Light-Guiding Polymer Drug-Delivery System

Andrew Isherwood, Brian Lawrey, Phil Szymanski, Eugenia Volkova

Evaluation of Properties: Index of Refraction

● No function to calculate index of refraction for a polymer a

priori1,2

● •Monomer units with high indices of refractiono •Carboxymethylated Chitosan ~1.332

o •Poly(n-isopropyl acylamide) ~1.5523

1.Alan R. Katritzky. "ChemInform Abstract: Correlation and Prediction of the Refractive Indices of Polymers by QSPR." ChemInform

2.R.K. Shukla "Density, Refractive Index and Molar Refractivity of Binary Liquid Mixture at 293.15, 298.15, 303.15, 308.15 and 313.15K." Arabian Journal of Chemistry3.M. Reufer "Temperature-sensitive Poly(N-Isopropyl-Acrylamide) Microgel Particles: A Light Scattering Study." The European Physical Journal E

Evaluation of optical properties: Water

•Approximation from volume fractions1

•Water: n=1.333 System: n~1.34•The system loses transparency at low swelling2

•Lower Critical Solution Temperature

1.M. Reufer "Temperature-sensitive Poly(N-Isopropyl-Acrylamide) Microgel Particles: A Light Scattering Study." The European Physical Journal E2.Li-Ming Yang. "Preparation and Characterization of N-isopropylacrylamide/carboxymethylated Chitosan Hydrogel." Journal of Shanghai University (English Edition)

Abbe’s Number

•High value desired (>40)•No correlative method available for polymer

•Able to estimate by volume fraction1

1. Eric Fest. Modeling Scatter in Composite Media.

Total Internal reflection● Total internal reflection (TIR)

o phenomenon when material has high refractive indexo Critical angle

● High water content allows for TIR

𝜽𝒄=𝐚𝐫𝐜𝐬𝐢𝐧 (𝒏𝟐/𝒏𝟏 )

𝑑=𝜆

2𝜋𝑛1√sin2𝜃− (𝑛2/𝑛1 )2

𝐸𝑧=𝐸0 exp (−𝑧 /𝑑 )

poly(N-isopropylacrylamide)

● Thermo-sensitive● Free Radical

Polymerization● LCST of 32oC● Non-biodegradable● low polymer mass per

unit volume

Chitosan

Crosslinking co-polymer

UV crosslinking

Nanoparticles for drug delivery● Most drugs limited by poor solubility, high toxicity, high dosage, non-

specific delivery, and in vivo degradation● Nanotechnology is a solution

o Nanoparticles (NPs) - metal based, magnetic, ceramic, polymeric Therapeutics Diagnostics Imaging

o Sizes range from 10-1000nm in diametero Drugs can be loaded by encapsulation, surface attachment, or

entrapment

Parveen, MS, Suphiya, Ranjita Misra, MS, and Sanjeeb K. Sahoo, PhD. "Nanoparticles: A Boon to Drug Delivery, Therapeutics, Diagnostics and Imaging." Nanomedicine: Nanotechnology, Biology and Medicine (2012): 147–166. Web. 3 Dec. 2014.

Nanomaterials

● Nanomaterials are typically divided into two distinct groups- soft and hard NMso Soft NMs are polymer and lipid based- many soft systems have

gone into clinical trials in a wide variety of medical research topics● Hard NMs include a wide range of metal and metal oxide nanoparticles,

which come with their own drawbacks for medical researcho Metal toxicity is a huge concern for biomedical application of

nanoparticleso not as widely researched as soft NMs for medical applications

Toxicity of Nanoparticles● Selection of a nanoparticle type must focus on a metal that will not

cause metal poisoningo Zn oxide has been used (sunscreen) and Ti oxide

(pharmaceutical tablets) but may present toxicity issueso Two nanoparticles types were found that have been used in

biomedical research- iron oxide and gold

Gold Nanoparticles● Gold nanoparticles have been studied for a wide range of

applicationso Diagnostic uses-o Therapeutic uses- targeting of tumors with deactivating agents

● Focus will be on a therapeutic use

Photothermal Activation - Au ● Gold-silica nanoshells were used in a hydrogel

o these nanoparticles have a “tunable plasmon resonance”o resonance is based on shell thickness and core size

