Targeted delivery of drugs using water-soluble polymeric carriers improves efficacy and reduces toxicity. However, the large size of most biopolymers necessitates administration via the parenteral route. As oral absorption remains the preferred route of administration, many pharmacologically active drugs as well as polymers have poor systemic availability when administered orally. Our preliminary data indicate that poly(amidoamine) (PAMAM) dendrimers efficiently translocate across epithelial cell monolayers and can effectively increase the transfer of small molecules. Thus, this polymeric carrier may be used to improve the oral absorption of therapeutic molecules into the systemic circulation and direct them to the target sites via the creation of a conjugate delivery system. In the current proposal we aim to evaluate the influence of structural features of PAMAM dendrimers on their transepithelial transport and capitalize on both their permeation enhancing effects to increase the oral bioavailability and their macromolecular nature to facilitate targeting of a model drug. The long-term objective of this proposal is to develop polymeric systems based on PAMAM dendrimers for targeted oral drug delivery. The central hypothesis to our proposed research is that the permeation and targeting potential of poorly absorbable drugs is enhanced by conjugation to PAMAM dendrimers. To test our hypothesis, we will study the following Specific Aims: 1) To evaluate the influence of charge and drug loading on intestinal transport and cytotoxicity of PAMAM dendrimers. 2) To evaluate the in vitro stability and in situ bioavailability of dendrimer-drug conjugates. 3) To evaluate the in vivo bioavailability, antitumor efficacy and toxicity of the conjugates in a murine model of liver metastasis of colorectal cancer. 4) To delineate the intestinal transport mechanism(s) of PAMAM dendrimers. By evaluating the influence of structural features on permeability and stability we expect to find prototype PAMAM dendrimers that can increase oral availability of SN38, exhibit minimal toxicity, and target the drug effectively to liver metastases. Delineation of the mechanism(s) of transport will aid in the rationale design of novel polymeric carriers for oral delivery. In the long term this may allow for the delivery of a variety of therapeutic molecules in a more controlled and targeted manner across the Gl tract using tailor-made PAMAM dendrimers as polymeric carriers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB007470-05
Application #
7848308
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Zullo, Steven J
Project Start
2007-08-22
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$296,344
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Jones, David E; Ghandehari, Hamidreza; Facelli, Julio C (2015) Predicting cytotoxicity of PAMAM dendrimers using molecular descriptors. Beilstein J Nanotechnol 6:1886-96
Astashkina, Anna I; Jones, Clint F; Thiagarajan, Giridhar et al. (2014) Nanoparticle toxicity assessment using an in vitro 3-D kidney organoid culture model. Biomaterials 35:6323-31
Hubbard, Dallin; Ghandehari, Hamidreza; Brayden, David J (2014) Transepithelial transport of PAMAM dendrimers across isolated rat jejunal mucosae in ussing chambers. Biomacromolecules 15:2889-95
Sadekar, S; Linares, O; Noh, Gj et al. (2013) COMPARATIVE PHARMACOKINETICS OF PAMAM-OH DENDRIMERS AND HPMA COPOLYMERS IN OVARIAN-TUMOR-BEARING MICE. Drug Deliv Transl Res 3:260-271
Thiagarajan, Giridhar; Greish, Khaled; Ghandehari, Hamidreza (2013) Charge affects the oral toxicity of poly(amidoamine) dendrimers. Eur J Pharm Biopharm 84:330-4
Thiagarajan, Giridhar; Sadekar, Shraddha; Greish, Khaled et al. (2013) Evidence of oral translocation of anionic G6.5 dendrimers in mice. Mol Pharm 10:988-98
Sadekar, S; Thiagarajan, G; Bartlett, K et al. (2013) Poly(amido amine) dendrimers as absorption enhancers for oral delivery of camptothecin. Int J Pharm 456:175-85
Sadekar, S; Ghandehari, H (2012) Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery. Adv Drug Deliv Rev 64:571-88
Larson, Nate; Ghandehari, Hamidreza (2012) Polymeric conjugates for drug delivery. Chem Mater 24:840-853
Greish, Khaled; Thiagarajan, Giridhar; Herd, Heather et al. (2012) Size and surface charge significantly influence the toxicity of silica and dendritic nanoparticles. Nanotoxicology 6:713-23

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