Advanced Drug Delivery Systems Course PDF

Advanced Drug Delivery Systems Site Directed Drug Targeting Lecture 4 Carriers for drug targeting Pepared by Prof. Magda EL-Massik, PhD Prof. of Pharmaceutics...

Advanced Drug Delivery Systems Site Directed Drug Targeting Lecture 4 Carriers for drug targeting Pepared by Prof. Magda EL-Massik, PhD Prof. of Pharmaceutics 1 Site Directed Drug Targeting Carriers for drug targeting I. Soluble macromolecular carrier systems √ II. Colloidal /Nano-carrier systems A. Lipid-based systems.e.g. liposomes, solid-lipid nanoparticles, nonoemulsions and others.√ B.Polymer-based systems. e.g. dendrimers, polymeric micelles, and others. C. Stimuli-responsive systems (smart delivery systems). 2 Site Directed Drug Targeting II. Colloidal /Nano-carrier systems B. Polymer-based systems 1. Dendrimers The name dendrimer was derived from the Greek word ‘dendron’ meaning ‘tree,’ which is representative of their ‘tree-like’ branched architecture Prof. Magda EL-Mass ik 2023-2024 3 II. Colloidal /Nano-carrier systems B. Polymer-based systems 1. Dendrimers Well defined structure They have tree like structure with highly branched polymer macromolecules Prof. Magda EL-Mass ik 2023- 4 2024 Site Directed Drug Targeting II. Colloidal /Nano-carrier systems B. Polymer-based systems 1. Dendrimers The branching units are described as generations. Branches stemming from the core represents generation 0 (G0) and increases as each layer of branching is added (G1, G2, etc..) 5 Kesharwani P, Jain K, Jain NK. Dendrimer as nanocarrier for drug delivery. Prog. Polym. Sci. 39(2), 268–307 (2014).  Site Directed Drug Targeting II. Colloidal /Nano-carrier systems B. Polymer-based systems 1. Dendrimers ❑ Their size ranges between 1-100nm ❑ May include different functional groups in each of the 3 parts to modulate properties such as solubility, permeability and thermal stability. ❑ Can be designed for passive targeting with PEG coats and active targeting by attaching targeting ligands such as folic acid. 7 Site Directed Drug Targeting II. Colloidal /Nano-carrier systems B. Polymer-based systems 1. Dendrimers Dendrimers under preclinical studies are made of the following building blocks: Polyamidoamine (PAMAM dendrimers). They are hydrophilic, biocompatible, and non-immunogenic. Poly-propyleneimine (PPI dendrimers) Contains alkyl and tertiary amine groups. Poly-L-lysine (PLL dendrimers) Have positively charged primary amine terminal groups. 8 Polyamidoamine (PAMAM) 9 Site Directed Drug Targeting II. Colloidal /Nano-carrier systems B. Polymer-based systems 1. Dendrimers Drugs can be covalently bound to the dendrimer structure or solubilized within the hydrophobic regions of the structure Adsorbed on surface Encapsulated (Hydrophilic drugs) (Hydrophobic drugs) 1 0  Site Directed Drug Targeting II. Colloidal/Nano-carrier Systems B. Polymer-based systems 2. Polymeric micelles ❑ Nano-sized particles made up of polymer chains and are spontaneously formed by self assembly in a liquid, as a result of hydrophobic or ion pair interaction between polymer segments. ❑Each polymer chain is amphiphilic in nature, consisting of hydrophobic polymer segment (in the core) and an outer hydrophilic polymer segment. Site Directed Drug Targeting B. Polymer-based systems 2. Polymeric micelles ❑ Hydrophilic components, used for the outer shell of the micelle, consist mainly of PEG. The hydrophilic polymer segments do not only provide the hydrophilic part of the molecule necessary for the formation of micelles but also provides the stealth character to the whole construct that enhances passive targeting. ❑ The hydrophobic component of the polymeric micelles include Polyaspartate, polylactide or polycaprolactone. ❑ Compared to surfactant micelles, polymeric micelles are generally more stable and have low critical micellar concentrations. Site Directed Drug Targeting B. Polymer-based systems 2. Polymeric micelles  Site Directed Drug Targeting B. Polymer-based systems 2. Polymeric micelles ❑ Their size is in the range of 5nm to 100nm and they have narrow particle size distribution. ❑ They have a high drug loading capacity. ❑ Various hydrophobic drugs can be incorporated in the inner core of the micelles by either chemical conjugation or physical entrapment. ❑ The addition of targeting moieties such as