1. Synthesis of paclitaxel-loaded polycarbonate nanoparticles
and hydrogels for improving oral bioavailability.
Introduction
Novel Drug Delivery Vehicles
Nanosponges: Preparation, Paclitaxel Encapsulation, &
Functionalization with PepT1-targeting peptide
Acknowledgements
References
Emily Douglas, David Stevens, Eva Harth*
Department of Chemistry, Vanderbilt University, 7619 Stevenson Center, Nashville, TN 37235-1822
Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy, Nashville, TN 37204
Oral drug therapies face numerous obstacles before reaching the
systemic circulation and exerting their pharmacologic effects. Certain
drugs might survive the harsh gastrointestinal conditions; however, due to
their charge or low affinity for influx receptors in the intestine, they will not
be absorbed into the bloodstream. In order to improve the oral
bioavailability of such drugs, we investigate the potential of ‘nanosponges’
and hydrogels as delivery vehicles. We predict that these drug carriers will
shield their cargo from the drastic pH gradient in the gastrointestinal
system, slow enzymatic degradation, and enhance intestinal uptake. By
observing paclitaxel-loaded ‘nanosponges’ and hydrogels in pseudo-
gastric conditions in vitro, we can predict the stability of our drug carrier in
vivo. If successful, these vehicles could potentially serve as a novel oral
drug delivery systems.
1. Foley, D.; Pieri, M.; Pettecrew, R.; Price, R.; Miles, S.; Lam, H. K.; Bailey, P.; Meredith, D., The in vitro transport
of model thiodipeptide prodrugs designed to target the intestinal oligopeptide transporter, PepT1. Organic &
Biomolecular Chemistry 2009, 7 (18), 3652-3656.
2. Grover, G.; et. al. Biocompatible hydrogels by oxime click chemistry. Biomacromolecules, 2012, 13 (10), 3013
3017.
3. Stevens, D. M.; Tempelaar, S.; Dove, A. P.; Harth, E. Nanosponge Formation from Organocatalytically
Synthesized Poly(carbonate) Copolymers. ACS Macro Letters 2012, 1(7), 915-918.
4. Truong, V.; et. al. Preparation of in situ-forming poly(5-methyl-5-allyloxycarbonyl-1,3-dioxan-2-one)
poly(ethyleneglycol) hydrogels with tuneable swelling, mechanical strength and degradability. J. Mater. Chem.
B, 2013, 1, 221.
Harth Lab:
Principle Investigator - Eva Harth, PhD
Mentor – David Stevens, graduate
student
Vanderbilt Summer Science Academy
Lipscomb College of Pharmacy
Characteristics Nanosponge Hydrogel
Hydrolytically stable Yes Yes
Enzymatic degradation Slow Slow
Solubility (organics) Yes No
Solubility (water) Partially (PEG) No
Functionalization PepT1 targeting peptide None
[mon]:[ini
tiator]
Mn
(Predicte
d)
Mn (NMR)
(g/mol)
PDI
Allyl %
incorporated
25 4,765 6,483 1.11 19.0
50 9,530 11,242 1.10 20.1
100 19,060 20,774 1.08 19.5
Time Points
Amount
Degraded (g)
Control (3 hr) 0
30 min 0.0019
1 hr 0.0014
2 hr 0.0012
3 hr 0.0005
6 hr 0.0007
12 hr 0.0011
Variable pH
throughout
GI tract
Enzymatic
degradation
Intestinal
absorption
barriers
First pass
metabolism
Nanosponge Hydrogel
Linear polycarbonate precursor
Polycarbonate resists
significant degradation
in simulated gastric fluid
Hydrogels: Preparation & Paclitaxel
Encapsulation
1) Nanosponge Preparation
Amine/Epoxide Method:
R-OH
initiator
MEC MAC
+ +
Sn(OTf)2
700C
(bulk)
3) Nanosponge Functionalization –
Targeting PepT1 Intestinal Transporter
m-CPBA
DCM
48 hrs
20%
10%DCM
450C, 12 hrs
500 nm
TEM reveals average
diameter of 500 nm
PTX+
Water
VitE-TPGS
(DMSO)
1) Isobutyl chloroformate
N-methylmorpholine
2) AF647
DMSO
2) PTX-Encapsulation
via Nanosolubilization:
12% (w/w)
Low Polydispersity ~100mg of polycarbonate per sample
PTX
DMPA
DMSO
hv, 2 min
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10
ReleasedPTX(%)
Time (days)
PTX-Hydrogel Exhibits
Slow, Linear Release
Gels suspended in PBS buffer (pH 7.4) @ 370C
for a [PTX] of 0.15mM
Reverse phase HPLC using isocratic gradient ACN:H2O
(50:50)
Conclusions & Future Directions
We have successfully demonstrated the synthesis of two novel drug
delivery systems – nanosponges & hydrogels. In order to further test their
applicability as oral delivery vehicles, we will perform drug release studies
in pseudo-gastric conditions and analyze the intestinal uptake of our
PeptT1-targeted nanoparticles.