A thermally responsive biopolymer conjugated to an acid-sensitive derivative of paclitaxel stabilizes microtubules, arrests cell cycle, and induces apoptosis

Abstract

Poor aqueous solubility limits the therapeutic index of paclitaxel as an anti-cancer drug. Synthesis of soluble prodrugs of paclitaxel, or conjugation of the drug to macromolecular carriers have been reported to increase its water-solubility. Macromolecular drug carriers have an added advantage of targeting the drug to the tumor site due to the abnormal tumor blood and lymphatic vasculature. This study describes a thermally responsive macromolecular carrier, elastin-like polypeptide (ELP) for the delivery of paclitaxel. Paclitaxel was bound to ELP by conjugation with the 6-maleimidocaproyl hydrazone derivative of paclitaxel, an acid-sensitive paclitaxel prodrug, for the potential treatment of breast cancer. Focused hyperthermia above a specific transition temperature at the site of a tumor causes ELP to aggregate and accumulate, thereby increasing the local concentration of the drug cargo. The paclitaxel prodrug described here bears an acid-sensitive linker that is cleavable at the lysosomal/endosomal pH, which allows a controlled intracellular release of the drug. The ELP-delivered paclitaxel in the presence of hyperthermia inhibits MCF-7 cell proliferation by stabilizing the microtubule structures, arresting the cells at the G2/M stage, and inducing apoptosis in a manner similar to conventional paclitaxel. It also inhibits proliferation of a paclitaxel resistant MCF-7 cell line. These data provide an in vitro proof of concept for the use of ELP as a delivery vehicle of paclitaxel.

Lx2-32c, a Novel Taxane Derivative, Exerts Anti-resistance Activity by Initiating Intrinsic Apoptosis Pathway <i>in Vitro</i> and Inhibits the Growth of Resistant Tumor <i>in Vivo</i>

“…Similar results have been detected by others. 21,22) In general, Lx2-32c enhanced microtubule polymerization and induced the bundling of microtubule as well as multinucleation in resistant cells with the pattern similar to that of paclitaxel in sensitive cells.…”

Cell-penetrating peptides: strategies for anticancer treatment

“…Cargos can be conjugated to a CPP by noncleavable linkers, such as maleimide or a sulfanyl bond. For example, doxorubicin (Dox) and paclitaxel have been derivatized to contain a moiety for a maleimide-thiol reaction when conjugated to a CPP-containing carrier [39]. The conjugating ratio between the two entities (CPP and drugs) is approximately 50%, as confirmed by mass spectrometry [40].…”

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

“…Elastin‐like polypeptide (ELP) is composed of a repeating 5 amino acid motif that is thermally responsive,25, 41, 42 facilitating purification of ELP and ELP‐fusion proteins by thermal cycling 43. Moreover, the genetically encoded ELP is nonimmunogenic,44, 45 is well suited as a carrier to stabilize therapeutic peptides, and offers protection from clearance and/or degradation 46, 47, 48. We previously showed that ELP does not cross the placental barrier 49.…”