folate, sugar residues or proteins at the end of the block copolymers has been studied in animals to enhance receptor mediated targeting of the polymeric micelles. Site Directed Drug Targeting B. Polymer-based systems 3. Solid polymeric nanoparticles ▪ Prepared using either natural or synthetic polymers. ▪ The most commonly used are the biodegradable synthetic polymers such as poly(lactide-co-glycolide) (PLGA); polylactic acid (PLA) and polycaprolactone (PCL). ▪ Polysaccharides such as chitosan are also used. ▪ Inside the body, copolymers of polylactic and glycolic acid undergo hydrolysis into the compatible moieties glycolic acid and lactic acid which are removed from the body through the citric acid cycle. ▪ These delivery systems are used for passive targeting of drugs to tumor sites via the EPR effect. ▪ PEG-PLGA copolymers are used, as ‘stealth’ nanoparticles to prolong the circulation time of the targeted drug-delivery systems. ▪ Active targeting of the nanoparticles bearing targeting ligands has been studied. Site Directed Drug Targeting II. Colloidal /Nano-carrier systems Formulations of Some Drug-Targeting Delivery Systems 1. Polymeric micellar systems Formulations a. Paclitaxel -incorporating micelles (NK105) ❑ Contain block copolymers formed of PEG and polyaspartate. The MW of the polymer is 20kDa in total, with PEG (12kDa). WHY? ❑ Paclitaxel (PTX) is physically entrapped (23%w/w) within the core of the micelle through hydrophobic interactions with the polyaspartate. ❑ In animal studies; NK 105 showed slower clearance from the plasma with half life being approximately 5 times longer than the free drug. PTX concentration at the tumour site was increased to 2-3 fold with the use of polymeric micelles. Site Directed Drug Targeting II. Colloidal /Nano-carrier systems Formulations of Some Drug-Targeting Delivery Systems 1. Polymeric micellar systems formulations (continued) b. Cisplatin-incorporating micelles (NC-6004) ❑ Cisplatin is an anticancer drug having major side effects including nephrotoxicity and neurotoxicity. ❑ NC-6004 is formulated with PEG-poly(sodium-L-glutamate) block copolymer. The PEG forms the outer hydrophilic shell. ❑ The hydrophobic core of the micelle contains cisplatin complexed with the PGA component of the copolymer. ❑ The overall MW of the copolymer is 18kDa with 12kDa PEG contribution. They have a size of 30nm. ❑ The polymer micelle formulation improved the circulation time and enhanced the tumour targeting of the drug, thereby reduced the side effects. Active or passive targeting? Site Directed Drug Targeting Carriers for drug targeting I. Water soluble macromolecular carrier systems √ II. Colloidal /Nano-carrier systems A. Lipid-based systems.e.g. liposomes, solid-lipid nanoparticles, nonoemulsions and others.√ B.Polymer-based systems. e.g. dendrimers, polymeric micelles, and others. √ C. Stimuli-responsive systems (smart delivery systems). 17 Site Directed Drug Targeting Colloidal /Nano-carrier systems C. Stimuli–responsive nano-carrier systems (Smart DDS) ❑ Ideal drug delivery systems in general and targeted delivery systems in particular should be able to release the required amount of the drug at the target site. ❑ To ensure drug release at the targeted cells, tissues or organs, efficient drug release strategies are needed, such as on-demand processes (also termed switch on/off) which provide tailored release profiles. ❑ On-demand drug-delivery is becoming possible through the design of stimuli-responsive systems. Site Directed Drug Targeting II. Colloidal /Nano-carrier systems C. Stimuli –responsive nano-carrier systems (Smart DDS) The carrier systems release the drug content in response to either an internal stimulus (pH, enzymes, temperature etc..) or an external stimulus (temperature change, magnetic field, ultrasound and electric field) 1. External stimuli 2. Internal stimuli Site Directed Drug Targeting 1. External stimuli-responsive systems a. Thermoresponsive systems. ❑ Governed by a great change in the properties of at least one component of the nanocarrier material with temperature. ❑ Such a change triggers the release of the drug following a variation in the surrounding temperature. ❑ Ideally, thermosensitive nanocarriers should retain their load at body temperature (~37 °C), and rapidly release the drug within a