Chapter 23. Nanochemistry
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1. Overview
2. Characterization Experiments
3. Types
6. Radiolabeling of Nanoparticles
1. Overview
⑴ Definition : Particles with sizes below 100 nm
⑵ In order to avoid capture by macrophages, the overall size of nanoparticles should be below 100 nm
⑶ Effects based on quantum properties
① Example 1: Transparency of Titanium oxide NP
② Example 2: UV-blocking effect of Antimony tin oxide
③ Example 3: Fluorescence of Gold NP
⑷ Methods
② Co-precipitation method
③ Hydrothermal method
2. Characterization Experiments
⑴ Immune system interaction experiments
① Haemolysis : Checking toxicity to RBC
② Platelet aggregation : Checking interference with blood coagulation cascade
③ Coagulation time : Checking alteration of coagulation factor function
④ Complement activation : Checking activation of the complement system
⑤ CFU-GM : Checking myelosuppression
⑥ Leukocyte proliferation : Checking inhibition of leukocyte proliferation
⑦ Uptake by macrophages : Checking if nanoparticles are taken up by macrophages
⑧ Cytokine induction : Checking promotion of cytokine generation or immunogenic action
⑨ Nitric oxide production : Indirectly measuring endotoxin contamination by checking oxidative stress
⑩ Cytotoxicity of natural killer cells : Checking inhibition of NK cells
⑪ Endotoxin contamination : Pyrogen contamination test
⑫ Microbial contamination : Sterility test
⑬ Viral/mycoplasma contamination : Sterility test
⑵ Supplement 1: Size
Figure. 1. In vivo distribution according to size
⑶ Supplement 2: Zeta potential
Figure. 2. Hydrophobicity of PEG head group and TNF-alpha gene expression
3. Types
⑴ Liposomes : One of the most commonly used nanoparticles
⑵ Lipid Nanoparticles (LNP) : Widely used in COVID-19 vaccines
⑶ Polymers
⑷ Polymer Micelles
⑸ Dendrimers
① Can load drugs inside dendrimers
⑹ Gold nanoparticles
① Advantage 1: Inert, low toxicity, easy synthesis
② Advantage 2: Well-known thiol binding mechanism for easy chemical attachment of drugs
③ Advantage 3: Detectable in infrared, applicable in infrared imaging
④ Advantage 4: Can generate heat using external AC magnetic field
⑺ Magnetic nanoparticles: Examples include iron oxide nanoparticles, silica-coated iron oxide nanoparticles
⑻ Ceramic nanoparticles
① Definition : Porous structures made from materials like silica, alumina, titanium dioxide
② Advantages : Biocompatibility, easy synthesis, surface modification capability
⑼ Carbon Nanostructures
① Carbon Nanotubes : Capable of drug delivery
② Fullerenes : Capable of drug delivery
③ Limited by known toxicity
⑽ Nanogels
⑾ DNA nanospheres
⑿ Porous nanoparticles
⒀ Virus-like particles
⒁ Up-conversion nanoparticles (UCNP)
⒂ Quantum-dot squares (QD2)
⒃ Antibodies
4. Targeting Agents
⑴ Antibodies
① Overview
○ Also called immunoglobulins (Ig)
○ Recognize antigens
② Structure : Y shape
③ Characteristics
○ Advantages : Specificity, diversity, affinity; well-known targets
○ Disadvantages : Immunogenicity, high cost, small quantities
⑵ Affibodies
① Overview : Refers to 58 amino acids from protein A of Staphylococcus aureus (SPA) IgG binding region
② Structure : Z-domain composed of 3 alpha helices
○ Only two alpha helices have IgG binding sites
○ One IgG binding site composed of 6 amino acids, and the other composed of 7 amino acids (total 13)
○ Various affibodies can be created by randomly substituting these 13 amino acids to achieve different binding characteristics
③ Characteristics
○ Advantages : Small, increased clearance, low cost
○ Disadvantages : Lower detection ability due to insufficient Fc fragment in 2’ staining (to be updated)
⑶ Peptides
① Overview : When used as targeting agents, composed of less than 50 amino acids
② Characteristics
○ Advantages : Small, diverse, low immunogenicity, low cost
○ Disadvantages : Low affinity, short lifespan
⑷ Aptamers
① Structure : Unique 3D shapes
○ Stem, loop, bulge, hairpin, pseudoknot, triplex, quadruplex
② Characteristics
○ Advantages : Small, diverse, low immunogenicity, high affinity
○ Disadvantages : High cost, small quantities
5. Nanoparticle Coating
⑴ Necessity
① As nanoparticles become more hydrophobic, adsorption of opsonin increases
② Increased opsonin adsorption leads to filtration by the reticuloendothelial system (RES)
③ Nanoparticles should be coated with hydrophilic, biocompatible materials on their surfaces
⑵ Method 1: Dextran : Feridex, Resovist, Sinerem, Feraheme, etc.
① Dextran is also used as a coating material in MRI contrast agents
⑶ Method 2: PEG (Polyethylene Glycol) : Clariscan, etc.
⑷ Method 3: Silicon : GastroMARK, etc.
