Preclinical Efficacy of the Camptothecin-Polymer Conjugate IT-101 in Multiple Cancer Models

Abstract

Preclinical efficacy of i.v. IT-101, a nanoparticulate conjugate of 20(S)-camptothecin and a cyclodextrin-based polymer, was investigated in several mouse xenografts.The effects of different multiple dosing schedules on tumor growth of LS174Tcolon carcinoma xenografts are elucidated. All multiple dosing schedules administered over15 to19 days resulted in enhanced efficacy compared with untreated or single-dose groups. Further improvements in antitumor efficacy were not observed when the dosing frequency was increased from three weekly doses to five doses at 4-day intervals or 5 days of daily dosing followed by 2 days without dosing repeated in three cycles using similar cumulative doses. This observation was attributed to the extended release characteristics of camptothecin from the polymer. Antitumor efficacy was further evaluated in mice bearing six different s.c. xenografts (LS174T and HT29 colorectal cancer, H1299 nonŝ mall-cell lung cancer, H69 small-cell lung cancer, Panc-1pancreatic cancer, and MDA-MB-231 breast cancer) and one disseminated xenograft (TC71-luc Ewing's sarcoma). In all cases, a single treatment cycle of three weekly doses of IT-101resulted in a significant antitumor effect. Complete tumor regression was observed in all animals bearing H1299 tumors and in the majority of animals with disseminated Ewing's sarcoma tumors. Importantly, IT-101is effective in a number of tumors that are resistant to treatment with irinotecan (MDA-MB-231, Panc-1, and HT29), consistent with the hypothesis that polymeric drug conjugates may be able to overcome certain kinds of multidrug resistance. Taken together, these results indicate that IT-101 has good tolerability and antitumor activity against a wide range of tumors.

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle

“…The synthesis and properties of preclinical nanoparticles of CRLX101 have been described previously (12)(13)(14)(15)(16)(17)(18). The nanoparticles were 20 to 30 nm in diameter, and characterization studies demonstrated that all the polymer chains were contained within the nanoparticles (i.e., no free polymer chains) (13).…”

“…CRLX101 slowly releases the CPT when inside cells to allow for long tumor exposures of the drug, and has been observed to do so over several days in mouse xenografts (16). Released, active CPT from CRLX101 has resulted in indications of prolonged topoisomerase I and HIF-1α inhibition (targets of CPT) in mouse xenografts (15,16), and has provided increased antitumor activity compared with irinotecan and topotecan (both are Food and Drug Administration-approved analogues of CPT) (12,(15)(16)(17). The CRLX101 nanoparticle is designed to disassemble when the CPT is released to give individual polymer strands that are synthesized to have molecular weights sufficiently small to allow for clearance via the kidney (Fig.…”

Chapter 8. Polymeric Nanoparticles and Cancer: Lessons Learnt from CRLX101

“…Three out of the seven models tested were resistant to CPT-11, and striking efficacy of CRLX101 was still observed in these models, demonstrating that CRLX101 can work even in resistant models. 137 In a pharmacokinetic and biodistribution study performed by the same group, intravenous administration of CRLX101 in rats and tumour-bearing mice resulted in prolonged plasma half-life and enhanced distribution to tumour tissue when compared to CPT alone. Moreover, the tumour concentration of active CPT was 160-fold higher after administration of polymer-bound CPT compared to the administration CPT alone.…”

Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration

“…41 ALN is an aminobisphosphonate used for the treatment of osteoporosis and bone metastases, as well as for bone targeting. This conjugate was demonstrated to have a great binding affinity to the bone mineral HAp in vitro, and an IC (50) comparable to that of the combination of free drugs in the cells of human adenocarcinoma of the prostate (PC3). 41 In addition, PTX-PEG-ALN could be solubilized directly in physiological solutions without the need for Cremophor ® EL.…”