Interaction of polymeric nanoparticles with a model cell membrane a langmuir film balance technique

INTERACTION OF POLYMERIC ANOPARTICLES WITH A MODEL CELL MEMBRANE – A LANGMUIR FILM BALANCE TECHNIQUE SEOW PEI HSING (B.Eng (Hons), NUS) A THESIS SUBMITTED FOR THE DEGREE OF MASTER OF ENGINEERING DEPARTMENT OF CHEMICAL & ENVIRONMENTAL ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2003 Acknowledgement The completion of this project would not have been possible without the help and support from many I would like to use this opportunity to express my heartfelt gratitude and appreciation to the following: My supervisor, A/P Feng Si-Shen, who has given me a good research topic and been very supportive Under his guidance, I have gained fruitfully both academically and in terms of character building I sincerely thank him for his nurture as well as giving me a great opportunity in undertaking research work My co-worker, Dr Mu Li, who has selflessly imparted her knowledge and expertise in various experimental works Through her teachings, I have picked up skills that a rational and independent researcher should be equipped with My fellow colleagues, Cui Weiyi, a helpful and sweet companion, whose outright, frank character greatly impresses me and whom I have spent an enjoyable time working with; as well as Ruan Gang, a brotherly figure who I often turned to for advice and with whom I have shared many intellectual and rewarding discussions Liancy, Jasmine, Weiling and Xinyi, the undergraduates whom I have worked with Their presence lightens the working atmosphere, making work in the laboratory less mundane All laboratory officers who have helped me one way or the other, either in the acquisition of chemicals, apparatus or the operation of various equipments i My fellow colleagues of various nationalities, who have given me an eyeopener on different cultures Most importantly, my family and friends, who have always been there for me, helping me through the most difficult of all times ii Table of Contents Page Acknowledgement .i Table of Contents iii Summary v List of Figures vi List of Tables .ix Notation .x Chapter : Introduction 1.1 General Background 1.2 Objectives 1.3 Thesis Organization .5 Chapter : Literature Review 2.1 Drug Delivery Systems 2.1.1 Advances in drug delivery .8 2.1.1.1 Application of delivery strategies in other fields .10 2.1.2 Economic Aspect of Drug Delivery Systems 10 2.2 Nanoparticles in drug delivery 11 2.2.1 Stages involved in the development of polymeric nanoparticles 12 2.2.2 Nanoparticles preparation methods using preformed polymers 17 2.2.3 Role of stabilizers in nanoparticle synthesis 20 2.2.3.1 Polyvinyl alcohol (PVA) 20 2.2.3.2 Vitamin E TPGS 21 2.2.3.3 Other stabilizers 22 2.2.4 Delivery routes and oral delivery of polymeric nanoparticles .23 2.2.4.1 Nanoparticles as a solution to problems in oral drug delivery 24 2.2.4.2 Sites of particle uptake .25 2.2.5 Fate of nanoparticles after entering the systemic circulation .26 2.2.5.1 Elimination from the circulation by the MPS 26 2.2.5.2 Extravasation 27 2.3 Interaction with cells – a therapeutics perspective 28 2.3.1 Drug-Membrane Interaction 28 2.3.2 Nanoparticle-membrane interaction .30 2.3.3 Techniques involved in studying molecular interactions .32 Chapter 3.1 : Materials and Methods .40 Materials .40 3.2 Methods .40 3.2.1 Particle coating .40 3.2.2 X-ray Photoelectron Spectroscopy (XPS) 41 3.2.3 Π-A isotherms and penetration 41 iii Chapter : Results and Discussions .44 4.1 Effect of Particle Size 44 4.1.1 Analysis of the Π-A isotherms of particulate monolayers 44 4.1.2 Inter-particle forces 46 4.1.2.1 Strength of the inter-particle forces 46 4.1.2.2 Nature of the inter-particle forces 48 4.1.3 Penetration Analysis 50 4.1.3.1 Penetration behaviour of 200, 500 and 800nm particles 51 4.1.3.2 Penetration of 20 and 200nm particles .54 4.1.3.3 Initial surface pressures ranging from 30 to 35mN/m .59 4.1.3.4 Initial surface pressures less than 30mN/m .61 4.2 Effect of surface coatings 65 4.2.1 XPS Analysis 65 4.2.2 Analysis of Π–A isotherms 67 4.2.3 Interaction between particles at the air-water interface 69 4.2.4 Penetration of the various particles 73 4.2.5 Relation between penetration and