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Fabrication and Characterization of Hybrid Stealth Liposomes.

ABSTRACT: Next-generation liposome systems for anticancer and therapeutic delivery require the precise insertion of stabilizing polymers and targeting ligands. Many of these functional macromolecules may be lost to micellization as a competing self-assembly landscape. Here, hybrid stealth liposomes, which utilize novel cholesteryl-functionalized block copolymers as the molecular stabilizer, are explored as a scalable platform to address this limitation. The employed block copolymers offer resistance to micellization through multiple liposome insertion moieties per molecule. A combination of thermodynamic and structural investigations for a series of hybrid stealth liposome systems suggests that a critical number of cholesteryl moieties per molecule defines whether the copolymer will or will not insert into the liposome bilayer. Colloidal stability of formed hybrid stealth liposomes further corroborates the critical copolymer architecture value.

SUBMITTER: Mineart KP

PROVIDER: S-EPMC7175670 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Fabrication and Characterization of Hybrid Stealth Liposomes.

Mineart Kenneth P KP Venkataraman Shrinivas S Yang Yi Yan YY Hedrick James L JL Prabhu Vivek M VM

Macromolecules 20180412 8

Next-generation liposome systems for anticancer and therapeutic delivery require the precise insertion of stabilizing polymers and targeting ligands. Many of these functional macromolecules may be lost to micellization as a competing self-assembly landscape. Here, hybrid stealth liposomes, which utilize novel cholesteryl-functionalized block copolymers as the molecular stabilizer, are explored as a scalable platform to address this limitation. The employed block copolymers offer resistance to mi ...[more]

PMID: 32322115

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Project description:Various liposomal drug carriers have been developed to overcome short plasma half-life and toxicity related side effects of chemotherapeutic agents. We developed a mathematical model to compare different liposome formulations of doxorubicin (DOX): conventional chemotherapy (Free-DOX), Stealth liposomes (Stealth-DOX), temperature sensitive liposomes (TSL) with intra-vascular triggered release (TSL-i), and TSL with extra-vascular triggered release (TSL-e). All formulations were administered as bolus at a dose of 9 mg/kg. For TSL, we assumed locally triggered release due to hyperthermia for 30 min. Drug concentrations were determined in systemic plasma, aggregate body tissue, cardiac tissue, tumor plasma, tumor interstitial space, and tumor cells. All compartments were assumed perfectly mixed, and represented by ordinary differential equations. Contribution of liposomal extravasation was negligible in the case of TSL-i, but was the major delivery mechanism for Stealth-DOX and for TSL-e. The dominant delivery mechanism for TSL-i was release within the tumor plasma compartment with subsequent tissue- and cell uptake of released DOX. Maximum intracellular tumor drug concentrations for Free-DOX, Stealth-DOX, TSL-i, and TSL-e were 3.4, 0.4, 100.6, and 15.9 µg/g, respectively. TSL-i and TSL-e allowed for high local tumor drug concentrations with reduced systemic exposure compared to Free-DOX. While Stealth-DOX resulted in high tumor tissue concentrations compared to Free-DOX, only a small fraction was bioavailable, resulting in little cellular uptake. Consistent with clinical data, Stealth-DOX resulted in similar tumor intracellular concentrations as Free-DOX, but with reduced systemic exposure. Optimal release time constants for maximum cellular uptake for Stealth-DOX, TSL-e, and TSL-i were 45 min, 11 min, and <3 s, respectively. Optimal release time constants were shorter for MDR cells, with ?4 min for Stealth-DOX and for TSL-e. Tissue concentrations correlated well quantitatively with a prior in-vivo study. Mathematical models may thus allow optimization of drug delivery systems to achieve a better therapeutic index.

Dataset Information

Fabrication and Characterization of Hybrid Stealth Liposomes.

Publications

Fabrication and Characterization of Hybrid Stealth Liposomes.

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