Abstract
Tubulysins are naturally occurring tetrapeptides with potent antiproliferative activity against multiple cancer cell lines. However, they are also highly toxic in animal models. In order to improve the therapeutic index of this class of compounds, a nanoparticle prodrug of tubulysin A (TubA) was synthesized and evaluated in vitro and in vivo. A thiol derivative of TubA was covalently attached to a linear, beta-cyclodextrin based polymer through a disulfide linker (CDP-TubA). The polymer conjugate assembled into stable nanoparticles. Inhibition of tubulin polymerization and antiproliferative activity of the polymer conjugate were evaluated in vitro. The preclinical efficacy of CDP-TubA administered i.v. was evaluated in nude mice bearing s.c. implanted human HT29 colorectal and H460 non-small cell lung carcinoma tumors. The IC(50) of CDP-TubA (in Tub A equivalents) was 24, 5, and 10 nmol/L versus 3, 1, and 2 nmol/L for Tub A in NCI-H1299 (lung), HT-29 (colon), and A2780 (ovarian) cell lines, respectively. Tub A and the active thiol derivative were potent inhibitors of tubulin polymerization, whereas CDP-TubA showed minimal inhibition, indicating that target inhibition requires release of the peptide drug from the nanoparticles. The maximum tolerated dose of CDP-TubA was 6 mg/kg (in TubA equivalents) versus 0.05 mg/kg for TubA in nude mice. In vivo, a single treatment cycle of three weekly doses of CDP-TubA showed a potent antitumor effect and significantly prolonged survival compared with TubA alone. Cyclodextrin polymerized nanoparticles are an enabling technology for the safe and effective delivery of tubulysins for the treatment of cancer.
Highlights
Tubulysins are naturally occurring tetrapeptides with potent antiproliferative activity against multiple cancer cell lines
The use of macromolecular carriers and nanoparticles in this setting is based on their ability to positively change the pharmacokinetics and pharmacodynamics of chemotherapeutics by (a) enhancing solubility and reducing third-spacing, (b) increasing circulation half-life by avoiding first-pass kidney clearance, (c) protecting drugs from enzymatic degradation, (d) increasing drug concentration in the tumor by the enhanced permeability and retention effect, (e) controlling release kinetics to more closely match the mode of action of these drugs, and (f) overcoming multidrug www.aacrjournals.org
We have previously reported that conjugation of another cytotoxic drug, camptothecin, to a linear, h-cyclodextrin (h-CD)-based polymer (CDP) can increase the solubility and improve the biodistribution to tumor tissue compared with the parent compound administered by itself [20]
Summary
Tubulysins are naturally occurring tetrapeptides with potent antiproliferative activity against multiple cancer cell lines They are highly toxic in animal models. We have previously reported that conjugation of another cytotoxic drug, camptothecin, to a linear, h-cyclodextrin (h-CD)-based polymer (CDP) can increase the solubility and improve the biodistribution to tumor tissue compared with the parent compound administered by itself [20]. This resulted in increased efficacy and reduced toxicity compared with camptothecin and irinotecan, a small molecule analog of camptothecin [21, 22]. The CDP-camptothecin conjugate IT-101 showed excellent tolerability and promising signs of early clinical activity in heavily pretreated patients with solid tumors [23]
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