A Computational/Experimental Assessment of Antitumor Activity of Polymer Nanoassemblies for pH-Controlled Drug Delivery to Primary and Metastatic Tumors

作者：Curtis Louis T; Rychahou Piotr; Bae Younsoo; Frieboes Hermann B

来源：Pharmaceutical Research, 2016, 33(10): 2552-2564.

DOI：10.1007/s11095-016-1981-6

• cancer nanotherapy
• computational simulation
• mathematical modeling
• nanoparticles
• pH-controlled release
• polymer micelles

Polymer nanoassemblies (PNAs) with drug release fine-tuned to occur in acidic tumor regions (pH < 7) while sparing normal tissues (pH = 7.4) were previously shown to hold promise as nanoparticle drug carriers to effectively suppress tumor growth with reduced systemic toxicity. However, therapeutic benefits of pH-controlled drug delivery remain elusive due to complex interactions between the drug carriers, tumor cells with varying drug sensitivity, and the tumor microenvironment.
We implement a combined computational and experimental approach to evaluate the in vivo antitumor activity of acid-sensitive PNAs controlling drug release in pH 5 similar to 7.4 at different rates [PNA1 (fastest) > PNA2 > PNA3 (slowest)].
Computational simulations projecting the transport, drug release, and antitumor activity of PNAs in primary and metastatic tumor models of colorectal cancer correspond well with experimental observations in vivo. The simulations also reveal that all PNAs could reach peak drug concentrations in tumors at 11 h post injection, while PNAs with slower drug release (PNA2 and PNA3) reduced tumor size more effectively than fast drug releasing PNA1 (24.5 and 20.3 vs 7.5%, respectively, as fraction of untreated control).
A combined computational/experimental approach may help to evaluate pH-controlled drug delivery targeting aggressive tumors that have substantial acidity.

• 出版日期2016-10