Nanomedicine 2024 PDF

Nanomedicine Gurvinder Singh School of Biomedical Engineering University of Sydney Email: [email protected] 23/09/2024  Learning goals  What is nano?  What is nanotechnology or nanomedicine?  Classificat...

Nanomedicine Gurvinder Singh School of Biomedical Engineering University of Sydney Email: [email protected] 23/09/2024  Learning goals  What is nano?  What is nanotechnology or nanomedicine?  Classification and characteristics of nanomaterials/nanoparticles  Synthetic strategy to fabricate nanomaterials/nanoparticles  Framework of designing nanoparticles-based medicine (Barriers, physiochemical and biological characteristics of nanoparticles)  Application of nanomedicine  Nanomedicine ( or Nano + Medicine)  Nano means “one billionth” or 10-9 nm (It indicates extreme smalless)  How small? Nano Micron  Any object or materials or particles that comes in the size range of 1 nm to 100 nm, we call them “nanoobject” or “nanomaterials” or “nanoparticle”  Nanomaterials classification based on dimension Dimensions XYZ nanoparticle Hard and brittle (inorganic) materials only Inorganic and soft materials All particles of the precursor may not break More control over particle size down to the required particle size More chances of contaminations Less chances of contaminations Low throughput fabrication of nanoparticles High throughput of nanoparticles and scalable Less or no control over shape Better control over shape Lithography, Ion beam milling Chemical reduction, Gas-phase synthesis, Flame pyrolysis. Design of nanoparticle-based delivery platforms  Design of nanoparticles for drug delivery High surface area allow the loading of multiple molecules to the surface of nanoparticles. Multiple molecules: Drug, targeting agents or polymeric molecules Drug molecules for disease treatment Targeting molecules Polyethylene glycol (PEG) i) guide the nanoparticle coating to the target site - longer circulation time ii) improve efficiency of - improve the stability of diagnosis and therapeutic nanoparticles in the solution treatment iii) reduce toxicity by preventing drug release to healthy tissue  Drug loading Polyethylene Glycol (PEG) Drug Targeting agent  Drug loading strategies Carbon nanotubes Liposomes Hydrophobic drug Hydrophilic drug Silica Drug release (Inorganic/Organic/Polymer)  Drug release (nanoporous nanoparticles)  Gatekeepers or plug open upon external stimulus: pH, light, magnetic field Gatekeepers: magnetic nanoparticles, gold nanoparticles, cyclodextrin, polymer Nanoscale, 2021, 13, 9091-9111  Alternative Drug release mechanism A) Diffusion controlled drug release B) Erosion controlled drug release  Biological barriers in nanoparticles-based therapeutics delivery RES: reticuloendothelial system LSEC: liver sinusoidal endothelial cell ECM: extracellular matrix. Organ Challenges/ Barriers increases Subcellular Nature Nanotech. 2020, 20, 829-839 Understanding the biology of barriers at each level (organ, sub-organ and cellular) and their interaction with nanoparticles A framework for designing nanoparticles based delivery system  Blood circulation time  Longer blood circulation or half-life, which depends on the size and shape of nanoparticles as well as the surface charge and type of coating around the nanoparticles.  For biomedical applications, nanoparticles of longer blood circulation time are preferred to ensure their delivery to target site.  Nanoparticles in the blood stream Albumins: ~60% Globulins: ~40%  Nano-bio interaction: Opsonization Pristine nanoparticle Protein corona When nanoparticles (NPs) are introduced in the blood, protein molecules collectively called opsonins (antibodies, complement proteins, plasma proteins) bind to the surface pristine NPs ------> Opsonization or protein corona  “Opsonin" is derived from the Greek word "opson (to prepare for eating).  British physician Sir William Watson Cheyne, who observed that the ingestion of bacteria by white blood cells was enhanced when the bacteria were coated with serum from an immune animal, which he referred to as an "opsonin."  The term has since been widely used in immunology to describe molecules that enhance phagocytosis.  Nano-bio interaction Synthetic identity Size, shape, and surface chemistry of synthesized NPs Biological identity Size and aggregation state of NPs in physiological environment along with with the structure and composition of protein corona Physiological Response Biological identity determines subsequent interaction of NPs with biomolecules, biological barriers and cells Chem. Soc. Rev., 2012, 41, 2780–2799  Protein corona/opsonization The formation of a protein corona or opsonization around NPs can have several consequences:  Alteration of physicochemical properties of NPs, such as size, shape, surface charge, and hydrophobicity -----> cellular uptake, toxicity, and clearance  Recognition by immune cells, such as mononuclear phagocyte system (MPS) that can eat NPs and remove from the circulation ----> reducing therapeutic efficiency  Activation of immune system leading to the production of inflammatory cytokines and other immune responses ------> adverse effect, such as inflammation, fever or allergic reaction  Masking the targeting ligands ------> reducing the specificity and efficacy of the NPs in delivering drugs or imaging agents to the target.  