Design of Cancer- -Targeting Targeting Design of Cancer - - PowerPoint PPT Presentation

Design of Cancer Design of Cancer-

• Targeting

Targeting Therapeutic Micelles Therapeutic Micelles

Eneida Chesnut Eneida Chesnut

Chemical Engineering Major Chemical Engineering Major Santa Barbara City College Santa Barbara City College INSET/CNSI Program INSET/CNSI Program

Mentor: Brian Lin Mentor: Brian Lin Mentor: Brian Lin

Matt Tirrell Matt Tirrell’ ’s Research Group s Research Group

• Currently research is developing more effective ways

Currently research is developing more effective ways to deliver therapeutics to deliver therapeutics

• Molecules that are able to target tumor cells

Molecules that are able to target tumor cells

• Synthesis of peptide

Synthesis of peptide-

• amphiphiles that self

amphiphiles that self-

• assemble into micelles

assemble into micelles

• Our Approach

Our Approach

Micelles could be Micelles could be multifunctional: multifunctional: tumor cell tumor cell targeting and targeting and therapeutic therapeutic

• Chemotherapy is highly toxic

Chemotherapy is highly toxic

An Alternative Delivery System An Alternative Delivery System For Cancer Therapy For Cancer Therapy

Courtesy of Amanda Trent

• Our goal is to conjugate

Our goal is to conjugate peptides to tails in a way that peptides to tails in a way that allows the resulting molecules allows the resulting molecules to self to self-

• assemble into spherical

assemble into spherical micelles. micelles.

R.S. Tu, M. Tirrell / Advanced Drug Delivery Reviews 56 (2004) 1537–1563

Theoretical approximation to predict Theoretical approximation to predict micro and nano structures micro and nano structures

Cancer Cancer-

• targeting

targeting peptides peptides (Hydrophilic head) (Hydrophilic head) Hydrophobic Hydrophobic tail tail

Surfactant Number Theory Surfactant Number Theory

Tai l Peptide UV light DMPA (2,2-dimethoxy-2-phenyl acetophenone) Tail-head group

• 1. Conjugation of a Peptide to a Hydrophobic Tail
• 1. Conjugation of a Peptide to a Hydrophobic Tail

Thiol-ene reaction O NH CH2 C H3 NH O C H3 Cys Ala Arg Glu Lys Ala Cys Ala Arg Glu Lys Ala

• 500

• 500

Sparged Reaction

• 2. High Performance Liquid Chromatography
• 2. High Performance Liquid Chromatography

(HPLC) (HPLC)

• 500

• 500

Sealed Reaction

Increasing concentration

• f acetonitrile

Time Relative intensity

Peaks correspond to the tail-head group

Tail-head group : Tail-Cys (Gly)7 Ala Arg Glu Lys Ala

• 3. Mass Spectrometry
• 3. Mass Spectrometry
• After separating the different molecules in our solution,

After separating the different molecules in our solution, through the HPLC, we collect the ones we are interested in to through the HPLC, we collect the ones we are interested in to analyze their molecular weight. analyze their molecular weight.

• In order to do so, we use a mass spectrometer.

In order to do so, we use a mass spectrometer.

Tail-Cys Gly7 Ala Arg Glu Lys Ala Molecular Weight: 1367.78 g/mol

Our Our Next Next Step: Step: Conjugate Two Peptides to One Tail Conjugate Two Peptides to One Tail

Tail Peptide UV light

O N CH2 CH2 C H3

Tail-head group DMPA (2,2-dimethoxy-2-phenyl acetophenone)

N O C H3 Cys Ala Arg Glu Lys Ala Cys Ala Arg Glu Lys Ala Cys Ala Arg Glu Lys Ala

Acknowledgements Acknowledgements

Brian Lin, from Matt Tirrell’s Research Group

• Dr. Nick Arnold and Dr. Jens Kuhn, from the INSET

Program.

Evelyn Hu and Liu-Yen Kramer, from CNSI

• Dr. Michael Young and Dr. Alexander Horwitz, from

Santa Barbara City College

Thank you! Thank you! Any questions? Any questions?

DMPA (2,2-dimethoxy-2-phenyl acetophenone) is used as an initiator: Under presence of UV light, cysteine will react with the tail (thiol-ene reaction):

O O O CH3 CH3 S H OH NH2 O

Cysteine (Cys)

N H2 NH NH OH NH2 O

Arginine (Arg)

NH2 OH O

Glycine (Gly)

C H3 NH2 OH O

Alanine (Ala)

N H2 OH O NH2

Lysine (Lys)

O H OH O NH2 O

Glutamic acid (Glu)

Theoretical approximation Theoretical approximation to predict micro and nanostructures: to predict micro and nanostructures:

v Ns a l =

• v: volume of the tail group

v: volume of the tail group a: head group area a: head group area l: fully extended l: fully extended hydrocarbon tail hydrocarbon tail

Surfactant Surfactant Number Number Theory Theory

R.S. Tu, M. Tirrell / Advanced Drug Delivery Reviews 56 (2004) 1537–1563