locally heated target site (~40–42 °C). ❑ These systems mainly include liposomes, polymer micelles or nanoparticles  Doxorubicin-loaded thermoresponsive liposomes Leucine zipper peptide Leucine zipper peptide (folded conformation) (unfolded conformation T= 43 C The temperature-triggered unfolding of a leucine zipper peptide inserted in the membrane of a doxorubicin (Dox)-carrying liposome opens a channel through which the drug is released © 2013 Macmillan Publishers Limited. All rights reserved Site Directed Drug Targeting 1. External stimuli-responsive systems (continued) b. Magnetically responsive systems The use of external magnetic field may provide the following responses: ❑A magnetic guidance and drug release under a permanent magnetic field, ❑A temperature increase when an alternating magnetic field is applied, The possibility of performing magnetic resonance imaging developed the so-called theranostic approach in which diagnostics and therapy are associated within a single system. Site Directed Drug Targeting 1. Liposomes  Site Directed Drug Targeting 1. External stimuli-responsive systems (continued) b. Magnetically responsive nanosystems Examples: ❑ Core–shell nanoparticles (a magnetic core made of magnetite (Fe3O4) coated with silica or polymer), ❑Magnetoliposomes (Fe3O4 nanocrystals encapsulated in liposomes) Core-shell magnetic nanoparticle Site Directed Drug Targeting 1. External stimuli-responsive systems (continued) b. Magnetically responsive systems (continued) ❑ Magnetic guidance is typically obtained by focusing an extracorporeal magnetic field on the biological target during the IV injection of a magnetically responsive nanocarrier (core-shell nanoparticles or magnetoliposomes) ❑This concept has demonstrated great potential in experimental cancer therapy because of improved drug accumulation inside solid-tumour models. Site Directed Drug Targeting 1. External stimuli-responsive systems (continued) b. Magnetically responsive systems (continued) ❑ The use of an oscillating or alternating magnetic field (AMF), in presence of magnetic nanoparticles may generate heat in the surrounding medium; offering a selective heating of tumours (hyperthermia) and drug release. Site Directed Drug Targeting 1. External stimuli-responsive systems (continued) b. Magnetically responsive systems (continued) ❑ A permanent magnetic field can also trigger drug delivery. For example, when applied to a ferrogel composed of Pluronic- F127 micelles encapsulating super paramagnetic iron oxide nanoparticles and a hydrophobic drug, the drug is released when iron oxide nanoparticles approach each other and squeeze the Micelles. Prof. Magda EL-Massik 2019-2020 Site Directed Drug Targeting 1. External stimuli-responsive systems (continued) b. Magnetically responsive systems ❑The heat generated by an AMF triggers nanocarrier structural alteration, such as shell or bilayer porosity increase disintegration of the Fe3O4 core, or single-crystal nanoshell lattice deformation and help drug release. ❑Hyperthermia generated by the AMF combined with the magnetic nanocarriers targeting the tumor tissue may achieve a synergistic cytotoxic effect 28 Site Directed Drug Targeting C. Stimuli–responsive nano-carrier systems (Smart DDS) 2. Internal stimuli-responsive systems These delivery systems take advantages of the endogenous variations in pH, redox potential or the concentrations of enzymes. pH responsive systems There are remarkable changes of pH existing across biological systems either in physiological conditions or in pathological conditions. These pH variations were exploited to control the delivery of drugs in specific organs (such as the GIT) or intracellular compartments (such as endosomes or lysosomes), as well as to trigger the release of the Drug to certain pathological situations, such as tumor , infection or inflammation. 29 Site Directed Drug Targeting C. Stimuli–responsive nano-carrier systems (Smart DDS) 2. Internal stimuli-responsive systems pH responsive systems Organ Cell level level Pathologi cal Acidic Acidic condition Stomach Endosome s Acidosis Alkaline Lysosome Tumor Intestine Alkaline Infections Mitochondria Inflammation  Pharm D-Clinical Program Advanced Drug Delivery Systems Course END of PART ONE Thank you For your attention Prof. Magda EL-Massik, Prof. of Pharmaceutics