initial surface pressure 75 Chapter : Conclusions .79 References 82 Appendices 93 A.1 Surface pressure vs trough area isotherms 93 A.2 Curve fitting for Figure 4.8a .94 iv Summary Polymeric nanoparticles have been regarded by many as an attractive class of drug delivery system Oral administration has always been the preferred route of administration of therapeutic agents and majority of the available evidence in literature suggest that the uptake of orally administered particulates occurs predominantly in the intestinal lymphatic tissues The uptake of particulates into cells involved mainly endocytotic processes, which depend primarily on the size and surface properties of the particles The objective of this work is to investigate the influence of the physico-chemical properties of polymeric nanoparticles on their interactions with cells Emphasis is placed on the effect of particle size and surfactants on (1) inter-particle forces and (2) the interaction of the particles with a cell membrane model The study was carried out on the Langmuir film balance in order to first obtain a basic, fundamental understanding on the subject prior to further in-depth investigations It was found that strength of repulsive interparticle forces increased with particle size, and the degree of repulsion exerted by these forces varied when the particles were coated with different surfactants The biological cell membrane was modelled by a lipid monolayer spread at the airwater interface The interacting behaviour of the particles with the lipid monolayer was distinctly different for particles of different sizes, as well as those with different coatings Finally, it was observed that the different compressed states of the lipid monolayer contributed significantly to its interaction with the particles v List of Figures Page Figure 2.1 Drug Levels in blood with a) traditional dosing b) controlled-delivery dosing Figure 2.2 Surface-modified nanoparticle as targeted drug delivery system Figure 2.3 Schematic showing the difference between nanosphere and nanocapsule 11 Figure 2.4 Stages involved in the development of polymeric nanoparticles as drug delivery systems 12 Figure 2.5 Schematic showing the function of stabilizers 20 Figure 2.6 Structure of PVA 21 Figure 2.7 Structure of Vitamin E TPGS 22 Figure 2.8 Various routes of drug administration 23 Figure 2.9 Pathway of ingested food materials 24 Figure 2.10 Schematic of a cell membrane and its components 28 Figure 2.11 Schematic showing phagocytosis, pinocytosis and receptor-mediated endocytosis 32 Figure 2.12 Schematic of a Langmuir trough and typical Π-A isotherm 33 Figure 2.13 Schematic showing penetration of molecules into the lipid monolayer 34 Figure 2.14 Diagrammatic representation of DSC 36 vi Figure 2.15 Flowchart showing how FTIR works 37 Figure 2.16 Schematic showing parts of AFM 38 Figure 2.17 Working principle of SPR 39 Figure 3.1 (a) Uncoated 200nm polystyrene particles (b) PVA-coated 200nm polystyrene particles (c) TPGS-coated 200nm polystyrene particles 41 Figure 3.2 Set-up of Langmuir film balance/trough used 42 Figure 4.1 Π-A isotherms for monolayers composed of polystyrene particles of diameters 200, 500 and 800nm 45 Figure 4.2 Force vs Spacing between particle centers curves showing the force between adjacent particles a) 200nm b) 500nm and 800nm 48 Figure 4.3 α values for 200, 500 and 800nm particles calculated from their Π-A isotherms 50 Figure 4.4 Final increase in surface pressure caused by 200, 500 and 800nm particles at different injected volumes 52 Figure 4.5 Penetration profiles of 200, 500 and 800nm particles when (a) 10µl (b) 500µl of suspension is injected 53 Figure 4.6 Final increase in surface pressure caused by 20 and 200nm particles at different injected volumes 55 Figure 4.7 Penetration profile of 20nm particles at various injected volumes 56 Figure 4.8 a) Penetration profiles of 500nm particles b) Final increase in surface pressure at initial surface pressures from 30mN/m to 35mN/m 60 Figure 4.9 Π -A isotherm of DPPC at 37°C 61 vii Figure 4.10 Final increase in surface pressure at initial surface pressures from 20mN/m to 30mN/m 62 Figure 4.11 a) Penetration profiles of 500nm particles b) Final increase in