Nanotechnology for Therapy

BIOE298DP

Drug Delivery

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• A nanoparticle carries the pharmaceutical agent inside its core, while its shell is functionalized with a ‘binding’ agent

• Through the ‘binding’ agent, the ‘targeted’ nanoparticle recognizes the target cell. The functionalized nanoparticle shell interacts with the cell membrane

• The nanoparticle is ingested inside the cell, and interacts with the biomolecules inside the cell

• The nanoparticle particles breaks, and the pharmaceutical agent is released

Source: Comprehensive Cancer Center Ohio University

Because of their small sizes, nanoparticles are taken by cells where large particles would be excluded or cleared from the body

Revisiting the Importance of Size in Distributive Properties of Probes

A Drug Delivery NanoparticleNanoparticles for drug delivery can be metal-, polymer-, or lipid-based. Below (left) an example of the latter, containing SiRNA encapsulated, and functionalized with an specific antibody. SiRNA can control often lethal inflammatory body responses, as shown in the microscopic images below (right)

Science 2008, Vol. 316, pp 627-630

antibodylipid

SiRNA Healthy tissue Sick tissue treated with non-targeted nanoparticles

Sick tissue treated with targeted nanoparticles

Clinical Example of EPR

Doxil is a polyethylene glycol coated liposomal formulation of doxorubicin.

Marketed by Ben Venue Laboratories of J&J. Outside the US, Doxil is known as Caelyx (Janssen).

Approved by the FDA for treatment of ovarian cancer and multiple myeloma and an AIDS-related cancer.

Example of an Approved Anticancer AgentProtein-bound paclitaxel is an injectable formulation of paclitaxel, a mitotic inhibitor drug used in the treatment of breast cancer, lung cancer and pancreatic cancer.

Paclitaxel

Albumin

Targeted NanoparticleA dual Nanoparticle, the targeting ligand allow it to diagnose if a cell is healthy or sick, and bind specifically to the tumorous cell

An imaging agent can be added as well

Imagingagent

Once inside the cell, the polymeric nanoparticle degrades and the anticancer agent is set free

Annu. Rev. Biomed. Eng. 2007. Vol. 9, pp. 257–88

The pH of the pathological tissue is lower than the normal tissue, e.g. at the site of inflammation pH drops from 7.4 to pH 6.5. The same is observed in the case of infarcts.

Also, the pH is lower in the tumor mass (pH 6.5) than the surrounding tissue (pH 7.4).

The microenvironment of a tumor is acidic because insufficient oxygen in tumors leads to hypoxia and causes production of lactic acid.

The pH stimuli sensitive systems

pH Sensitive NanoCarrier As a Theranostic Platform

AuNPs for cancer imaging (A) enzyme sensitive AuNPs for NIRF imaging, (B) tumor targeting: AuNPs for NIRF/CT dual imaging, and (C) schematic illustration of PEGylated DoxAuNP@CaP for

theranosis.

Subcutaneously implanted rat prostate carcinomas seven minutes after administration of unspecific microbubbles (L) and RGD-coated microbubbles (R)

Ultrasound Mediated Therapy

Nanotubes

Source: www.nanotechweb.org

Carbon nanotubes have been found to have a very interesting property, they release heat when exposed to radio frequencies

Chemical properties of nanotubes allow them to be easily functionalized

For this studies the nanotubes were produced by the CoMoCAT procedure, and functionalized with the polymer Kentera

Source: Southwest nanotechnologies

CoMoCAT nanoparticles with grown nanotubes

Heat Release Tests

Nanotube suspensionSource:Hamamatsu Nanotechnology

Radiowaves

Cancer 2007;Vol.110, pp. 2654–2665

250mg/L50mg/L0mg/L

Suspensions of nanotubes at different concentrations were remotely irradiated with radio waves, resulting in heating correlated to the concentration of nanotubes in suspension

Cytotoxicity testsThe following human cells were grown with 24h contact with 500mg/L nanotube solutions:

Hepatocellular carcinoma Hep3B Hepatocellular carcinoma HepG2

Panc-1 pancreatic adenocarsinoma

The results shown correspond to fluorescence cytometric results, the segments represent stages of cellular growth, which appear unaltered despite the presence of the nanotubes. NO CYTOTOXICITY

Cancer 2007;Vol.110, pp. 2654–2665

Intracellular Accumulation of NanotubesDespite the lack of cytotoxicity, bright field images clearly shows the accumulation of

nanotube structure inside the cellular structure

nanotubes

nanotubes

Culture without SWCNT’s

Culture with SWCNT’s

Also, the optical response of the cultures to other imaging techniques is shown by this IR image

Cancer 2007;Vol.110, pp. 2654–2665

In Vivo cytotoxicity test

Cancer 2007;Vol.110, pp. 2654–2665

In the top panel, the photomicrograph of a hepatic tumor on a rabbit.

The black stains correspond to nanotube accumulation on the tumorous cell

The purple staining is characteristic of live tissues

In the bottom panel, the photomicrograph of the same hepatic tumor after 2 min. radio frequency waves irradiation.

The brownish color is indicative of necrosis (tissue death)

Therapy w/o Any ChemotherapeuticsNanometer-sized particles are particularly responsive to electromagnetic and acoustic excitations through a variety of phenomena (e.g. plasmon resonance) that lead to local extreme conditions (e.g. heating). The nanoparticle is able to tolerate this condition, but no so the biological material nearby

Intramuscular injections of colloidal gold, a suspension of gold nanoparticles, has been used for decades to alleviate pain linked to rheumatoid arthritis. The mechanism is still unknown

Colloidal gold

Source: www.wikipedia.com

Source: John Hopkins CenterAn infrared beam illuminates two mice specimens. The local temperature increases for the mouse that received and injection of gold nanorods.

Adv. Mater. 2009, 21, 3175–3180

Tackling Alzheimer Disease

Alzheimer and other degenerative diseases are caused my the clustering of amyloidal beta (Aβ) protein.

Gold nanoparticles can be functionalized to specifically attach to aggregates of this protein (amyloidosis)

Functionalized nanoparticle

Source: www.internetchemistry.com

Chemical structure of Aβ-protein

Source: wwwthefutureofthings.com

Alzheimer’s brain Healthy brain

Source: Berkeley Lab

Gold Nanoparticles vs. Alzheimer• The functionalized gold nanoparticles selectively attach to the aggregate of amyloidal protein. The microwaves of certain frequency are irradiated on the sample.

• Resonance with the gold nanoparticles increases the local temperature and destroy the aggregate

Nanoletters 2006, Vol. 6, pp.110-115

Before irradiation After irradiation