title: pH-triggered echogenicity and contents release from liposomes.
abstract: Liposomes are representative lipid nanoparticles widely used for delivering anticancer drugs, DNA fragments, or siRNA to cancer cells. Upon targeting, various internal and external triggers have been used to increase the rate for contents release from the liposomes. Among the internal triggers, decreased pH within the cellular lysosomes has been successfully used to enhance the rate for releasing contents. However, imparting pH sensitivity to liposomes requires the synthesis of specialized lipids with structures that are substantially modified at a reduced pH. Herein, we report an alternative strategy to render liposomes pH sensitive by encapsulating a precursor which generates gas bubbles in situ in response to acidic pH. The disturbance created by the escaping gas bubbles leads to the rapid release of the encapsulated contents from the liposomes. Atomic force microscopic studies indicate that the liposomal structure is destroyed at a reduced pH. The gas bubbles also render the liposomes echogenic, allowing ultrasound imaging. To demonstrate the applicability of this strategy, we have successfully targeted doxorubicin-encapsulated liposomes to the pancreatic ductal carcinoma cells that overexpress the folate receptor on the surface. In response to the decreased pH in the lysosomes, the encapsulated anticancer drug is efficiently released. Contents released from these liposomes are further enhanced by the application of continuous wave ultrasound (1 MHz), resulting in substantially reduced viability for the pancreatic cancer cells (14%).
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University , Fargo, North Dakota 58108, United States.
authors.forename: Rahul
authors.initials: R
authors.lastname: Nahire
authors.forename: Rayat
authors.initials: R
authors.lastname: Hossain
authors.forename: Rupa
authors.initials: R
authors.lastname: Patel
authors.forename: Shirshendu
authors.initials: S
authors.lastname: Paul
authors.forename: Varsha
authors.initials: V
authors.lastname: Meghnani
authors.forename: Avinash H
authors.initials: AH
authors.lastname: Ambre
authors.forename: Kara N
authors.initials: KN
authors.lastname: Gange
authors.forename: Kalpana S
authors.initials: KS
authors.lastname: Katti
authors.forename: Estelle
authors.initials: E
authors.lastname: Leclerc
authors.forename: D K
authors.initials: DK
authors.lastname: Srivastava
authors.forename: Kausik
authors.initials: K
authors.lastname: Sarkar
authors.forename: Sanku
authors.initials: S
authors.lastname: Mallik
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016503:Drug Delivery Systems; D058975:Folate Receptor 1 / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D018625:Microscopy, Atomic Force; D053758:Nanoparticles; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014465:Ultrasonics / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D058975:Folate Receptor 1; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: drug delivery; echogenic liposomes; pH-sensitive liposomes; pancreatic cancer; ultrasound