Systemic delivery of gemcitabine triphosphate via LCP nanoparticles for NSCLC and pancreatic cancer therapy.

Abstract

Nucleoside analogs are a significant class of anti-cancer agent. As prodrugs, they terminate the DNA synthesis upon transforming to their active triphosphate metabolites. We have encapsulated a biologically activate nucleotide analog (i.e. gemcitabine triphosphate (GTP)), instead of the nucleoside (i.e. gemcitabine) derivative, into a novel Lipid/Calcium/Phosphate nanoparticle (LCP) platform. The therapeutic efficacy of LCP-formulated GTP was evaluated in a panel of human non-small-cell lung cancer (NSCLC) and human pancreatic cancer models after systemic administrations. GTP-loaded LCPs induced cell death and arrested the cell cycle in the S phase. In vivo efficacy studies showed that intravenously injected GTP-loaded LCPs triggered effective apoptosis of tumor cells, significant reduction of tumor cell proliferation and cell cycle progression, leading to dramatic inhibition of tumor growth, with little in vivo toxicity. Broadly speaking, the current study offers preclinical proof-of-principle that many active nucleotide or phosphorylated nucleoside analogs could be encapsulated in the LCP nanoplatform and delivered systemically for a wide variety of therapeutic applications.

• Authors: Yuan Zhang, William Y Kim, Leaf Huang
• Journal: Biomaterials (Biomaterials) Vol. 34 Issue 13 Pg. 3447-58 (Apr 2013) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 23380359 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Lipids
• Phosphates
• Polyethylene Glycols
• Cytidine Triphosphate
• gemcitabine triphosphate
• Poly(ADP-ribose) Polymerases
• Caspases
• Calcium

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Calcium (chemistry)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, pathology)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cytidine Triphosphate (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology, therapeutic use)
• Enzyme Activation (drug effects)
• Female
• Humans
• Lipids (chemistry)
• Lung Neoplasms (drug therapy, enzymology, pathology)
• Mice
• Mice, Nude
• Nanoparticles (chemistry, ultrastructure)
• Pancreatic Neoplasms (drug therapy, enzymology, pathology)
• Particle Size
• Phosphates (chemistry)
• Poly(ADP-ribose) Polymerases (metabolism)
• Polyethylene Glycols (chemistry)
• S Phase (drug effects)
• Static Electricity
• Xenograft Model Antitumor Assays