surface pressure from 10mN/m to 20mN/m 64 Figure 4.12 XPS spectra of a) Uncoated PS particles, b) TPGS-coated particles and c) PVA-coated particles 66 Figure 4.13 Π-A isotherms of coated and uncoated particles of size a) 200nm, b) 500nm and c) 800nm 68 Figure 4.14 Force vs Spacing between particle centers curves for various particles of size a) 200nm, b) 500nm and c) 800nm 70 Figure 4.15 α values for coated and uncoated 500nm particles as a function of S 71 Figure 4.16 Penetration profile of the various particles at initial Π = 25mN/m 73 Figure 4.17 Final increase in surface pressure for the various particles at monolayer initial surface pressure 30-33mN/m 76 Figure 4.18 Final increase in surface pressure for the various particles at monolayer initial surface pressure 20-30mN/m 78 Figure A.1 Surface pressure vs trough area for a) uncoated particles of different sizes, b) coated and uncoated 500nm particles 93 Figure A.2 Fitted curves for data from Figure 4.8a 94 viii List of Tables Page Table 2.1 Classification of DDSs based on release mechanism and technology Table 2.2 Principle techniques for the physicochemical characterisation of nanoparticles 15 Table 2.3 Potential solutions to problems of oral delivery of poorly absorbed molecules using nanoparticles 25 Table 2.4 Events leading from Drug-Membrane Interaction 30 Table 4.1: Summary of the XPS analysis of the C1s region 67 ix Conclusions attributable to the small change in total system energy, as well as loss of materials due to rearrangement within the monolayer To study the effect of surface coatings, the particles were coated with PVA and TPGS PVA is a commonly used surfactant for synthesizing nanoparticulate drug delivery systems and recently TPGS has exhibited its potential as an effective stabilizing agent The inter-particle forces existing between the various particles were found to be repulsive and got stronger as the particle size increases regardless of the type of coating However, it was observed that the repulsion between the PVA and TPGS coated particles was weaker than that between the uncoated ones In comparison, the PVA coated particles exhibit greater interparticle repulsion than those coated with TPGS and this could be due to the larger stabilizing moiety of the PVA molecule The penetration results suggest that the lipid monolayer interacts preferentially with hydrophobic materials, hence agreeing with the notion that surface hydrophobicity is an important factor influencing cellular uptake of particulates Although there have yet been any cellular uptake publications based on TPGS 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Phagocytosis, Journal of Colloid & Interface Science, 190, pp.118-133 1997 92 Appendices Appendices A.1 Surface pressure vs trough area isotherms Surface Pressure (mN/m) 12 10 800nm 500nm 200nm 0 10 15 20 Trough Area (cm ) Surface Pressure, Π (mN/m) 12 Uncoated 10 PVA TPGS 0 20 40 60 80 100 Area, A (cm ) Figure A.1 Surface pressure vs trough area for a) uncoated particles of different sizes, b) coated and uncoated 500nm particles 93 Appendices A.2 Curve fitting for Figure 4.8a Increase in suface pressure (mN/m) 1.4 30mN/m 31mN/m 1.2 33mN/m 0.8 35mN/m 0.6 0.4 0.2 0 500 1000 1500 2000 2500 3000 3500 Time (s) Figure A.2 Fitted curves for data from Figure 4.8a Equations of various fitted curves: For data at 30mN/m, y = -2E-20x6 + 2E-16x5 - 1E-12x4 + 3E-09x3 - 3E-06x2 + 0.0022x R2 = 0.9951 For data at 31mN/m, y = 2E-21x6 + 3E-18x5 - 1E-13x4 + 7E-10x3 - 1E-06x2 + 0.0013x R2 = 0.99 For data at 33mN/m, y = -2E-20x6 + 2E-16x5 - 8E-13x4 + 2E-09x3 - 1E-06x2 + 0.0009x R2 = 0.9907 For data at 35mN/m, y = -1E-20x6 + 1E-16x5 - 6E-13x4 + 1E-09x3 - 1E-06x2 + 0.001x R2 = 0.9848 94 [...]