QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.107.121632v1 322/1/80    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lu, D. Articles by Au, J. L.-S. Search for Related Content PubMed PubMed Citation Articles by Lu, D. Articles by Au, J. L.-S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Cancer Cancer Chemotherapy Hazardous Substances DB DOXORUBICIN TAXOL

CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

Tumor Priming Enhances Delivery and Efficacy of Nanomedicines

Division of Pharmaceutics, College of Pharmacy (D.L., M.G.W., J.L.-S.A.), James Cancer Hospital and Solove Research Institute (M.G.W., J.A.), Ohio State University, Columbus, Ohio; and Optimum Therapeutics, LLC, Columbus, Ohio (D.L., Z.L.)

We have shown that high epithelial cell density is a major barrier to the distribution of protein-bound drugs in solid tumors, and tumor priming (expansion of interstitial space using an apoptosis-inducing pretreatment) can promote drug delivery. This study evaluated the optimal conditions of paclitaxel tumor priming (time window, particle size) and its effects on the delivery and efficacy of nanomedicines. Paclitaxel tumor priming was applied to mice bearing human xenograft tumors. The kinetics of paclitaxel-induced apoptosis was evaluated to identify the time window of tumor priming. The effects of tumor priming on the tumor delivery and interstitial dispersion of fluorescence-labeled nanoparticles of various sizes, the perfusion of tumor and normal tissues, the delivery of doxorubicin HCl liposomes to tumor and host tissues, and the antitumor activity and host toxicity were studied. Tumor priming by a single i.v. injection of paclitaxel induced apoptosis, expanded the interstitial space, vessel diameter and blood-perfused area, and promoted the delivery and interstitial dispersion of nanoparticles (100- and 200-nm diameter, administered 48 h after paclitaxel) in a tumor-selective manner. Tumor priming also enhanced the tumor delivery and antitumor activity of doxorubicin HCl liposomes (85 nm) without affecting the delivery to noncancerous host tissues or enhancing host toxicity. Tumor priming represents a potentially useful means to promote tumor-selective delivery and efficacy of nanomedicines. The current study will have significant impact on enhancing delivery and efficacy of nanomedicines and dosing regimen optimization of combination chemotherapy in the clinical setting.

Address correspondence to: Jessie L.-S. Au, 506 Riffe Building, 500 West 12th Avenue, Columbus, OH 43210. E-mail: Au.1{at}osu.edu