PTX-RPPR, a conjugate of paclitaxel and NRP-1 peptide inhibitor to prevent tumor growth and metastasis.

Abstract

Paclitaxel, a potent anti-tumor drug widely recognized for its therapeutic efficacy, has faced limitations in clinical application due to its poor solubility. The use of Cremophor EL (CrEL) as a cosolvent in paclitaxel injections has been associated with hypersensitivity reactions in some patients. To overcome these challenges, we have developed a novel conjugate by linking a neuropilin-1 targeting peptide, RPPR, to paclitaxel, resulting in PTX-RPPR. This innovative approach has significantly enhanced the solubility of paclitaxel, achieving a 3.8 mg/mL concentration, a remarkable 90-fold increase over the native drug. PTX-RPPR has shown potent anti-tumor activity, inhibiting tumor cell proliferation with an IC₅₀ ranging from 0.26 to 1.64 μM and effectively suppressing migration, invasion, and angiogenesis at a concentration of 75 nM. Notably, in a 4T1 mammary carcinoma model, PTX-RPPR administered at a dose of 0.7 μmol/kg exhibited tumor growth inhibition comparable to that of paclitaxel at a higher dose of 3.5 μmol/kg, with superior efficacy in preventing lung metastasis. Furthermore, PTX-RPPR effectively reduced NRP-1 expression in both tumors and lungs post-treatment. In contrast to paclitaxel formulated with CrEL, PTX-RPPR did not induce IL-6 expression, suggesting a safer profile in terms of immunological response. Characterized by a particle size of 200 nm and a zeta potential of +30 mV, the nano-formulation of PTX-RPPR demonstrated remarkable stability over seven days. This study introduced PTX-RPPR as a promising peptide-drug conjugate that addresses the solubility and hypersensitivity issues associated with paclitaxel, offering a safer therapeutic strategy for cancer treatment.