Nanomedicine Lecture 27 PDF

Nanomedicine Lecture 27  Learning Objectives Understand the basics of nanomedicine and its potential applications in drug delivery. Describe the differences between different types of nanoparticle-based drug delivery systems. Exp...

Nanomedicine Lecture 27  Learning Objectives Understand the basics of nanomedicine and its potential applications in drug delivery. Describe the differences between different types of nanoparticle-based drug delivery systems. Explain the advantages and disadvantages of different types of nanoparticle-based drug delivery systems. Understand the factors to consider when choosing nanotechnology for drug delivery. Discuss the potential of nanomedicine for personalized medicine and the future of drug  Medicinal Chemistry Drug-Target Drugs Targets Drug Interactions Discovery Development & Optimization Physicochemical Property of Drug-1 Enzymes Forces in Drug- Functional Group (FG) Receptor Target Acidity and Basicity of FG Optimization of Drug Interactions SAR, Bioisosterism, Rigidification Enzyme and Discovery & Design Physicochemical Property of Drug-2 Receptor Peptide/Protein based drug - Salt and Solubility Interactions Combinatorial & Parallel Chemistry - Chirality Use of Computers in Drug Design (Molecular Modelling, QSAR, AI) Physicochemical Properties of Drug Absorption and Membrane Drug Drug Nanomedicin transporters Metabolism e Examples of Drug Classes Nanoparticle Characteristics o Smaller in size o Solubility o Different physical and chemical properties compared to small-molecule drugs Advantages of Nanoparticles o High surface area-to-volume ratio for the ability to load drugs o Improve drug accumulation at pathological tissue by attaching target molecules (active targeting mechanism) through enhanced permeability and retention (EPR) effect (passive targeting mechanism) o Increase water solubility of poorly water-soluble drugs to increase biocompatibility o Multifunctional features o Distinguish between pathological tissue and normal tissue o Contribute toward personalized medicines Nanocarrier Size & Types Nanomedicine o Using nanoparticles (NPs) to improve solubility and stability of poorly water- soluble drugs o NPs act as radiosensitizers by attenuating high-energy X-rays to destroy pathological tissues o Using NPs to deliver the drugs to specific cells or organs aka nanocarriers o Theranostic NPs allow the combination of treatment and monitor the target of treatment, providing critical feedback to physicians and researchers, such as no response of tumor due to drug resistance or insufficient drug delivery. https://www.fiercepharma.com/m-a/updated-j-j-releases-more-doxil-its-popular-canc er-med-has-been-dogged-by-supply-issues https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/overview- COVID-19-vaccines.html Theranostic NPs Applications o Imaging and Therapy o Targeted drug delivery systems toward cancer, diabetes, CNS disorders, immune disorders, and genetic disorders. Schematic for applications of theranostic NPs https://chemistry-europe.onlinelibrary.wiley.com/doi/ 10.1002/cmdc.202200142?af=R Liposomes o Composed of phospholipid bilayers similar to the human plasma membrane o Encapsulate with a hydrophobic bilayer and a hydrophilic core o Size: 20nm to more than 1μm o Good biocompatibility to promote drug diffusion across the plasma membrane o Ability to carry hydrophilic drugs or hydrophobic drugs Figure 1 Figure 2 https://holisticprimarycare.net/topics/quality-counts/liposomes- micelles-nanoparticles-major-advance-or-marketing-hype/ Four Generations of Liposomes First generation Fourth generation Second generation Third generation https://www.mdpi.com/1999-4923/14/10/2195 Drug loading on liposomes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459376/  Liposomes Advantages Disadvantages Easy modification and Reduced bioavailability targeting potential Limit high drug loading of Ability to carry hydrophobic drugs hydrophobic or Fast clearance from the hydrophilic drugs bloodstream Cost effective Commercially available liposomal drugs and vaccine Pharmacist Marqibo Alert (Liposomal Formulation of Vincristi Sphingomylein- and cholesterol-based nanoformulation Loading and retention of vincristine and slow drug release in the tumor environment Broad-spectrum activity against hematological Biomolecules 2019, malignancies 9:279 Solid-Lipid Nanoparticles (SLNs) o Colloidal carriers consist of one or more solid lipids at room temperature dispersed in water or aqueous solution containing surfactants. o Biocompatible substances such as triglycerides, fatty acids, steroids, and biowaxes are often used to prepare