An official website of the United States government
Abstract Liposomes are effective therapeutic delivery nanocarriers due to their ability to encapsulate and enhance the pharmacokinetic properties of a wide range of therapeutics. Two primary areas in which improvement is needed for liposomal drug delivery is to enhance the ability to infiltrate cells and to facilitate derivatization of the liposome surface. Herein, we report a liposome platform incorporating a cyclic disulfide lipid (CDL) for the dual purpose of enhancing cell entry and functionalizing the liposome membrane through thiol‐disulfide exchange. In order to accomplish this,CDL‐1andCDL‐2, composed of lipoic acid (LA) or asparagusic acid (AA) appended to a lipid scaffold, were designed and synthesized. A fluorescence‐based microplate immobilization assay was implemented to show that these compounds enable convenient membrane decoration through reaction with thiol‐functionalized small molecules. Additionally, fluorescence microscopy experiments indicated dramatic enhancements in cellular delivery when CDLs were incorporated within liposomes. These results demonstrate that multifunctional CDLs serve as an exciting liposome system for surface decoration and enhanced cellular delivery.
more »
« less
Sticking the Landing: Enhancing Liposomal Cell Delivery using Reversible Covalent Chemistry and Caged Targeting Groups
Abstract Liposomes are highly effective nanocarriers for encapsulating and delivering a wide range of therapeutic cargo. While advancements in liposome design have improved several pharmacological characteristics, an important area that would benefit from further progress involves cellular targeting and entry. In this concept article, we will focus on recent progress utilizing strategies including reversible covalent bonding and caging groups to activate liposomal cell entry. These approaches take advantage of advancements that have been made in complementary fields including molecular sensing and chemical biology and direct this technology toward controlling liposome cell delivery properties. The decoration of liposomes with groups including boronic acids and cyclic disulfides is presented as a means for driving delivery through reaction with functional groups on cell surfaces. Additionally, caging groups can be exploited to activate cell delivery only upon encountering a target stimulus. These approaches provide promising new avenues for controlling cell delivery in the development of next‐generation liposomal therapeutic nanocarriers.
more »
« less
- Award ID(s):
- 1807689
- PAR ID:
- 10391748
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemBioChem
- Volume:
- 24
- Issue:
- 2
- ISSN:
- 1439-4227
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Liposomes are effective therapeutic nanocarriers due to their ability to encapsulate and enhance the pharmacokinetic properties of a wide range of drugs and diagnostic agents. A primary area in which improvement is needed for liposomal drug delivery is to maximize the delivery of these nanocarriers to cells. Cell membrane glycans provide exciting targets for liposomal delivery since they are often densely clustered on cell membranes and glycan overabundance and aberrant glycosylation patterns are a common feature of diseased cells. Herein, we report a liposome platform incorporating bis‐boronic acid lipids (BBALs) to increase valency in order to achieve selective saccharide sensing and enhance cell surface recognition based on carbohydrate binding interactions. In order to vary properties, multiple BBALs (1 a–d) with variable linkers in between the binding units were designed and synthesized. Fluorescence‐based microplate screening of carbohydrate binding showed that these compounds exhibit varying binding properties depending on their structures. Additionally, fluorescence microscopy experiments indicated enhancements in cellular association when BBALs were incorporated within liposomes. These results demonstrate that multivalent BBALs serve as an exciting glycan binding liposome system for targeted delivery.more » « less
-
The wide-scale use of liposomal delivery systems is challenged by difficulties in obtaining potent liposomal suspensions. Passive and active loading strategies have been proposed to formulate drug encapsulated liposomes but are limited by low efficiencies (passive) or high drug specificities (active). Here, we present an efficient and universal loading strategy for synthesizing therapeutic liposomes. Integrating a thermal equilibration technique with our unique liposome synthesis approach, co-loaded targeting nanovesicles can be engineered in a scalable manner with potencies 200-fold higher than typical passive encapsulation techniques. We demonstrate this capability through simultaneous co-loading of hydrophilic and hydrophobic small molecules and targeted delivery of liposomal Doxorubicin to metastatic breast cancer cell line MDA-MB-231. Molecular dynamic simulations are used to explain interactions between Doxorubicin and liposome membrane during thermal equilibration. By addressing the existing challenges, we have developed an unparalleled approach that will facilitate the formulation of novel theranostic and pharmaceutical strategies.more » « less
-
Sphingomyelin is a cell membrane sphingolipid that is upregulated in synovial sarcoma (SS). Jaspine B has been shown to inhibit sphingomyelin synthase, which synthesizes sphingomyelin from ceramide, a critical signal transducer; however, jaspine B’s low bioavailability limits its application as a promising treatment option. To address this shortcoming, we used microfluidics to develop a liposomal delivery system with increased anticancer efficacy. The nano-liposome size was determined by transmission electron microscopy. The jaspine B liposome was tested for its tumor inhibitory efficacy compared to plain jaspine B in in vitro and in vivo studies. The human SS cell line was tested for cell viability using varying jaspine B concentrations. In a mouse model of SS, tumor growth suppression was evaluated during four weeks of treatment (3 times/week). The results show that jaspine B was successfully formulated in the liposomes with a size ranging from 127.5 ± 61.2 nm. The MTT assay and animal study results indicate that jaspine B liposomes dose-dependently lowers cell viability in the SS cell line and effectively suppresses tumor cell growth in the SS animal model. The novel liposome drug delivery system addresses jaspine B’s low bioavailability issues and improves its therapeutic efficacy.more » « less
-
Targeted delivery of drugs or other therapeutic agents through internal or external triggers has been used to control and accelerate the release from liposomal carriers in a number of studies, but relatively few utilize energy of therapeutic X-rays as a trigger. We have synthesized liposomes that are triggered by ionizing radiation (RTLs) to release their therapeutic payload. These liposomes are composed of natural egg phosphatidylethanolamine (PE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and 1,2-disteroyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG-2000), and the mean size of the RTL was in the range of 114 to 133 nm, as measured by nanoparticle tracking analysis (NTA). The trigger mechanism is the organic halogen, chloral hydrate, which is known to generate free protons upon exposure to ionizing radiation. Once protons are liberated, a drop in internal pH of the liposome promotes destabilization of the lipid bilayer and escape of the liposomal contents. In proof of principle studies, we assessed RTL radiation-release of fluorescent tracers upon exposure to a low pH extracellular environment or exposure to X-ray irradiation. Biodistribution imaging before and after irradiation demonstrated a preferential uptake and release of the liposomes and their cargo at the site of local tumor irradiation. Finally, a potent metabolite of the commonly used chemotherapy irinotecan, SN-38, was loaded into RTL along with near infrared (NIR) fluorescent dyes for imaging studies and measuring tumor cell cytotoxicity alone or combined with radiation exposure, in vitro and in vivo. Fully loaded RTLs were found to increase tumor cell killing with radiation in vitro and enhance tumor growth delay in vivo after three IV injections combined with three, 5 Gy local tumor radiation exposures compared to either treatment modality alone.more » « less
