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Targeted delivery of oligomannose-coated liposome to the omental micrometastasis by peritoneal macrophages from patients with gastric cancer.
Cancer Sci. 2010 Jul;101(7):1670-7
Authors: Matsui M, Shimizu Y, Kodera Y, Kondo E, Ikehara Y, Nakanishi H
We recently developed a novel drug delivery system (DDS) using oligomannose-coated liposomes (OMLs), which are effectively taken up by mouse peritoneal macrophages to carry anticancer drugs to omental milky spots known as initial metastatic sites in the peritoneal cavity in mice. However, the feasibility of the clinical application of this DDS to gastric cancer patients remains essentially unknown. In the present study, we investigated whether human peripheral blood monocytes (PBMs) and human peritoneal macrophages (PEMs) could successfully uptake OMLs and deliver them to the micrometastatic foci in the mouse omentum and resected omentum from cancer patients ex vivo. When OMLs were incubated with the PBMs from four healthy volunteers in vitro, an average 88% of CD14-positive PBMs, most of which also express CD206, took up OMLs, and this uptake was significantly inhibited by alpha-methylmannoside. In the experiment using PEMs obtained from peritoneal washes of five gastric cancer patients, the average uptake rate (63%) of OML by CD14-positive PEMs was somewhat lower than that of PBMs, but in three advanced gastric cancer patients the uptake rate of OMLs was 76% which was comparable to that of mouse PEMs. Oligomannose-coated liposome (OML)-incorporated PBMs and PEMs were successfully accumulated at the micrometastatic foci at the omentum formed after intraperitoneal injection of GFP-tagged gastric cancer cells into mice. Furthermore, OML-incorporated PBMs substantially accumulated to tumor foci in the surgically resected human omentum ex vivo. These results suggest that OMLs using human monocytes/macrophages as a cellular vehicle have the potential to target peritoneal micrometastasis in the omentum of gastric cancer patients.
PMID: 20507320 [PubMed - in process]
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Multi-functional nanoparticles delivering siRNA and doxorubicin overcome drug resistance in cancer.
J Biol Chem. 2010 May 11;
Authors: Chen Y, Bathula SR, Li J, Huang L
Drug resistance is a major challenge to the effective treatment of cancer. We have developed two nanoparticle formulations cationic liposome polycation DNA (LPD) and anionic liposome polycation DNA (LPD II) for systemic codelivery of doxorubicin (Dox) and a therapeutic siRNA to multiple drug resistance (MDR) tumors. In this study, we have provided four strategies to overcome drug resistance. First, we formed the LPD nanoparticles with a guanidinium containing cationic lipid, i.e. DSAA which can induce reactive oxygen species (ROS), down regulate MDR transporter expression and increase Dox uptake. Second, to block angiogenesis and increase drug penetration, we have further formulated LPD nanoparticles to co deliver vascular endothelial growth factor (VEGF) siRNA and Dox. An enhanced Dox uptake and therapeutic effect were observed when combined with VEGF siRNA in the nanoparticles. Third, to avoid Pgp mediated drug efflux, we further designed another delivery vehicle, LPD II, which showed much higher entrapment efficiency of Dox than LPD. Finally, we delivered a therapeutic siRNA to inhibit MDR transporter. We demonstrated the first evidence of c Myc siRNA delivered by the LPD II nanoparticles down-regulating MDR expression and increasing Dox uptake in vivo. Three daily intravenous injections of therapeutic siRNA and Dox (1.2 mg/kg) coformulated in either LPD or LPD II nanoparticles showed a significant improvement in tumor growth inhibition. This study highlights a potential clinical use for the multifunctional nanoparticles with an effective delivery property and a function to overcome drug resistance in cancer. The activity and the toxicity of LPD and LPD II mediated therapy are compared.
PMID: 20460382 [PubMed - as supplied by publisher]
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Vascular targeting by EndoTAG-1 enhances therapeutic efficacy of conventional chemotherapy in lung and pancreatic cancer.
Int J Cancer. 2010 Mar 1;126(5):1235-45
Authors: Eichhorn ME, Ischenko I, Luedemann S, Strieth S, Papyan A, Werner A, Bohnenkamp H, Guenzi E, Preissler G, Michaelis U, Jauch KW, Bruns CJ, Dellian M
Cationic lipid complexed paclitaxel (EndoTAG-1) is a novel vascular targeting agent for the treatment of cancer. Here, the aim was to investigate intratumoral drug distribution after EndoTAG-1 therapy and analyze the impact of EndoTAG-1 scheduling on antitumoral efficacy. The therapeutic effect of EndoTAG-1 in combination with conventional gemcitabine or cisplatin therapy was evaluated in L3.6pl orthotopic pancreatic cancer and a subcutaneous Lewis lung (LLC-1) carcinoma model. Oregon Green paclitaxel encapsulated in cationic liposomes in combination with intravital fluorescence microscopy clearly exhibited delivery of the drug by EndoTAG-1 to the tumor endothelium, whereas Oregon Green paclitaxel dissolved in cremophor displayed an interstitial distribution pattern. The therapeutic efficacy of EndoTAG-1 was critically dependent on the application schedule with best therapeutic results using a metronomic rather than a maximum tolerated dose application sequence. The combination of EndoTAG-1 therapy and cytotoxic chemotherapy significantly enhanced antitumoral efficacy in both tumor models. Interestingly, only EndoTAG-1 in combination with gemcitabine was able to inhibit the incidence of metastasis in pancreatic cancer. In conclusion, vascular targeting tumor therapy by EndoTAG-1 combined with standard small molecular chemotherapy results in markedly enhanced antitumoral efficacy. Therefore, this combination represents a promising novel strategy for clinical cancer therapy.
PMID: 19697323 [PubMed - indexed for MEDLINE]
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