the SLN system. o Orally administration as aqueous dispersions or in the dosage forms https://www.intechopen.com/chapters/80519 of capsules, tablets, and pellets  Advantages of Solid-Lipid Nanoparticles (SLNs) o Increased drug loading capacity o Effective release of drug o Stability of pharmaceuticals o Easy manufacturing o High long-term stability o Ability to encapsulate antitumor drugs and other substances with poor water solubility due to their high lipid content https://www.reuters.com/business/healthcare-pharmaceuticals/ https://www.mpg.de/12224399/0823-mpin-116799- covid-19-vaccine-scheme-worlds-poorest-pushes-delivery- rnai-medication-max-planck-technology  Nanostructured Lipid Carriers (NLCs) o Solid matrix at room temperature o Have enhanced bioavailability, superior formulation properties and increased drug loading capacity https://link.springer.com/article/10.1007/s11051-  Nanoemulsions o A dispersed system with ≤ 100nm drops o Unique properties of small-sized droplets with high surface area o 3 types of nanoemulsions o O/W oil in water o W/O water in oil o Bi-continuous/multiple emulsion where microdomains of oil and water phases are interdispersed (W/O/W and O/W/O) https://www.researchgate.net/figure/Structure-of-an-O-W-nanoemulsion-top- and-W-O-nanoemulsion-bottom-Based-on-58-59_fig2_349596121  Pharmacist Alert Examples of Nanoemulsions for Encapsulated Drugs https://mms.mckesson.com/ https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3806207/ product/924487/APP- Pharmacist Alert Abraxane DOI:10.2217/nnm-2018-0120 Enhances Permeability and Retention (EPR) https://www.oncoprescribe.com/abraxane-superior-to-taxol-in-high-risk-breast- cancer-including-triple-negative-tumors/ DOI:10.2174/1568009618666180628160211 Polymer o Polymers are materials that consist of macromolecules composed of many repeating subunits. o They can be natural or synthetic Polymeric Nanoparticles (PNs) o PNs are produced from biodegradable polymers o They are more stable and easier to reproduce than liposomes Polymeric Nanoparticles (PNs) o Two types: nanospheres and nanocapsule o Disadvantages: o Low encapsulation rate o Easily induce immune response due to the high molecular weight of the polymer https://www.verywellhealth.com/what-is-a-pegylated-drug-176013 0 https://www.mdpi.com/1999-4923/14/12/2639 Pharmacist Alert Onivyde: A pegylated liposomal formulation of irinotecan Stable in the circulation, and is preferentially taken up and retained for a longer period of time in the tumor cell. The elimination t1/2 of liposomal irinotecan and SN-38 is approximately 26 and 68 hours, respectively. SN38 is detectable in plasma for up to one week (slower clearance). Binding to serum proteins is blocked by the polyethylene glycol attached to the liposomal surface. The inclusion of PEG chains decreases phagocytosis by tissue macrophages. The size (110 nm) aids in accumulating in tumor tissues. SN38 has a lower maximum concentration (Cmax) than free Irinotecan. A more potent therapeutic effect with fewer adverse reactions: The boxed warning for life-threatening neutropenia and diarrhea still applies. Indicated for the treatment of the metastatic pancreas. Pharmacist Alert Onivyde: A pegylated liposomal formulation of irinotecan Stable in the circulation, and is preferentially taken up and retained for a longer period of time in the tumor cell. The elimination t1/2 of liposomal irinotecan and SN-38 is approximately 26 and 68 hours, respectively. SN38 is detectable in plasma for up to one week (slower clearance). Binding to serum proteins is blocked by the polyethylene glycol attached to the liposomal surface. The inclusion of PEG chains decreases phagocytosis by tissue macrophages. The size (110 nm) aids in accumulating in tumor tissues. SN38 has a lower maximum concentration (Cmax) than free Irinotecan. A more potent therapeutic effect with fewer adverse reactions: The boxed warning for life-threatening neutropenia and diarrhea still applies. Indicated for the treatment of the metastatic pancreas. Polymer micelles o Belong to nano colloid class o It is formed by self-assembly of amphiphilic block copolymers in an aqueous solution o Hydrophobic drugs are encapsulated in the hydrophobic core, and the hydrophilic shell maintains particle stability. o Particle size 5-100 nm https://www.mdpi.com/1996-1944/11/5/688 Polymer Vesicles o Polymer vesicle membranes are composed of special amphiphilic block copolymers, biomimetic analogs of natural phospholipids. o Hydrophobic segments of copolymers gather together to reduce contact with water o Hydrophilic groups are distributed on the outer side of the membrane o