EBME 306-Sen Gupta-Polymeric Biomaterials-Lecture 6-Drug Delivery-Fall 2023.ppt

BIOMATERIALS IN DRUG DELIVERY AND NANOMEDICINE Anirban Sen Gupta, Ph.D. Department of Biomedical Engineering Case Western Reserve University PHARMACOKINETICS DRUGS WILL UNDERGO ADME: (A)Enter (ADMINISTERED or ABSORBED) the body (mouth, lings, eye, injection, skin etc) - must cross barriers to e...

BIOMATERIALS IN DRUG DELIVERY AND NANOMEDICINE Anirban Sen Gupta, Ph.D. Department of Biomedical Engineering Case Western Reserve University PHARMACOKINETICS DRUGS WILL UNDERGO ADME: (A)Enter (ADMINISTERED or ABSORBED) the body (mouth, lings, eye, injection, skin etc) - must cross barriers to entry (B)Are DISTRIBUTED in the body (by blood or local mechanisms) to reach the site of action - distribution affects concentration at site of action and also affects therapeutic action and subsequent excretion (C) Are biotransformed (METABOLIZED) via interactions with plasma proteins, enzymes etc in their mechanism of therapy action - this may increase, decrease or change drug actions (D) Are EXCRETED/ELIMINATED (by urine, stool etc) which removes them and/or their metabolites from the body PHARMACOKINETICS: quantification of these processes ROLE OF BIOMATERIALS IN DRUG DELIVERY  Control/manipulation of PHARMACOKINETICS: Body on the Drug A : Absorption (Administration) D : Distribution M : Metabolism E : Elimination  Control/manipulation of PHARMACODYNAMICS: Drug on the Body This is the actual mechanism of therapy (molecular pathways of drug action) CONTROLLED DRUG DELIVERY  Conventional delivery: Easy design/administration Repeated dosing Risk of overdose Fluctuating action  Engineered/ Controlled delivery: Complicated design/administration Single dosing Less risk of overdose Consistent action Main Types of ‘Controlled’ Delivery Delivery Paths lead to Different ADME Paths POLYMERS IN DRUG DELIVERY • • • Polymers are large chains formed from sub-units (monomers) - Natural origin e.g. alginates, cellulose, gelatin, collagen, hyaluronate etc. - synthetic e.g. PLGA, poly(HMPA), PCL, PMMA, PDMS etc. - Properties governed by chemistry (bonds and ‘mer’ arrangement) and physics (configuration, conformation, etc.) - Drug encapsulation and release functions governed by properties (Tg, Tm, crystallinity, hydrophobicity, charge, disassembly, degradation etc.) How are polymers obtained - Processing of natural sources (Full natural polymers) - Synthesis from chemical feedstocks (Full synthetic polymers) - Semi-synthetic systems via physical blending or chemical conjugation Parameters to consider - How much drug loaded or encapsulated - How much drug released and by what kinetics - Mechanism of drug release - Fate of polymer carrier in vivo TYPES OF POLYMERIC DDS • Matrix (Monolithic) devices - Drug is dispersed or distributed (solid solution) in an inert polymer - Drug released by Fickian diffusion without matrix volume change - • Can add porosity and tortuosity in the matrix Reservoir (often membrane-controlled) devices - Drug core surrounded by a static inert diffusional barrier (e.g. membrane) - Drug release is controlled by membrane properties or membrane+ core diffusion - Can add porosity and tortuosity in the matrix as well as the membrane TYPES OF POLYMERIC DDS • Devices with Physical or Chemical changes o Physically changing systems - o Stimuli-responsive hydrogels Chemically changing (degradable) systems - Surface-eroding polymers - Bulk-degrading polymers - Polymer-drug conjugates with sacrificial links NON-DEGRADABLE POLYMERS in DDS DEGRADABLE POLYMERS in DDS HYDROGEL SYSTEMS in CDD Physical Chemical Synthetic Hydrogels: Natural Hydrogels: •Collagen-GAG •Gelatin (Jell-O) •Alginate •Cellulose-based •Hyaluronic Acid-based Both Affinity-based (Physical) Loading Electrostatic Entrapment Aqueous Phase Aqueous Phase HO OH OH Dodecyl Sodium Sulfate Dodecyl Sodium Sulfate NH NH CH3 CH3 CH3 [CH2]11 OSO3 Cl Na CH3 [CH2]11 OSO3 Cl = Drug Complex Na Na Cl l-PhenylephrineHydrochloride Na Cl l-PhenylephrineHydrochloride OH HO Organic Phase NH OH CH CH [CH ] OSO Gene Delivery Polyplexes : NH 3 3 2 11 CH3 CH3 [CH2]11 OSO3 l -Phenylephrine-Dodecyl Sulfate Complex l -Phenylephrine-Dodecyl Sulfate Complex 3 Organic Phase PEI polymer Chemically-conjugated (Chemical) Loading Stimuli-responsive (Loading and Release)     Respond to the changes in the pH of surrounding medium Expand or collapse depending on the pH of the environment Due to presence of certain functional groups in the polymer chain  Acidic group (-COOH, -SO3H )  Basic group (-NH2 ) After ionization of these groups: hydrodynamic volume increase due to electrostatic repulsion poly(acrylic acid) (PAA) PDMAEMA PDEAEMA PMMA Stimuli-responsive (Loading and Release)    Respond to temperature changes A critical solution temperature (UCST and LCST)  Phase of the polymer and solution is changed Types:  Systems which shows UCST  One phase above certain temp  Phase separation below it  Systems which shows LCST  Monophasic below a specific temp  Biphasic above this temp Self-assembly Systems • • Formed via ‘selfassembly’ of lipids, blockcopolymers or lipidpolymer conjugates • Self-assembly dictated by ‘packing parameter v/al’ where ‘v’ is hydrophobic volume, ‘a’ is hydrophilic surface area and ‘l’ is hydrophobic length Drug loading by association, encapsulation or ionic transport; drug release by biodegradation or stimuli-responsive triggers (pH, temp, charge, ultrasound, light etc) Liposomes Micelles POLYMER ARCHITECTURES POLYMER CONJUGATES & POLYMER ASSEMBLIES Design Criteria in Polymer Selection for DD  It must be convenient synthesis, characterization and scale-up processes  Consistent physico-chemical and mechanical characteristics (Chemical purity, MW, Crystallinity, Tg, Tm, Td, Mechanical modulus, Hydrophobicity/philicity etc.)  Should provide convenient drug attachment/encapsulation/ entrapment avenues and controlled release mechanisms  Should be compatible with biological environment, i.e. non-toxic, noncarcinogenic, non-mutagenic, non-immunogenic.  Should be bioinert (if not degradable) or biodegradable; degradation products should be eliminated from body easily. Osmotically Controlled Drug Del Systems Engineered Delivery Devices: Hollow MicroNeedle Array Systems Balloon Angioplasty Drug Eluting Stents Angioplasty with Stenting BMS vs DES Thrombolytic Drugs Anti-proliferative Drugs Anti-inflammatory Drugs What is Nano? 1 nanometer = One-billionth of a meter!! The Nano-(time)line Nanoparticles in Medicine Quantum Dot Cyclodextrin Fullerene Single- and Multiwalled Nanotubes Liposomes Micelles Gold Nanoshell Polymer Nanospheres and Nanoshells Perfluorocarbon Nanobubble Magnetic Nanoparticles Advantages of Biomedical Nanoparticles • Due to site-specific delivery, lower dose is needed: saves money • Due to site-specific action, minimal side-effect on healthy tissue • Due to encapsulation within nanoparticles drugs stay protected in circulation • Due to intravenous delivery, administration is minimally invasive • Nanoparticles can be engineered to biodegrade naturally after action Targeting Of Nanoparticulate Drug Carriers Additional biological mechanisms may be exploited to render internalization of the particles and/or drugs within the diseased cells to enhance therapeutic effect (e.g. receptor-mediated, fusionmediated, transport channels, chargemediated etc) Leaky vasculature in the vicinity of tumor allows drug-carrying nanoparticles (50100 nm) to pass through inter-endothelial junctions (~ 200-400 nm) to accumulate as therapeutic reservoirs at the pathology site Surface Modification for ‘Stealth’ In Vivo: Long Circulating Nanoparticle Systems • Low grafting density: High grafting density: ‘mushroom’ mobility lateral pressure restricts mobility limited surface coverage entropy loss Hydration (steric) barrier defects Dehydration, micellization and membrane destabilization Optimization of polymer conformational characteristics and particle surface grafting density important Dimensional Factors in Nanoparticle Transport Tao et al. Exp Biol & Med Eng, 2011, 236: 20 Decuzzi et al. Annals Biomed Eng, 2005, 33: 179 Biophysical Design Parameters in Nanomedicine Multistage Silica NPs (Ferrari et al, Methodist Hospital, Texas) Spheroidal PLGA particles (Eniola-Adefeso et al , UMichigan) Plant Virus NPs (Steinmetz et al, CWRU) Nanochains (Karathanasis et al, CWRU) Lithographic imprinting of designer NPs (DeSimone et al, Duke) Platelet-mimetic polymeric particles (Sen Gupta et al, CWRU and Mitragotri et al, UCSB)