Drug Amphiphiles for the Treatment of Brain Tumors - Poster
1. Drug Amphiphiles for the Treatment of Brain
Tumors
Danielle Pompa, Rami Chakroun, Ran Lin, Honggang Cui, PhD
BACKGROUND
• Gliadel® wafers are made of a biodegradable polymer, polifeprosan,
that encapsulates carmustine at a drug loading of 3.85%
• Wafers are implanted into resection cavity
• Polymer degradation releases carmustine which is an alkylating agent
that penetrates tissue and kills cells
• Alkylating agents act on DNA to prevent cell division
OBJECTIVES
Drug Amphiphile Hydrogels as Local Drug
Delivery – An Alternative to Wafers
• Could provide a greater tumor to cell surface area exposure
• Biocompatible
• Controllable drug release
• Broader and more uniform distribution and diffusion
• Can be engineered to gain desired qualities such as tumor specific
targeting
• Hydrogels encapsulating drugs have been proven to increase
survival rates of patients with breast cancer
McKenzie, M., Betts, D., Suh, A., Bui, K., Kim, L. D., & Cho, H. (2015). Hydrogel-Based Drug Delivery Systems for Poorly
Water-Soluble Drugs. Molecules, 20(11), 20397-20408.
GLIADEL® Wafer (polifeprosan 20 with carmustine implant) | How GLIADEL Wafer is Used. Retrieved from http://www.gliadel.com/about-
gliadel/how-gliadel-used/
RESULTS
• Using MALDI we confirmed the
synthesis of above molecule using
molecular weight
• We then checked the purity of our
molecule using HPLC, since there is
only one peak we can conclude that
our product was pure
CONCLUSIONS
We created an alternative to Carmustine wafers using drug amphiphile hydrogels. This could offer controllable drug release, greater
biocompatible, and targeted therapy. Hydrogels could offer greater cell surface exposure and a more broad and uniform distribution and
diffusion.
ABSTRACT
Drug Delivery
Local
pros
• Bypass blood brain barrier
• High concentration of drug
surrounding tumor cells
• Drug localized only to target
area therefore reducing drug
side effects
Cons
• Surgical procedure must be
performed
• Drug replenishment isn’t
possible (with exception of
convection enhanced delivery)
Systemic
Pros
• Can be administered
intravenously or orally; easy
administration
Cons
• Chemotherapeutic drugs spread
to healthy cells; increasing
negative side effects from drug
• Low concentrations of drug
reaches tumor cells due to blood
brain barrier
Local Delivery Technology
Drug (Paclitaxel)
Linker
Glycine is good for
spacing
Valine promotes β-
sheet formation
Arginine-Glycine-Aspartic
Acid-Arginine sequence
penetrates tumor cells
Cysteine
contains a
sulfide which
gives it the
ability to bind
to linker
• Using TEM technology we
confirmed that our
molecule formed
nanofibers at a
concentration of 4mmol
dissolved in water
• Immediately
after the
addition of PBS
our molecule
formed a
hydrogel
Fiber diameter: 6.23nm ± 0.0597
Chemdraw diameter: 6.09-6.19nm
Molecules with Drug Control Molecules
Modeling of our Molecule
• Having drug directly attached to our peptide gives a greater drug loading density
• Glycine has been shown as a good spacer to provide the bulky drug distance from periphery of peptide
• VVV sequence has been shown to promote β-sheet formation, which will lead to formation of nanofibers
• Having one negative and one positive charge promotes solubility which is necessary for biocompatibility
• RGDR sequence has been shown to penetrate cells
CURRENT MOLECULE
• After synthesizing GGVVVRDRGDR
sequence we manually attached cysteine
• We then made the drug/linker molecule
through a 2 step reaction
• We lastly connected the drug/linker
molecule with the peptide through a
disulfide bond formation reaction
• This disulfide bond will be cleaved once
integrated into cell with an intercellular
enzyme (Glutathione)
Evidence of Formation of Pure Molecule
Evidence of Formation of Nanofibers and Hydrogel
Next Steps:
Gel Release & Drug Release Studies
• We are currently studying how quickly our drug is cleaved from our peptide to determine if drug release is optimal for biological applications
• We are also studying how quickly our hydrogel degrades so we can optimize for biological application
Animal Studies
• Using the following molecules, we plan to conduct animal studies
• Two of the molecules have a drug attached, one with a fluorescents attached to it, this will be the experimental molecule
• Two of the molecules do not contain a drug, one with a fluorescents attached to it, this will be the control molecule
• We will be able to track the migration of these molecules within an animal model and determine if they prove to be advantageous in treatment of brain
tumors
• An estimated 23,770 cases of brain cancer are projected to occur in 2016
• Brain tumors are particularly difficult to treat due to the blood brain barrier
• Only allows passage of small hydrophobic uncharged particles to pass
• Most chemotherapeutic drugs don’t meet these criteria
• Our research seeks to create an alternative drug delivery system to wafer
based localized drug delivery
• We have created a hydrogel from a network of bundled drug amphiphile
nanofibers
• Within the core of these nanofibers is a FDA approved cancer drug,
Paclitaxel
Siegel, R., Miller, K., & Jemal, A. (2016). Cancer statistics, 2016. CA: A Cancer Journal for Clinicians, 66(1), 7-30.
Charged amino acids
promote solubility