Forming a typical bilayer membrane structure o Encapsulate hydrophobic substances in the membrane o Sub-encapsulate hydrophilic groups in the water-based corehttps://www.dovepress.com/stimulus-responsive-vesicular-polymer-nano- integrators-for-drug-and-ge-peer-reviewed-fulltext-article-IJN Dendrimers o Highly branched polymer molecules o Consists of a core and branches connected around the core o Size 5-20 nm o Advantages: o High stability o Easy size control o Easy surface functionalization o Multiple sites for binding https://www.researchgate.net/figure/Fig-1-Structure-of-a-typical- multiple drugs or targeting dendrimer-with-all-the-components_fig1_297737775 Lipid- Polymer Hybrid Nanoparticles (LPHNs) o Multilayered particle o Lipid and polymeric layers give biocompatibility, high loading efficiency, and stability o Inner layers are weakly bound by van der Waals forces, hydrophobic interactions, and noncovalent bonds. o The outer layer is a water-soluble polymer that enhances steric stabilization and increases circulation time in vivo. https://www.mdpi.com/1999-4923/13/8/1291  Pharmacist Alert Multitherapy Nanoparticles o Contain two or more therapeutics to effectively achieve treatment of diseases Vyxeos Cytarabine Daunorubicin Nanoliposome Cytarabine (Antimetabolite; Inhibition of DNA Synthesis; Apoptotic death inducer) Daunorubicin (Intercalation into DNA duplex; Inhibition of topoisomerase II activity; Replication arrest and DNA double-stranded breaks) Prolonged plasma half-life; Accumulation in bone marrow; Treatment of high-risk acute myeloid leukemia Factors to consider when choosing Nanotechnology for drug delivery o Macromolecule loading efficiency o Production conditions that should be mild to prevent protein instability o Final properties of the nanosystems o Liposomes, polymeric NPs, and nanostructured lipid carriers are widely studied in drug delivery due to their potential for more https://www.researchgate.net/figure/Fig-3-Different-types- specific targeting of-Nano-Carrier-Systems-for-Brain-Drug- Enhanced Permeability and Retention (EPR) o This effect is the driving force of nanocarrier in the tumor tissues o Utilizing the passive mechanisms of EPR is a critical design parameter of nanocarrier delivery to tumors o The pore size in endothelial https://www.researchgate.net/figure/A-schematic-representation walls determines the entry of-the-Enhanced-Permeability-and-Retention-EPR-effect- Nanoparticles for Active Targeting https://www.understandingnano.com/nanomedicine- nanoparticles-targeted-chemotherapy.html Controlled Release of Drugs from Nanoparticles https://www.sciencedirect.com/science/article/pii/ S0009250914004710 Challenges of Using Nanoparticles o Lack of specific regulations o Complex design process, multi-step synthesis, no standard purification methods o Large scale production o Cost of production o Possible toxicity and immunogenicity o More efforts to approve and regulate nano- formulations for FDA and EMA o High product price Concerns of safety, biodistribution, and stability of nanocarriers 1. Safety o Toxic effects such as oxidative stress, inflammation, and DNA damage o Viable epidermal cells with penetration of solid nanoparticles into the skin o Some evidence suggests that certain bioactive substance-loaded nanocarriers are efficient and safe to use in food or medicine. 2. Biodistribution and Stability o Large amount of NPs in unintended organs leads to toxicity o Therapeutics loaded inside NPs are protected from liver metabolism while binding of serum proteins can increase their size and prevent their renal elimination o Major organs such as livers, spleen, and bone marrow have been shown to take up large quantities of NPs and eliminate them Toxic Effects of Nanoparticles o Hypersensitivity reactions o Pathology of Alzheimer’s disease is associated with the accumulation of high concentrations of magnetite (Fe3O4) iron. o Exposure to diesel exhaust (a combustion- derived NP) shows increased systolic blood pressure and vasodilation due to vascular oxidative stress o Chronic exposure to silver shows accumulation of severe DNA damage and  Take Home Message Nanoparticle-based drug delivery systems offer advantages over small-molecule drugs. Different types of nanoparticles have different advantages and disadvantages. Liposomes, solid-lipid nanoparticles, and nanoemulsions are all types of nanoparticle-based drug delivery systems. Polymeric nanoparticles, dendrimers, and lipid-polymer hybrid nanoparticles are other types of nanoparticle-based drug delivery systems. Multitherapy nanoparticles can effectively treat diseases by combining two or more therapeutics.