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Pharmacokinetics, biodistribution and intratumoral distribution of Celludo nanoparticles

University of British Columbia

Anti-tubulin agents are the most potent and broadest spectrum drugs for cancer therapy, including taxanes and vinca alkaloids. However, there are two major limitations for their clinical use: multidrug resistance (MDR), and significant side effects such as neutropenia and neuropathy. The overexpression of P-glycoprotein (Pgp) is the most commonly found mechanism for MDR in cancer. Our lab has screened several anti-tubulin agents against different MDR tumor cells. The results show that podophyllotoxin (PPT) remained highly active against the resistant cell lines with an IC50 of ~10 nM. However, PPT is insoluble and exhibits significant side effects due to poor selectivity. A nanoparticle dosage form of PPT was developed by covalently conjugating PPT and polyethylene glycol (PEG) to acetylated carboxymethyl cellulose (CMC-Ac) via ester linkages. The optimized polymer conjugates self-assembled into 20 nm particles (named Celludo) and displayed significantly improved efficacy against MDR tumors in mice compared to free PPT and the standard taxane chemotherapies. My thesis focused on developing a robust and reproducible HPLC method to measure PPT concentrations in biological samples in order to compare the pharmacokinetics (PK) and biodistribution (BD) of Celludo and free PPT. The kinetics of intratumoral distribution of the Celludo nanoparticles was also examined. Compared to free PPT, Celludo displayed extended blood circulation with 18-fold prolonged half-life, 9,000- fold higher area under the curve (AUC), and 1,000-fold reduced clearance compared to free PPT. The tumor uptake of Celludo was 500-fold higher than that of free PPT. With Celludo, the overall delivery to the tumor was 4.5-, 3.8-. 3.4-and 1.2- fold higher than that delivered to the liver, lung, heart, and spleen respectively. At 6 h, Celludo nanoparticles accumulated equally in the hypervascular and hypovascular region within the tumor. One and two days post-injection, the amount of Celludo in the hypervascular region remained the same, while the penetration to the hypovascular area increased constantly over 48 h post-injection. The data suggest that Celludo was an effective system targeting PPT to the tumor with enhanced penetration to the tumor core.

Text

2017-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/59454

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/