● Exposition to wavelengths of light that match the resonance causes electron band oscillation, which in turn releases heato These wavelengths are far above those that the body’s cells can

absorb, so they can pass through biological tissue without incident● The hydrogel used collapsed at a temp range of 37-45 degrees Celsius

o This range is important, as its proximity to body temperature makes it an ideal choice for biological uses

● The heat released by the gold nanoparticles causes the hydrogel to collapse, resulting in a release of the nanoparticles

Gold Nanoparticle Vesicles● Gold nanoparticles coated with semi-fluorinated ligands self assemble into

vesicles in THFo Sub-100 nm diameter

● Cross-linked with dithiol-PEGo More robusto Showed twice the level of cellular uptake compared to dispersed

AuNPs● Encapsulated molecules released much more rapidly upon laser irradiation

than upon solvent heatingo Maintain vesicular structure after irradiation o 532 nm laser

Niikura, Kenichi, Naoki Iyo, Yasutaka Matsuo, Hideyuki Mitomo, and Kuniharu Ijiro. "Sub-100 Nm Gold Nanoparticle Vesicles as a Drug Delivery Carrier Enabling Rapid Drug Release upon Light Irradiation." ACS Applied Materials & Interfaces (2013): 3900-907. Web. 15 Dec. 2014. <www.acsami.org>.

Iron Oxide● he highly paramagnetic nature of iron oxide nanoparticles offers

some very useful possibilities for targeted drug delivery● Co and Ni have similar magnetic properties, but iron oxides do not

present the same toxicity issues● Maghnetite and Maghemite are the most biocompatible- potentially

nontoxic

Magnetic NPs● Magnetic fluids - stable colloidal suspensions of magnetic NPs in organic

or inorganic liquid carriers o Ability to target specific site using locally applied magnetic field

● Two types of iron oxide - magnetite and maghemiteo Both magnetize strongly under external field, but retain no permanent

magnetismo Magnetite is biocompatible

● Precoating with natural polymers makes them biostable, biodegradable and nontoxic

● Can be made hollow or solid - hollow have higher drug loading potential

Xing, Ruijun, Ashwinkumar A. Bhirde, Shouju Wang, Xiaolian Sun, Gang Liu, Yanglong Hou, and Xiaoyuan Chen. "Hollow Iron Oxide Nanoparticles as Multidrug Resistant Drug Delivery and Imaging Vehicles." Nano Research (2013): 1-9. Web. 3 Dec. 2014.

Magnetic Nanoparticle Hydro Gel

● MagNaGelTM

● Maghemite Particles

Polymeric Micelles● Block copolymers consisting of hydrophilic and hydrophobic

monomer units● Increase water solubility of poorly soluble drugs● Improve drug bioavailability by enhancing permeability across

physiological boundarieso EPR - enhanced permeability and retention effect

● High drug-loading capacity● Controlled release profile for incorporated drug● Can be made target specific by chemical attachment of targeting

moiety● Effectively used with diazepam, indomethacin, adriamycin,

anthracycline antibiotics

Final Project ConsensusMaterial: Poly(N-isopropylacrylamide)Crosslinker: ChitosanMeans of polymerization: UV-CrosslinkingNanoparticle: Gold nanoparticlesDrug: ?Disease:CancerMeans by which nanoparticle and drug are linked: Encapsulation

Materials

Material Amount Cost

Poly(N-isopropylacrylamide) MW 20,000 - 40,000 10g $240

Chitosan 50g $50

Optical fiber 1 Borrow

Total $290

Testing Goals● Synthesize and crosslink our hydrogel● Measure the optical properties (Abbe’s number, refractivity) of both

the polymeric materials● Synthesize and crosslink the nanoparticles● Test nanoparticle loading ● Develop diffusion model from nanoparticles● Test various optical fibers over temperature ranges

Required Measurements● Rainometer: elastic moduli of materials● Refractometer: refractive index, abbe number● Mass measurements: density, degree of swelling● Flourescence detection: light exiting polymer● Thermogravimetric analysis: LCST temperature, particle loading● Differential Scanning Calorimetry: melting temp, heat capacity● Spectrophotometer: particle size● Differential light scattering: particle size