Oral disposition of G3.5 PAMAM dendrimer across mice intestinal epithelia and anticancer activity of its drug conjugate

G.Thiagarajan1, 3, *, A. Ray2, 3, *, L. Götz4, D. Hubbard1, 3, S. Sadekar2, 3, R. Price2, 3 and H. Ghandehari1, 2, 3
1Department of Bioengineering, 2Department of Pharmaceutics and Pharmaceutical Chemistry and 3Utah Center for Nanomedicine, Nano Institute of Utah, University of Utah, Salt Lake City, Utah, 84108, USA; 4Department of Pharmaceutics and Biopharmacy, Philipps University of Marburg, Marburg, Germany; *Authors contributed equally to the work

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Summary
Development of carrier systems to improve oral bioavailability and target specific sites remains an unmet need. The goal of this study was to evaluate the in vivo oral toxicity and bioavailability of anionic G3.5 dendrimers. In addition, a model drug, SN38 was also conjugated to this carrier to evaluate its anti-tumor activity. Dose escalation studies in CD-1 mice showed that G3.5 was well tolerated and demonstrated an oral bioavailability of about 16.9%. Subsequently, SN38 (Camptothecin analog) was covalently conjugated to these dendrimers at a relatively high drug loading (20% by weight). The conjugate also inhibited the proliferation of human colorectal cells (HCT-116) as characterized by a potent IC50 of 197.2 nM. Ongoing studies are focused on evaluating the in vivo anti-tumor efficacy of these dendrimer-drug conjugates in subcutaneous mouse tumor models.

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