Photo activation of HPPH encapsulated in "Pocket" liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts. Int J Nanomedicine 2015;10:125-45
Date
01/08/2015Pubmed ID
25565809Pubmed Central ID
PMC4278788DOI
10.2147/IJN.S72143Scopus ID
2-s2.0-84919762288 (requires institutional sign-in at Scopus site) 28 CitationsAbstract
We recently reported laser-triggered release of photosensitive compounds from liposomes containing dipalmitoylphosphatidylcholine (DPPC) and 1,2 bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC(8,9)PC). We hypothesized that the permeation of photoactivated compounds occurs through domains of enhanced fluidity in the liposome membrane and have thus called them "Pocket" liposomes. In this study we have encapsulated the red light activatable anticancer photodynamic therapy drug 2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) (Ex/Em410/670 nm) together with calcein (Ex/Em490/517 nm) as a marker for drug release in Pocket liposomes. A mole ratio of 7.6:1 lipid:HPPH was found to be optimal, with >80% of HPPH being included in the liposomes. Exposure of liposomes with a cw-diode 660 nm laser (90 mW, 0-5 minutes) resulted in calcein release only when HPPH was included in the liposomes. Further analysis of the quenching ratios of liposome-entrapped calcein in the laser treated samples indicated that the laser-triggered release occurred via the graded mechanism. In vitro studies with MDA-MB-231-LM2 breast cancer cell line showed significant cell killing upon treatment of cell-liposome suspensions with the laser. To assess in vivo efficacy, we implanted MDA-MB-231-LM2 cells containing the luciferase gene along the mammary fat pads on the ribcage of mice. For biodistribution experiments, trace amounts of a near infrared lipid probe DiR (Ex/Em745/840 nm) were included in the liposomes. Liposomes were injected intravenously and laser treatments (90 mW, 0.9 cm diameter, for an exposure duration ranging from 5-8 minutes) were done 4 hours postinjection (only one tumor per mouse was treated, keeping the second flank tumor as control). Calcein release occurred as indicated by an increase in calcein fluorescence from laser treated tumors only. The animals were observed for up to 15 days postinjection and tumor volume and luciferase expression was measured. A significant decrease in luciferase expression and reduction in tumor volume was observed only in laser treated animal groups injected with liposomes containing HPPH. Histopathological examination of tumor tissues indicated tumor necrosis resulting from laser treatment of the HPPH-encapsulated liposomes that were taken up into the tumor area.
Author List
Sine J, Urban C, Thayer D, Charron H, Valim N, Tata DB, Schiff R, Blumenthal R, Joshi A, Puri AAuthor
Amit Joshi PhD Professor in the Biomedical Engineering department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Breast Neoplasms
Cell Line, Tumor
Chlorophyll
Drug Liberation
Female
Fluoresceins
Humans
Lasers
Light
Liposomes
Luminescent Measurements
Mice
Mice, Nude
Photochemotherapy
Tissue Distribution
Xenograft Model Antitumor Assays