomedicine : nanotechnology, biology, and medicine.

[68]  J. Dolatabadi,et al.  Nano graphene oxide: a novel carrier for oral delivery of flavonoids. , 2014, Colloids and surfaces. B, Biointerfaces.

[69]  Bruno Sarmento,et al.  The impact of nanoparticles on the mucosal translocation and transport of GLP-1 across the intestinal epithelium. , 2014, Biomaterials.

[70]  Yan Zhang,et al.  Decanoic acid grafted oligochitosan nanoparticles as a carrier for insulin transport in the gastrointestinal tract. , 2014, Carbohydrate polymers.

[71]  Jarno Salonen,et al.  Fabrication of a Multifunctional Nano‐in‐micro Drug Delivery Platform by Microfluidic Templated Encapsulation of Porous Silicon in Polymer Matrix , 2014, Advanced materials.

[72]  Meiying Wang,et al.  Aspect ratio plays a role in the hazard potential of CeO2 nanoparticles in mouse lung and zebrafish gastrointestinal tract. , 2014, ACS nano.

[73]  H. Bouwmeester,et al.  Sub-chronic toxicity study in rats orally exposed to nanostructured silica , 2014, Particle and Fibre Toxicology.

[74]  Hyun-Jong Cho,et al.  Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake , 2014, International journal of nanomedicine.

[75]  A. K. Kondapi,et al.  A Target-Specific Oral Formulation of Doxorubicin-Protein Nanoparticles: Efficacy and Safety in Hepatocellular Cancer , 2013, Journal of Cancer.

[76]  Vesa-Pekka Lehto,et al.  Co-delivery of a hydrophobic small molecule and a hydrophilic peptide by porous silicon nanoparticles. , 2013, Journal of controlled release : official journal of the Controlled Release Society.

[77]  V. Demin,et al.  Transfer of Silver Nanoparticles through the Placenta and Breast Milk during in vivo Experiments on Rats , 2013, Acta naturae.

[78]  Frank A Witzmann,et al.  Nanoparticle toxicity by the gastrointestinal route: evidence and knowledge gaps. , 2013, International journal of biomedical nanoscience and nanotechnology.

[79]  H. Ghandehari,et al.  Charge affects the oral toxicity of poly(amidoamine) dendrimers. , 2013, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[80]  U. Murty,et al.  Biochemical alterations induced by acute oral doses of iron oxide nanoparticles in Wistar rats , 2013, Drug and chemical toxicology.

[81]  Kai Yang,et al.  In vivo biodistribution and toxicology of functionalized nano-graphene oxide in mice after oral and intraperitoneal administration. , 2013, Biomaterials.

[82]  A. Youssef Polymer Nanocomposites as a New Trend for Packaging Applications , 2013 .

[83]  Linlin Li,et al.  The absorption, distribution, excretion and toxicity of mesoporous silica nanoparticles in mice following different exposure routes. , 2013, Biomaterials.

[84]  F. Wang,et al.  Application of Drug Nanocrystal Technologies on Oral Drug Delivery of Poorly Soluble Drugs , 2013, Pharmaceutical Research.

[85]  M. Rekha,et al.  Oral delivery of therapeutic protein/peptide for diabetes--future perspectives. , 2013, International journal of pharmaceutics.

[86]  Jianqing Gao,et al.  Enhanced absorption of hydroxysafflor yellow A using a self-double-emulsifying drug delivery system: in vitro and in vivo studies , 2012, International journal of nanomedicine.

[87]  J. Hanes,et al.  Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. , 2012, Advanced drug delivery reviews.

[88]  Mandy B. Esch,et al.  Oral exposure to polystyrene nanoparticles affects iron absorption. , 2012, Nature nanotechnology.

[89]  Zhenhai Zhang,et al.  Preparation of tripterine nanostructured lipid carriers and their absorption in rat intestine. , 2012, Die Pharmazie.

[90]  U. Vogel,et al.  Subacute oral toxicity investigation of nanoparticulate and ionic silver in rats , 2012, Archives of Toxicology.

[91]  Zigang Xu,et al.  Changes in Small Intestinal Morphology and Digestive Enzyme Activity with Oral Administration of Copper-Loaded Chitosan Nanoparticles in Rats , 2012, Biological Trace Element Research.

[92]  Mei-Chin Chen,et al.  A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery. , 2011, Biomaterials.

[93]  E. Souto,et al.  Preparation, characterization and biocompatibility studies on risperidone-loaded solid lipid nanoparticles (SLN): high pressure homogenization versus ultrasound. , 2011, Colloids and surfaces. B, Biointerfaces.

[94]  V. Préat,et al.  Fate of polymeric nanocarriers for oral drug delivery , 2011 .

[95]  Hans Bouwmeester,et al.  Characterization of translocation of silver nanoparticles and effects on whole-genome gene expression using an in vitro intestinal epithelium coculture model. , 2011, ACS nano.

[96]  H. Swai,et al.  In vivo uptake and acute immune response to orally administered chitosan and PEG coated PLGA nanoparticles. , 2010, Toxicology and applied pharmacology.

