Intracellular targeting therapy of cisplatin‐encapsulated transferrin‐polyethylene glycol liposome on peritoneal dissemination of gastric cancer

Abstract

Peritoneal dissemination in gastric cancer is a common fatal clinical condition with few effective therapies available. We studied the therapeutic effect of a tumor-targeting drug delivery system that uses cisplatin-encapsulated and Tf-conjugated PEG liposomes (Tf-PEG liposomes) in nude mice with peritoneal dissemination of human gastric cancer cells. Small unilamellar Tf-PEG, PEG or DSPC/CH liposomes (bare liposomes) encapsulating cisplatin were prepared by reversephase evaporation followed by extrusion. Electron microscopic studies revealed that Tf-PEG liposomes were internal- Key words: liposome; targeting; transferrin; peritoneal dissemination; gastric cancerPeritoneal dissemination is the most frequent noncurative factor and the most common type of recurrence after curative surgery in patients with gastric cancer. 1 Control of this metastasis is one of the most important challenges in treating gastric cancer. There have been few reports of effective treatment for peritoneal dissemination in patients with gastric cancer. 2,3 As a clinical locoregional chemotherapy, various anticancer drugs in solution form have been administered i.p. to expose the drug directly to peritoneal tumor cells. 4 However, small water-soluble molecules, such as cisplatin or mitomycin C, are absorbed easily through the large peritoneal surface into the circulating blood. It is difficult to maintain a high drug concentration for a long time in the peritoneal cavity. 5,6 Therefore, i.p. administration of anticancer drugs in solution form does not always produce the desired effect.Liposomes, known to be drug carriers, have various advantages. 7,8 First, they encapsulate various drugs such as water-soluble, lipid-soluble or high m.w. substances and release them in a sustained manner. Second, the antigenicity and toxicity of liposomes are very low because they consist of lipid, which is a natural component of organisms. Third, the biodistribution of liposomes can be controlled by the size or lipid component. Fourth, various materials, such as antibodies or chemical compounds, can modify the surfaces of liposomes. However, the therapeutic application of liposomes has been limited by their rapid clearance from the bloodstream and by their uptake by the RES. Recent efforts have been made to reformulate the liposome composition, to reduce its affinity to the RES. Liposomes modified with amphipathic PEG are not readily taken up by macrophages in the RES and, hence, stay in the circulation for a relatively long time. 9 -14 To increase the therapeutic effect and decrease side effects, tumor-specific targeting therapy has been advocated. Intracellular targeting using iron-saturated Tf as a ligand for receptor-mediated endocytosis has attracted attention. Tf is a glycoprotein that transports ferric ions in the body and the Tf receptor is internalized into cells by endocytosis through the binding of Tf. This receptormediated endocytosis is a normal physiologic process by which iron is delivered to cells. [15][16][17] Also, the Tf receptor concen...

Cyclic RGD peptide-modified liposomal drug delivery system: enhanced cellular uptake in vitro and improved pharmacokinetics in rats

“…This is consistent with studies of RGD-SSL-DXR and SSL-DXR, as previous reported, 40 and this phenomenon is shared by other ligand-modified liposomes. 42,43 As the published studies have explained, the liver and spleen might be responsible for the rapid clearance of ligand-modified liposomes. 44 Further studies are needed to define the impact of clearance on antitumor activity in vivo in the future.…”

Cyclic RGD peptide-modified liposomal drug delivery system for targeted oral apatinib administration: enhanced cellular uptake and improved therapeutic effects

“…Furthermore, according to recent reports, when cRGD 31 and other targeted ligands (folate, transferrin, and others) 32,33 are used to modify liposomes, these are usually cleared faster than nontargeted liposomes.…”

Peritoneal cancer treatment with CYP2B1 transfected, microencapsulated cells and ifosfamide

“…4,30 We describe here the application of ifosfamide in combination with CYP2B1 expressing, microencapsulated cells as a proof of principle for the treatment of experimental peritoneal carcinomatosis. While a single dose of ifosfamide þ Capcell s t already resulted in a significant reduction in tumor mass, administration of ifosfamide þ Capcell s for a prolonged period resulted in complete tumor remission in some animals (treatment on days 2-6) and a partial response in the remainder (treatment on days [5][6][7][8][9]. No side effects of this chemotherapy could be observed.…”

“…3,4 Despite continuous efforts to develop medical and surgical treatments, options are limited and most often palliative. 5 Targeted chemotherapy is a novel approach towards treatment of intraperitoneal cancer either by improving drug delivery from the site of application into the tumor cell 6 or by switching the site of the activation of a prodrug from the liver into the abdominal cavity, thereby enhancing the locoregional antitumor effect. Furthermore, regional application and activation of a prodrug allows a reduction of dosage of the prodrug and minimizes initial systemic distribution and thus systemic side effects of the drug.…”