... between the particles and the cell membrane Hence, the lipid monolayer is employed as a cell membrane model to study its interaction with polymeric nanoparticles as a means to predict the possibility of cell uptake of the particles The work is carried out using the Langmuir film balance/ trough The advantage of using this instrument is that it is simple to operate, give fast, direct and fundamental results... hydrophobic nature [3] The small size of nanoparticles greatly facilitated the transport of active agents across biological membranes, allows them to as pass through the smallest capillaries in the body that are 5-6µm in diameter, and can minimize possible carcinogenic effects and irritant reactions at the injection site as well [3,4] The use of adjuvants that can cause toxic side effects can be avoided... release mechanism and technology (Source: Reference 24) Classification Rate-preprogrammed CDDSs* Sub-classification Polymer membrane permeation Polymer matrix diffusion Microreservoir partition Physical-activated DDSs# Osmotic-pressure-activated Hydrodynamic-pressure-activated Hydration-activated Vapor-pressure-activated Mechanically activated Magnetically activated Ultrasound-activated Electrically activated... small size of nanoparticles greatly facilitated the transport of active agents across biological membranes, allows them to as pass through the smallest capillaries in the body that are 5-6µm in diameter, and can minimize possible carcinogenic effects or irritant reactions at the injection site [3,4] The use of adjuvants that can cause toxic side effects, such as Cremophor EL for the administration of. .. clinical trials and is approved by the authorities concerned (e.g U.S Food and Drug Administration), it can then be produced at a large scale and marketed as a product 2.2.2 Nanoparticles preparation methods using preformed polymers Nanoparticles can be prepared from preformed polymers and by polymerisation reactions of monomers The materials used to prepare nanoparticles can be broadly classified as... quickly and easily placing the 23 Literature Review therapeutics in contact with the relatively large surface membrane of the gastrointestinal tract, which has a rich supply of capillaries for entry into the plasma compartment [41] The pathway of the ingested therapeutics is analogous to that of food materials as shown in Figure 2.9 Figure 2.9 Pathway of ingested food materials (Source:http://www.ultranet.com/~jkimball/BiologyPages/G/ingestion)... of Paclitaxel [5], can be avoided when the drugs are encapsulated into the polymeric nanoparticles In addition, with their small size and appropriate surface modifications, nanoparticles can bypass the mononuclear phagocyte system to prolong their circulation The effectiveness of the nanoparticulate drug delivery system can only be realised if they are taken into the cells The uptake of particulates... PVA used in the synthesis of poly(DL-lactide-co-glycolide) nanoparticles can affect the productivity and physical properties of particles formed [35] Aggregation of the nanoparticles during post preparative steps such as purification and freeze-drying is avoided when PVA is used and it can also enhance particle yield in the absence of other adjuvants [30] Other advantages of using PVA include formation... formation of smaller particles with more uniform size, and easy dispersion in aqueous medium [8] The oral administration of PVA is found to be harmless and can be safely used as a coating agent for pharmaceutical and dietary products [36] Figure 2.6 Structure of PVA 2.2.3.2 Vitamin E TPGS TPGS is a water-soluble derivative vitamin E manufactured by Eastman Chemical Company It is prepared by the esterification...Notation α 2-dimensional van der Waals constant γ Surface tension of the colloidal solution ω Wetting contact angle of a particle (∆E) Penetration Energy change in the system for the penetration of particles through lipid monolayers ∆E Change in the total system energy γm Surface tension of a monolayer γw Surface tension of water A Area occupied by the particles in the monolayer A0 Co-area of a particle ... activated Magnetically activated Ultrasound-activated Electrically activated Chemically activated DDSs pH-activated Ion-activated Hydrolysis-activated Biochemically activated DDSs Enzyme-activated... matrix diffusion Microreservoir partition Physical-activated DDSs# Osmotic-pressure-activated Hydrodynamic-pressure-activated Hydration-activated Vapor-pressure-activated Mechanically activated... the administration of Paclitaxel [5], can be avoided when the drugs are encapsulated into the polymeric nanoparticles In addition, with their small size and appropriate surface modifications, nanoparticles