Strategies to overcome protein corona/opsonization and MPS clearance Coating NPs with Polyethylene Coating NPs with 'don't signal regulatory protein alpha (SIRPα) glycol (PEG): eat-me' marker CD47 'self' peptides :  Ethylene glycol form tight associations with water molecules, resulting in the  Reduce opsonization formation of a hydrating  Prolong circulation layer that hinders protein  Inhibit MPS clearance corona  Enhanced delivery  Increased circulation Coating NPs with red blood cell (RBC) membranes (rich in Leukocyte membrane- proteins, such as CD47 and coated NPs produce glycophorin A) similar effect to RBC coated NPs.  Reducing opsonization  Increased circulation  Not recognized by immune system and thus avoid MPS Camouflage NPs clearance (non-immunogenic and non-fouling) Nature Biotechnology 2015, 33, 941–951  Strategies to overcome clearance of NPs NPs larger than 200 nm in size are more likely to activate a cascade of reactions that can lead to the opsonization of the particles, or the coating of the particles with complement proteins that can signal to phagocytes to engulf and clear the particles. Size of NPs should be below 200 nm Mononuclear phagocyte system (MPS)  Nanoparticles entry to solid tumor : Enhanced Permeability and Retention (EPR) Effect  Passive targeting mechanism  Leaky vasculature structure surrounding tumors due to the uncontrolled growth of tumor cells.  This leakiness allows NPs that would not normally be able to cross the blood vessel walls  Gap size~100-500 nm but healthy tissue tight interendothelial junctions  EPR effect is not universal and depends on the tumor type, size, and location.  Nanomaterials-cell interaction  Getting nanoparticles into cell for intracellular drug delivery  Size, shape, surface charge and materials property (soft or stiff) dependent interaction with cell. ACS Nano 2015, 9, 9, 8655–8671 Size-dependent cellular uptake of gold nanoparticles Incubation of HeLa cells with gold nanoparticles with various sizes  Size-dependent cellular uptake of gold nanoparticles Transmission electron microscopy imaging and measurements of gold nanoparticles in cells. (A) The graph of number of gold nanoparticles per vesicle diameter vs nanoparticle size. (B−F) TEM images of gold nanoparticles with sizes 14, 30, 50, 74, and 100 nm trapped inside vesicles of a Hela cell, respectively.  Size-dependent cellular uptake of gold nanoparticles There is an optimal particle diameter for the smallest internalization time. The optimal particle size is a result of competition between thermodynamic driving forces of membrane wrapping (permitted by receptor binding) and receptor diffusion kinetics (recruitment of receptors to the binding sites). This model elucidates the mechanism of size-dependent cellular uptake of NPs from a kinetic point of view and has addressed ‘how fast’ a single NP can be endocytosed into the cell. Shape-dependent cellular uptake of gold nanoparticles  Dependence of cell uptake on surface charge of nanoparticles When positively charged Au nanospheres are attached to a negatively charged cell surface, the cell membrane will try to maintain the original charge distribution by getting rid of the attached Au nanospheres through endocytosis. During this process, cell membrane probably would lose its rigidity, and its morphology would be changed----> change in fluidity and permeability of cell membrane Key Characteristics of nanoparticles for medical applications  Size and surface area of nanoparticles  Polydispersity  Shape of nanoparticles (spherical, cube, triangle, rod)  Surface charge  Materials type (gold, iron oxide, polymer)  Protein-nanoparticles interaction (Biological factor because abundance of protein in the blood)  Toxicity, clearance or minimum side effect (for in vivo applications) Application of nanoparticles to medicine Disease diagnosis: water-dispersible MnO nanoparticles In Vivo MRI-Mouse Imaging Selectively the Breast Cancer Cells in the Metastatic Brain Tumor Model Using MnO Nanoparticles (T1-weighted MRI) Cancer cells were selectively enhanced in T1-weighted MRI (Magnetic resonance imaging) because the functionalized 15 nm MnO nanoparticles with tumor-specific antibody were delivered to and accumulated in the cancer cells with a clear marginal detectability without destroying the anatomic background. Gold Nanorod-Based Engineered Cardiac Patch for Suture-Free Engraftment by Near IR Gold nanorods absorb the light and convert it to thermal energy, which locally change the molecular structure of the fibrous scaffold, and strongly, but safely, attach it to the wall of the heart.  Summary  Nanomaterials show size and shape dependent physical properties.  Nanomaterials can be synthesized by top-down and bottom-up approaches.  The performance of nanomaterials depends on their interaction with biological species.  Nanotechnology has radically changed the way we diagnose, treat and prevent cancerous and non-cancerous diseases. BMET5931: Nanomaterials in Medicine