Journal of Gastrointestinal Oncology, Vol 2, No 3, September 2011 185 Nanovector-based therapies in advanced pancreatic cancer Chang-Sung Tsai1,2, John W. Park3, Li-Tzong Chen1,2,4 1National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; 2Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; 3Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, California, USA; 4Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan ABSTRACT Systemic therapy for advanced pancreatic cancer has been largely disappointing owing to the unfavorable pharmacoki- netic profile and poor penetration of current chemotherapeutic agents ,as well as the fragile patient population with compromised tolerance to toxic chemotherapies. Nanovectors can provide passive drug delivery through abnormal tu- mor neo-vasculature microanatomy or active targeting via binding to receptors or macromolecules associated with the tumor. In such a manner, nanovector-based therapy may not only modulate the pharmacokinetics and therapeutic index of chemotherapeutic agents but also provide new treatment options in patients with advanced pancreatic cancer. In this article, we present the rationale and currently available clinical results of nanovector-based therapies to highlight the po- tential use of this class of agent in patients with advanced pancreatic cancer. KEY WORDS nanovector; pancreatic cancer; liposome; PEP02; nab-paclitaxel; EndoTAG-1; nanoplatin; platinum; CPT-11 J Gastrointest Oncol 2011; 2: 185-194. DOI: 10.3978/j.issn.2078-6891.2011.034 Introduction achieve significantly better tumor response rate, progression-free survival and overall survival than Pancreatic cancer is one of the most detrimental gemcitabine monotherapy in patients with metastatic malignancies and the fourth most common cause of pancreatic cancer in a randomization phase III trial (6,7). cancer-related death in the United Stated. There were However, the application of either doublet of triplet 43,140 newly diagnosed cases and 36,800 deaths in combination chemotherapy in patients with advanced 2010 (1). Early detection is uncommon with no more pancreatic cancer is often hindered by their toxicity and than 15–20% of the patients being amenable for curative the performance status of the patients. intent surgery at the time of diagnosis. Gemcitabine New treatment strategies are mandatory to improve either alone or in combination with erlotinib are the the therapeutic outcomes of patients with advanced only approved treatments for patients with advanced pancreatic cancer. Recently, two major potential new pancreatic cancer, of whom the overall survival time is approaches are emerging that may have the chance to generally around 6 months (2-5). Recently, Conroy et change our practice in treating advanced pancreatic al showed that a gemcitabine-free triplet chemotherapy, cancer. The first one is molecular targeted agent targeting FOLFIRINOX regimen consisting of oxaliplatin, on dysregulated signaling pathway and the second is irinotecan and infusional 5-FU/leucovorin, could the use of nanovector drug delivery system to provide ‘passive” or “active” targeting drug delivery thus to modulate the pharmacokinetics and therapeutic index of No potential conflict of interest. chemotherapeutic agents in pancreatic cancer (8). Corresponding to: John W. Park, Professor. UCSF Helen Diller Family Com- prehensive Cancer Center, 1600 Divisadero St., 2nd Fl., San Francisco, CA This review will focus on the selective nanovector 94115-1710. Tel: 415-502-3844; Fax: 415-353-9592. E-mail: [email protected]. treatments in pancreatic cancer, especially those with Li-Tzong Chen, Professor. National Institute of Cancer Research, National available clinical data, including albumin-bound Health Research Institutes, No 367, Sheng-Li Road, Tainan 70456, Taiwan. Tel: +886-6-208 3422; Fax: +886-6-208 3427. Email: [email protected]. nanoparticles, liposome-encapsulation nanoparticle, cationic liposomal nanoparticle, polymeric micellar agents, Submitted Aug 02, 2011. Accepted for publication Aug 02, 2011. and a non-replicating, retroviral vector delivered gene Available at www.thejgo.org therapy construct. ISSN: 2078-6891 © 2011 Journal of Gastrointestinal Oncology. All rights reserved. Albumin-bound Nanoparticle Paclitaxel (Nab- 186 Tsai et al. Nanovector-based therapies in pancreatic paclitaxel) used dose/schedule was 260 mg/m2, 30-min intravenous injection, every 3 weeks. Albumin is a particular vehicle for drug delivery in oncology Because SPARC is frequently overexpressed and because it is a natural carrier of hydrophobic molecules associated with poor clinical outcomes in pancreatic cancer, with reversible, noncovalent binding