Introduction : Membrane-type matrix metalloproteinases (MT-MMPs) are highly active in prostate tumours, but absent or inactive in normal tissues. MT-MMPs are also known to be elevated in the majority of solid human tumours and to be central to tumor invasion and angiogenesis. Our objective has been to design inactive prodrugs of paclitaxel that are converted to the active drug by selected MMPs within the prostate tumor microenvironment.
Methods and Results : We report the synthesis and biological evaluation of a new series of peptide-based conjugates of paclitaxel designed to be selectively cleaved by MT-MMPs in the tumour microenvironment. Paclitaxel is conjugated to the peptide C-terminus via a self-immolative linker, while the N-terminus is protected from non-specific exopeptidase cleavage through the use of a masking group.
The relative importance of individual amino acids within the MT-MMP peptide recognition sequence has been investigated following extensive ex vivo metabolic studies. These studies employed tissue homogenates to assess activation of prodrug conjugates in tumour (PC-3) tissues and stability in normal tissues (liver kidney lung). ICTTax5 emerged as our lead agent, demonstrating in vitro stability in normal tissue with differential release of free paclitaxel in tumour tissue.
Further in vivo murine pharmacokinetic studies monitoring paclitaxel release in liver, lung, kidney heart and plasma revealed a substantial increase in tumour exposure to paclitaxel following ICTTax5 prodrug administration (20mg/kg) compared to the molar equivalent dose of paclitaxel alone (7mg/kg). AUC (uM.h) ratios of paclitaxel released from ICTTax5 compared to paclitaxel administered alone were 16.2 for tumour and in the range of 0.05-0.99 for normal tissues. Similar highly significant changes in Cmax were demonstrated with a 10-fold (9.77) increase in tumour concentrations and a substantially decreased Cmax ratio (0.02 - 0.19) in other tissues when administered as ICTTax5.
Anti-tumour efficacy studies (PC3 xenografts) resulted in a highly significant growth delay following single dose administration of ICTTax5 [20mg/kg] with paclitaxel alone (7mg/kg; the molar equivalent dose to the paclitaxel released from ICTTax5) having no significant anti-tumour effect.
Conclusion : A series of peptide-based prodrug conjugates of paclitaxel were synthesized. ICTTax5 was identified as the lead molecule, enabling selective delivery of active paclitaxel to PC3 prostate tumours resulting in superior pharmacokinetics and efficacy when compared to delivery of paclitaxel alone.
Citation Format: Paul M. Loadman, Javier Giménez-Warren, Andrew Mitchell, Amanda D. Race, Jade A. Spencer, Steve D. Shnyder, Jason H. Gill, Robert A. Falconer. Improved delivery of paclitaxel to prostate tumors: a membrane-type matrix metalloproteinase (MT-MMP)-targeted approach. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2054.