CRLX101
CRLX101 is a novel approach to cancer chemotherapy that is currently under investigation in human trials, and is an example of a nanomedicine.
The agent represents a nanoparticle conjugate that consists of a drug delivery molecule, namely a cyclodextrin-based polymer (CDP) and an anti-cancer compound (camptothecin). It was developed by Dr. Mark E. Davis, professor of Chemical Engineering at the California Institute of Technology, and associates at Insert Therapeutics, Inc., now Calando Pharmaceuticals, Inc., hence the original name "IT-101". Its novel delivery mode allows the agent, and thus the toxic anti-cancer component, to be preferentially accumulated in cancer tissue. In turn, toxic side effect are expected to be reduced. The technology was licensed by Calando and Caltech to Cerulean Pharma Inc., in June, 2009.
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[edit] Rationale
Camptothecin (CPT), an alkaloid extract with poor water solubility from plants such as camptotheca acuminata, exhibits anti-cancer activity possibly due, at least in part, by the inhibition of DNA topoisomerase I resulting in cell death. In CRLX101, CPT is linked covalently through a glycine link to the linear copolymer CDP, which in turn consists of alternating subunits of beta-cyclodextrin and polyethylene glycol (PEG). The CRLX101 nanoparticle is water soluble. After intravenous injection, active CPT is slowly released as the linkage is hydrolysed. The size of the nanoparticle (20-50 nm in diameter) facilitates its extravasation in the more leaky vessels of tumors via the enhanced permeability and retention effect and as a result, the anticancer drug is enhanced and retained in the tumor tissue.
[edit] Animal studies
CRLX101 (formerly IT-101) was studied in mouse xenografts using different cancer models and showed good tolerability and anti-cancer effectiveness in a variety of tumors.[1] [2] [3] A pharmacokinetic and biodistribution study in rats and tumor-bearing mice demonstrated that ntravenous administration of IT-101 gave prolonged plasma half-life and enhanced distribution to tumor tissue when compared to camptothecin alone. The data also show that active camptothecin is released from the conjugate within the tumor for an extended period of time. These effects likely play a significant role in the enhanced antitumor activity of IT-101 when compared to CPT alone or irinotecan.[4] In addition, multiorgan pharmacokinetics and accumulation in tumor tissue of IT-101 was investigated by using PET. The calculated tumor vascular permeability indicates that the majority of nanoparticles stay intact in circulation and do not disassemble into individual polymer strands. A key assumption to modeling the tumor dynamics is that there is a "sink" for the nanoparticles within the tumor. Histological measurements using confocal microscopy show that IT-101 localizes within tumor cells and provides the sink in the tumor for the nanoparticles. [5]
[edit] CRLX101 Clinical Trials
The Phase 1 clinical trial was conducted at the City of Hope National Medical Center, the Translational Genomics Research Institute and San Juan Oncology Associates[6]. Patients who were entered had refractory and resistant solid tumor cancer of various types, including pancreatic cancer, ovarian cancer and non small cell lung cancer. A total of 60 evaluable patients were enrolled, and enrollment completed in January 2011. Treatment consists of two injections per month. A randomized Phase 2 trial has begun in non-small cell lung cancer in Russia and the Ukraine[7]
[edit] Alternate Drug Name
CRLX101 was originally named "IT-101" and was changed to CRLX101 after licensing to Cerulean Pharma Inc. CRLX101 is the official name in clinical trials.
[edit] Media
IT-101 and Dr. Mark E. Davis were included in the PBS documentary Curious titled "Survival."
[edit] References
- ^ Schluep T, Hwang J, Cheng J, Heidel JD, Bartlett DW, Hollister B, Davis ME (2006). "Preclinical efficacy of the camptothecin-polymer conjugate IT-101 in multiple cancer models". Clin. Cancer Res. 12 (5): 1606–14. doi:10.1158/1078-0432.CCR-05-1566. PMID 16533788.
- ^ Numbenjapon T, Wang J, Colcher D, Schluep T, Davis ME, Duringer J, Kretzner L, Yen Y, Forman SJ, Raubitschek A (2009). "Preclinical results of camptothecin-polymer conjugate (IT-101) in multiple human lymphoma xenograft models". Clin. Cancer Res. 15 (13): 4365–73. doi:10.1158/1078-0432.CCR-08-2619. PMID 19549776.
- ^ Cheng J, Khin KT, Davis ME (2004). "Antitumor activity of beta-cyclodextrin polymer-camptothecin conjugates". Mol. Pharmaceutics 1 (3): 183–93. doi:10.1021/mp049966y. PMID 15981921.
- ^ Schluep T, Cheng J, Khin KT, Davis ME (2006). "Pharmacokinetics and biodistribution of the camptothecin-polymer conjugate IT-101 in rats and tumor-bearing mice". Cancer Chemother. Pharmacol. 57 (5): 654–62. doi:10.1007/s00280-005-0091-7. PMID 16133526.
- ^ Schluep T, Hwang J, Hildebrandt IJ, Czernin J, Choi CH, Alabi CA, Mack BC, Davis ME (2009). "Pharmacokinetics and tumor dynamics of the nanoparticle IT-101 from PET imaging and tumor histological measurements". Proc. Natl. Acad. Sci. USA 106 (27): 11394–9. doi:10.1073/pnas.0905487106. PMID 19564622.
- ^ Study of CRLX101 (Formerly Named IT-101) in the Treatment of Advanced Solid Tumors (clinicaltrials.gov)
- ^ A Phase 2 Study of CRLX101 in Patients With Advanced Non-Small Cell Lung Cancer (clinicaltrials.gov)
[edit] External links
- Calando Pharmaceuticals, Inc. was Insert Therapeutics, Inc.
- Cerulean Pharma Inc. CRLX101 licensee and current developer
- Q&A with Mark Davis on Thirteen
- Mark E. Davis Research Group at California Institute of Technology
