Ionic liquids (ILs) have emerged as promising biomaterials for enhancing drug delivery by functionalizing polymeric nanoparticles (NPs). Despite the biocompatibility and biofunctionalization they confer upon the NPs, little is understood regarding the degree in which non‐covalent interactions, particularly hydrogen bonding and electrostatic interactions, govern IL‐NP supramolecular assembly. Herein, we use salt (0‐1 M sodium sulfate) and acid (0.25 M hydrochloric acid at pH 4.8) titrations to disrupt IL‐functionalized nanoassembly for four different polymeric platforms during synthesis. Through quantitative1H‐nuclear magnetic resonance spectroscopy and dynamic light scattering, we demonstrate that the driving force of choline trans‐2‐hexenoate (CA2HA 1:1) IL assembly varies with either hydrogen bonding or electrostatics dominating, depending on the structure of the polymeric platform. In particular, the covalently bound or branched 50:50 block co‐polymer systems (diblock PEG‐PLGA [DPP] and polycaprolactone [PCl]‐poly[amidoamine] amine‐based linear‐dendritic block co‐polymer) are predominantly affected by hydrogen bonding disruption. In contrast, a purely linear block co‐polymer system (carboxylic acid terminated poly[lactic‐co‐glycolic acid]) necessitates both electrostatics and hydrogen bonding to assemble with IL and a two‐component electrostatically bound system (electrostatic PEG‐PLGA [EPP]) favors hydrogen‐bonding with electrostatics serving as a secondary role.
- Award ID(s):
- 2011401
- NSF-PAR ID:
- 10324209
- Date Published:
- Journal Name:
- Nanoscale
- Volume:
- 14
- Issue:
- 16
- ISSN:
- 2040-3364
- Page Range / eLocation ID:
- 6021 to 6036
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
Abstract -
Abstract Poly(lactic‐co‐glycolic acid) (PLGA) is widely used as a vehicle for delivery of pharmaceutically relevant payloads. PLGA is readily fabricated as a nano‐ or microparticle (MP) matrix to load both hydrophobic and hydrophilic small molecular drugs as well as biomacromolecules such as nucleic acids and proteins. However, targeting such payloads to the cell cytosol is often limited by MP entrapment and degradation within acidic endolysosomes. Poly(propylacrylic acid) (PPAA) is a polyelectrolyte polymer with the membrane disruptive capability triggered at low pH. PPAA has been previously formulated in various carrier configurations to enable cytosolic payload delivery, but requires sophisticated carrier design. Taking advantage of PPAA functionality, we have incorporated PPAA into PLGA MPs as a simple polymer mixture to enhance cytosolic delivery of PLGA‐encapsulated payloads. Rhodamine loaded PLGA and PPAA/PLGA blend MPs were prepared by a modified nanoprecipitation method. Incorporation of PPAA into PLGA MPs had little to no effect on the size, shape, or loading efficiency, and evidenced no toxicity in Chinese hamster ovary epithelial cells. Notably, incorporation of PPAA into PLGA MPs enabled pH‐dependent membrane disruption in a hemolysis assay, and a three‐fold increased endosomal escape and cytosolic delivery in dendritic cells after 2 h of MP uptake. These results demonstrate that a simple PLGA/PPAA polymer blend is readily fabricated into composite MPs, enabling cytosolic delivery of an encapsulated payload. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1022–1033, 2018.
-
Abstract Delivering cargo to the central nervous system (CNS) remains a pharmacological challenge. For infectious diseases such as HIV, the CNS acts as a latent reservoir that is inadequately managed by systemic antiretrovirals (ARTs). ARTs thus cannot eradicate HIV, and given CNS infection, patients experience neurological deficits collectively referred to as “neuroHIV”. Herein, the development of bioinspired ionic liquid‐coated nanoparticles (IL‐NPs) for in situ hitchhiking on red blood cells (RBCs) is reported, which enables 48% brain delivery of intracarotid arterial‐ infused cargo. Moreover, IL choline trans‐2‐hexenoate (CA2HA 1:2) demonstrates preferential accumulation in parenchymal microglia over endothelial cells post‐delivery. This study further demonstrates successful loading of abacavir (ABC), an ART that is challenging to encapsulate, into IL‐NPs, and verifies retention of antiviral efficacy in vitro. IL‐NPs are not cytotoxic to primary human peripheral blood mononuclear cells (PBMCs) and the CA2HA 1:2 coating itself confers notable anti‐viremic capacity. In addition, in vitro cell culture assays show markedly increased uptake of IL‐NPs into neural cells compared to bare PLGA nanoparticles. This work debuts bioinspired ionic liquids as promising nanoparticle coatings to assist CNS biodistribution and has the potential to revolutionize the delivery of cargos (i.e., drugs, viral vectors) through compartmental barriers such as the blood‐brain‐barrier (BBB).
-
Abstract Vascular‐targeted drug delivery remains an attractive platform for therapeutic and diagnostic interventions in human diseases. This work focuses on the development of a poly‐lactic‐co‐glycolic‐acid (PLGA)‐based multistage delivery system (MDS). MDS consists of two stages: a micron‐sized PLGA outer shell and encapsulated drug‐loaded PLGA nanoparticles. Nanoparticles with average diameters of 76, 119, and 193 nm are successfully encapsulated into 3–6 µm MDS. Sustained in vitro release of nanoparticles from MDS is observed for up to 7 days. Both MDS and nanoparticles arebiocompatible with human endothelial cells. Sialyl‐Lewis‐A (sLeA) is successfully immobilized on the MDS and nanoparticle surfaces to enable specific targeting of inflamed endothelium. Functionalized MDS demonstrates a 2.7‐fold improvement in endothelial binding compared to PLGA nanoparticles from human blood laminar flow. Overall, the presented results demonstrate successful development and characterization of MDS and suggest that MDS can serve as an effective drug carrier, which can enhance the margination of nanoparticles to the targeted vascular wall.
-
Abstract Hematopoietic stem and progenitor cells (HSPCs) are desirable targets for gene therapy but are notoriously difficult to target and transfect. Existing viral vector‐based delivery methods are not effective in HSPCs due to their cytotoxicity, limited HSPC uptake and lack of target specificity (tropism). Poly(lactic‐
co ‐glycolic acid) (PLGA) nanoparticles (NPs) are attractive, nontoxic carriers that can encapsulate various cargo and enable its controlled release. To engineer PLGA NP tropism for HSPCs, megakaryocyte (Mk) membranes, which possess HSPC‐targeting moieties, were extracted and wrapped around PLGA NPs, producing MkNPs. In vitro, fluorophore‐labeled MkNPs are internalized by HSPCs within 24 h and were selectively taken up by HSPCs versus other physiologically related cell types. Using membranes from megakaryoblastic CHRF‐288 cells containing the same HSPC‐targeting moieties as Mks, CHRF‐wrapped NPs (CHNPs) loaded with small interfering RNA facilitated efficient RNA interference upon delivery to HSPCs in vitro. HSPC targeting was conserved in vivo, as poly(ethylene glycol)–PLGA NPs wrapped in CHRF membranes specifically targeted and were taken up by murine bone marrow HSPCs following intravenous administration. These findings suggest that MkNPs and CHNPs are effective and promising vehicles for targeted cargo delivery to HSPCs.