Synthesis of paclitaxel-loaded polycarbonate nanoparticles
and hydrogels for improving oral bioavailability.
of 1


Published on: Mar 4, 2016

Transcripts - Polycarbonate_2013

  • 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.

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