[97]  C. Lehr,et al.  A three-dimensional coculture of enterocytes, monocytes and dendritic cells to model inflamed intestinal mucosa in vitro. , 2010, Molecular pharmaceutics.

[98]  A. Oomen,et al.  The kinetics of the tissue distribution of silver nanoparticles of different sizes. , 2010, Biomaterials.

[99]  I. Yu,et al.  Subchronic oral toxicity of silver nanoparticles , 2010, Particle and Fibre Toxicology.

[100]  Vesa-Pekka Lehto,et al.  Biocompatibility of thermally hydrocarbonized porous silicon nanoparticles and their biodistribution in rats. , 2010, ACS nano.

[101]  M. Thanou,et al.  Biodegradation, biodistribution and toxicity of chitosan. , 2010, Advanced drug delivery reviews.

[102]  Lichen Yin,et al.  Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery. , 2009, Biomaterials.

[103]  I. M. Shaikh,et al.  Lipid-based nanoparticulate systems for the delivery of anti-cancer drug cocktails: Implications on pharmacokinetics and drug toxicities. , 2009, Current drug metabolism.

[104]  C. Lehr,et al.  PLGA Nanoparticles Stabilized with Cationic Surfactant: Safety Studies and Application in Oral Delivery of Paclitaxel to Treat Chemical-Induced Breast Cancer in Rat , 2009, Pharmaceutical Research.

[105]  B. Prasad,et al.  Acute and subacute toxicity studies of chitosan reduced gold nanoparticles: a novel carrier for therapeutic agents. , 2009, Journal of biomedical nanotechnology.

[106]  M. Fondevila,et al.  Silver nanoparticles as a potential antimicrobial additive for weaned pigs. , 2009 .

[107]  M. Yudasaka,et al.  Toxicity of single-walled carbon nanohorns. , 2008, ACS nano.

[108]  F. Veiga,et al.  Toxicological assessment of orally delivered nanoparticulate insulin , 2008 .

[109]  A. Basit,et al.  Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in‐vivo experiments , 2008, The Journal of pharmacy and pharmacology.

[110]  I. Yu,et al.  Twenty-Eight-Day Oral Toxicity, Genotoxicity, and Gender-Related Tissue Distribution of Silver Nanoparticles in Sprague-Dawley Rats , 2008 .

[111]  Yan Li,et al.  Chitosan nanoparticle as gene therapy vector via gastrointestinal mucosa administration: results of an in vitro and in vivo study. , 2007, Life sciences.

[112]  Shubiao Zhang,et al.  Toxicity of cationic lipids and cationic polymers in gene delivery. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[113]  J. Gao,et al.  Safety evaluation of short-term exposure to chitooligomers from enzymic preparation. , 2006, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[114]  J. Nah,et al.  Influence of molecular weight on oral absorption of water soluble chitosans. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[115]  M. Hirose,et al.  Subchronic toxicity study of dietary N-acetylglucosamine in F344 rats. , 2004, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[116]  R M Albrecht,et al.  Gastrointestinal persorption and tissue distribution of differently sized colloidal gold nanoparticles. , 2001, Journal of pharmaceutical sciences.

[117]  Claus-Michael Lehr,et al.  Size-Dependent Bioadhesion of Micro- and Nanoparticulate Carriers to the Inflamed Colonic Mucosa , 2001, Pharmaceutical Research.

[118]  T. Kararli Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals , 1995, Biopharmaceutics & drug disposition.

[119]  J. Hardcastle,et al.  Measurement of gastrointestinal pH profiles in normal ambulant human subjects. , 1988, Gut.

[120]  Kannan M. Krishnan,et al.  In vivo Delivery, Pharmacokinetics, Biodistribution and Toxicity of Iron Oxide Nanoparticles , 2016 .

[121]  Keyvan Nasirzadeh,et al.  In vivo toxicity of orally administrated silicon dioxide nanoparticles in healthy adult mice , 2014, Environmental Science and Pollution Research.

[122]  U. Murty,et al.  Comparative study of genotoxicity and tissue distribution of nano and micron sized iron oxide in rats after acute oral treatment. , 2013, Toxicology and applied pharmacology.

[123]  S. Iyuke,et al.  A Review of Nanoparticles Toxicity and Their Routes of Exposures , 2012 .

[124]  Amit Jain,et al.  The effect of the oral administration of polymeric nanoparticles on the efficacy and toxicity of tamoxifen. , 2011, Biomaterials.

[125]  I. Yu,et al.  Histochemical study of intestinal mucins after administration of silver nanoparticles in Sprague–Dawley rats , 2009, Archives of Toxicology.

[126]  G. Abraham,et al.  Management of Rheumatoid Arthritis: Rationale for the Use of Colloidal Metallic Gold , 1997 .

[127]  Peixun Liu,et al.  International Journal of Nanomedicine Dovepress Toxicologic Effects of Gold Nanoparticles in Vivo by Different Administration Routes , 2022 .