Abstract!Degradable 3-D polyester nanoparticles, or nanosponges, have been

receiving more attention for their potential biomedical applications. Conventional cancer treatments involve the use of drugs that are toxic to healthy cells as well as tumor cells. A more ideal form of treatment could be facilitated through the use of nanoparticles crosslinked with targeting units, such as peptides, that selectively recognize receptors on the surfaces of tumor cells. Unlike other delivery systems, nanosponges have the advantage of enabling a controlled, linear release of a large amount of drug over a defined period of time. In addition, post modification strategies can be utilized to alter several properties of nanosponges, such as hydrophobicity, morphology, particle size, and functionality. We utilized two different linear copolymers for nanoparticle formation: one is poly(valerolactone-allylvalerolactone) and the other is poly(valerolactone-allylvalerolactone–oxepanedione). These two linear polymers have different morphologies and will be investigated with future in vivo and in vitro drug release studies. In particular, temozolomide, a chemotherapeutic used to treat advanced brain tumors, was encapsulated inside these nanoparticles and the rate of drug release was measured with UV-visible spectroscopy. Furthermore, the nanoparticles have been labeled with a fluorescent dye in order to conduct biodistribution studies to determine if they are capable of crossing the blood-brain barrier.!!

Nanoparticle Formation!

Drug Encapsulation!

Synthesis and Characterization of Nanosponges for Drug Delivery and Cancer Treatment!William Kornahrens, Benjamin Spears and Eva Harth*!

Department of Chemistry, Vanderbilt University, 7210 Stevenson Center, Nashville, TN 37235-1822!

Acknowledgements!Mentor: Ben Spears!Principle Investigator: Dr. Eva Harth, Department of Chemistry!Funding: NSF DMR-1005023!

References!1.  van der Ende, A.; Kravitz, Evan J.; Harth, Eva. J. Am. Chem. Soc. 2008, 130, 8706-8713.!2.  Passarella, R. J.; Spratt, D. E.; van der Ende A. E.; Phillips J. G.; Wu, Hongmei;

Sathiyakumar, V.; Zhou, Li; Hallahan, D. E.; Harth, E.; Diaz, R. Cancer Res 2010, 70(11), 4550-9 !

Monomer Synthesis!

Synthesis of 2-oxepane-1,5-dione (OPD)!

Synthesis of α-allyl-δ-valerolactone (AVL)!

Ring-Opening Polymerization!

Synthesis and Attachment of Targeting Peptide !

Linear Polymer

Crosslinker

Dropped in H2O/Vit. E

m-CPBA oxidation

Sn(OTf)2

EtOH

Temozolomide in DMSO

DMSO, 37 °C

BuLi, DIPA

HMPA

CH2Cl2

44°C

45°C, 12 h

CH2Cl2

TFA

Cleaving cocktail

DMF, HOBt, HBTU, DIPEA

DMF, Piperidine

Conclusion!Individual monomers (AVL, VL, and OPD) were synthesized

and used to make two different copolymers. The synthesis of the polymers was optimized by using tin triflate rather than tin octanoate as a catalyst to increase reaction rate and thereby decrease PDI. Poly (VL/AVL) and poly (VL/AVL/OPD) were synthesized to determine how the presence of OPD in the nanoparticle affected hydrophobicity. The allyl functional groups were then partially oxidized to allow for a crosslinking reaction to form the nanoparticle. A peptide known to bind to cell receptors on tumor cell surfaces was synthesized and attached to the nanoparticle to allow for targeted drug delivery. Preliminary results show that drugs such as paclitaxel have a linear release profile as the nanoparticle degrades. !

y  =  1.5481x  -­‐  0.0055  R²  =  0.99185  

0  0.2  0.4  0.6  0.8  1  

1.2  1.4  1.6  1.8  

0   0.1   0.2   0.3   0.4   0.5   0.6   0.7   0.8   0.9   1  

Absorban

ce  

Concentra-on  (mg/mL)  

Calibra-on  Curve  for  Temozolomide  Concentra-on  

Drug Loading!

Drug Release!

y  =  0.3652x  +  0.2332  R²  =  0.99075  

0  

2  

4  

6  

8  

10  

0   2   4   6   8   10   12   14   16   18   20   22   24  

Total  D

rug  Re

leased

 (mg)  

Time  (days)  

Paclitaxel  Drug  Release  Study