⑸ Confirmation of coating status
① Confirmation Method 1: Can be confirmed using FTIR (Fourier transform infrared)
○ Specific absorption bands related to nanoparticle and coating material binding can be observed
② Confirmation Method 2: NMR (Nuclear Magnetic Resonance)
○ Only applicable when dissolved in organic solvents
6. Radiolabeling of Nanoparticles
⑴ Overview
① Advantages : Simple and reproducible
② It’s better to do this in the final step : Due to half-life issues
③ Characteristics of the substance to be labeled should not change
○ Nanoparticles are advantageous in this regard
○ Small molecule inhibitors are disadvantageous in this regard
⑵ Type 1: Extrinsic radiolabeling method
① Overview
○ Disadvantage 1: Pharmacokinetics and toxicity profile may change
○ Disadvantage 2: Radiolabeling may detach
② 1-1. Surface Modifications of Nanoparticles
○ Types of Chelators
○ DOTA
○ NOTA
○ DTPA : Selects Tc99m over other radioactive isotopes
○ DFO
○ HYNIC + tricine
○ NODAGA
○ BAT
○ TETA
○ CB-TE2A
○ NTA
○ It is important to confirm chelator challenging, which means whether the chelator is detached.
○ Example 1. 18F-SFB prosthetic group : Disadvantage due to two binding reactions.
○ Example 2. Silica anchor
○ Example 3. 18F-FDG-thiol
○ Example 4. 18F-Si bond formation
○ Example 5. Bisphosphonate anchor
○ Example 6. Micelle encapsulation method
③ 1-2. Variations in Nanoparticle Coating
○ -COOH + -NH2 : Catalyzed by DCC, EDC, HATU, or HOBT
○ -NHS + -NH2
○ TFP + -NH2
○ -NCS + -NH2
○ -NHS + -SH
○ Azide + alkyne
○ Tetrazine + transcyclooctent : Utilizes Diels-Alder reaction
④ 1-3. Chelator π-π Stacking
○ Example 1. Graphene oxide binding with HPPH
⑶ Type 2. Intrinsic Radiolabeling Method
① 2-1. Radiochemical Doping
② 2-2. Physisorption : Utilizes electrostatic or van der Waals forces. No actual examples.
③ 2-3. Direct Chemisorption
○ Example 1. Mesoporous silica + 89Zr4+
○ Example 2. Heat-induced radiolabeling
④ 2-4. Isotope Exchange
○ Example 1. 19F / 18F exchange
⑤ 2-5. Cation Exchange
○ Example 1. CdSe / ZnS quantum dot via M2+ cation exchange
⑥ 2-6. Particle Beam or Reactor Activation
○ Example 1. Holmium iron garnet nanoparticle
⑦ 2-7. Cavity Encapsulation
○ In cases of hollow nanoparticles
○ Example 1. Carbon nanotube
○ Example 2. Intraliposomal radiolabeling
○ Ionophore-chelator binding
○ Unassisted loading
○ Ionophore-drug binding
○ Remote loading
7. FDA Approved Nanodrugs
⑴ Overview
① FDA approved drugs as of 2019: 350
② Majority are liposomes
③ Second most common type is nanocrystals
④ One-third are cancer drugs
⑵ Brentuximab Vedotin
① Class : ADC (Antibody-Drug Conjugate)
② Drug : Monomethyl auristatin E
③ Diameter : ~ 10 nm
④ Drug / Carrier Ratio : ≤ 8
⑤ Key Design Feature
○ Valine-citrulline linker cleaved by cathepsin in endosomes
⑥ Problem Addressed
○ MMAE (monomethyl auristatin E) is too toxic for standalone use
⑶ Trastuzumab Emtansine
① Class : ADC (Antibody-Drug Conjugate)
② Drug : Mertansine
③ Diameter : ~ 10 nm
④ Drug / Carrier Ratio : ≤ 8
⑤ Key Design Feature
○ Non-cleavable linker
○ Drug release by proteolytic degradation of antibody in endosomes
⑥ Problem Addressed
○ Mertansine is too toxic for standalone use
⑷ Doxil
① Class : Liposome
② Drug : Doxorubicin
③ Diameter : 100 nm
④ Drug / Carrier Ratio : 10,000-15,000
⑤ Target : Breast cancer, ovarian cancer
⑥ Key Design Feature
○ Lipid encapsulation for a high drug/carrier ratio
○ Polyethylene glycol coating to evade the mononuclear phagocyte system (MPS)
○ Crystallization of the drug in liposomes minimizes escape during circulation
○ Daunorubicin (DOX) interacts with DNA by intercalation and inhibits the process of replication
⑦ Problem addressed
○ Drug toxicity and adverse cardiac side effects
⑸ DaunoXome
① Class : Liposome
② Drug : Daunorubicin
③ Diameter : 50 nm
④ Drug/carrier ratio : ~10,000
⑤ Key design feature
○ No polyethylene glycol coating
○ Targeted by MPS, resulting in slow release into circulation
⑥ Problem addressed
○ Drug toxicity and adverse cardiac side effects
⑹ Marqibo
① Class : Liposome
② Drug : Vincristine
③ Diameter : 100 nm
④ Drug/carrier ratio : ~10,000
⑤ Key design feature
○ No polyethylene glycol coating
○ Targeted by MPS, resulting in slow release into circulation
⑥ Problem addressed
○ Drug toxicity and adverse side effects
⑺ Abraxane
① Class : Protein carrier
② Drug : Paclitaxel
③ Diameter : 130 nm
④ Drug/carrier ratio ＞ 10,000
⑤ Target : Breast cancer, lung cancer, pancreatic cancer
⑥ Key design feature
○ Non-specific binding of paclitaxel to albumin
○ Dissolved in Cremophor EL and ethanol
○ Nanoparticle albumin-bound paclitaxel is an injectable formulation of paclitaxel
○ Paclitaxel destroys cancer cells by preventing the normal breakdown of microtubules during cell division
⑦ Problem addressed
○ Overcomes the very low solubility of paclitaxel
Input : 2020.02.10 00:44
Modification : 2023.06.23 14:44