characteristics and Von Hoff et al conducted a phase I/II study to evaluate the able to enhance the delivery of drug into the extravascular MTD of weekly nab-paclitaxel (100 – 150 mg/m2/week) space through a process of receptor-mediated endothelial in combination with gemcitabine (1000 mg/m2/week), transcytosis. Such process is initiated by the binding of and the therapeutic efficacies of the regimen. Both agents albumin to an endothelium surface, 60-kDa glycoprotein were given on day 1, 8, and 15 every 28 days (13). A total of (gp60) receptor (albondin), which will then bind with 67 patients were treated. Despite MTD of nab-paclitaxel an intracellular protein (caveolin-1) to result in the was determined as 125 mg/m2/week, dose reduction was invagination of the endothelium membrane to form required in 30% (6/20), 18% (8/44) and 33% (1/3) of transcytotic vesicles, the caveolae (9). The caveolae will patients receiving 100 mg/m2, 125 mg/m2 and 150 mg/m2, subsequently move across the cytoplasm and release the respectively. The most common grade 3-4 toxicity at the albumin and its conjugated compound into the extracellular MTD dose were fatigue 23%, neutropenia 59% (grade 4 in space (the peritumoral microenvironment) where the 23%), thrombocytopenia 20% (grade 4 in 9%) and sensory albumin will bind to SPARC (secreted protein acid and neuropathy in 9%. Of the 58 patients whose CT image were rich in cysteine), an extracellular matrix albumin-binding revaluated with RECIST criteria by independent reviewer, glycoprotein that is structurally and functionally closely the best tumor response was partial response in 40% and related to gp60, and overexpressed in a variety of cancers, stable disease in 37%, with an overall disease control rate including breast cancer, gastric cancer and pancreatic of 78%. The median progression-free and overall survival cancer. of the intent-to-treat (N=67) patients were 6.9 months and Nab-paclitaxel (Abraxane) is a cremophor (CrEL)-free, 10.3 months, respectively; while the survival parameters for albumin-bound, nanoparticle formulation of paclitaxel. the 44 patients receiving MTD dose were 7.9 months and Its CrEL-free formulation permits nab-paclitaxel to be not yet reached, respectively. Of 54 patients with available administered within a shorter infusion period of time CA19.9 level, 42 (77.8%) patients had a more than 50% (30 minutes) and without the requirement of routine pre- reduction of CA19.9 level after the treatment (14). The medications for preventing the hypersensitivity reactions in therapeutic efficacy of nab-paclitaxel in combination with association with the administration of cremophor solvent- vandetanib, a potent inhibitor of VEGF2, RET and EGFR, based paclitaxel (10). In preclinical study, the transport of has also been evaluated in a phase I trial with expansion radiolabeled paclitaxel across the endothelial cell monolayer cohort of patients with pancreatic cancer (15). The MTD in vitro, and intratumor paclitaxel accumulation after equal of vandetanib in combination with two different schedule doses of paclitaxel in vivo were both significantly enhanced of nab-paclitaxel, either 100 mg/m2 weekly or 260 mg/ by 4.2-folds (P < 0.0001) and 33% (P < 0.0001), respectively, m2 every 3 weeks, was 300 mg daily. Of the 29 enrolled for nab-paclitaxel as compared with CrEL-paclitaxel with gemcitabine-refractory pancreatic cancer patients, the best an increase 4.2 folds. In addition, endothelial transcytosis tumor was partial response in 6 (20.7%) and stable disease was completely inhibited by inhibitor of gp60/caveolar in 10 (34.5%), and the median progression-free survival and transport, methyl ß-cyclodextrin (11). These observations overall survival were 5.3 (95% CI: 3.7 to 7.3) months and supported that gp60-mediated transcytosis and SPARC- 8.2 (95% CI: 6.2 to 11.5) months, respectively. No statistical aided sequestration may be an important biological pathway significant correlation between SNP (rs1059829 and to target tumor cells by novel albumin-bound therapeutics. rs3210714) of SPARC and clinical outcomes was observed. In a phase I trial, the maximum tolerated dose (MTD) of intravenous injection nab-paclitaxel monotherapy, Liposome-based Drugs every 3 weeks in 19 patients with standard therapy-failure solid tumors was 300 mg/m2. No acute hypersensitivity A liposome is often a spherical vesicle with a bilayer reactions were observed. The most frequent toxicities were membrane whose size typically ranges from ~40 nanometers myelo-suppression, sensory neuropathy, nausea/vomiting, to several microns. Because the micro- or nanoparticles arthralgia and alopecia (12). The drug has subsequently can form spontaneously