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Flame-Made Calcium Phosphate Nanoparticles with High Drug Loading for Delivery of Biologics.

ABSTRACT: Nanoparticles exhibit potential as drug carriers in biomedicine due to their high surface-to-volume ratio that allows for facile drug loading. Nanosized drug delivery systems have been proposed for the delivery of biologics facilitating their transport across epithelial layers and maintaining their stability against proteolytic degradation. Here, we capitalize on a nanomanufacturing process famous for its scalability and reproducibility, flame spray pyrolysis, and produce calcium phosphate (CaP) nanoparticles with tailored properties. The as-prepared nanoparticles are loaded with bovine serum albumin (model protein) and bradykinin (model peptide) by physisorption and the physicochemical parameters influencing their loading capacity are investigated. Furthermore, we implement the developed protocol by formulating CaP nanoparticles loaded with the LL-37 antimicrobial peptide, which is a biological drug currently involved in clinical trials. High loading values along with high reproducibility are achieved. Moreover, it is shown that CaP nanoparticles protect LL-37 from proteolysis in vitro. We also demonstrate that LL-37 retains its antimicrobial activity against Escherichia coli and Streptococcus pneumoniae when loaded on nanoparticles in vitro. Therefore, we highlight the potential of nanocarriers for optimization of the therapeutic profile of existing and emerging biological drugs.

SUBMITTER: Tsikourkitoudi V

PROVIDER: S-EPMC7181047 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Flame-Made Calcium Phosphate Nanoparticles with High Drug Loading for Delivery of Biologics.

Tsikourkitoudi Vasiliki V Karlsson Jens J Merkl Padryk P Loh Edmund E Henriques-Normark Birgitta B Sotiriou Georgios A GA

Molecules (Basel, Switzerland) 20200410 7

Nanoparticles exhibit potential as drug carriers in biomedicine due to their high surface-to-volume ratio that allows for facile drug loading. Nanosized drug delivery systems have been proposed for the delivery of biologics facilitating their transport across epithelial layers and maintaining their stability against proteolytic degradation. Here, we capitalize on a nanomanufacturing process famous for its scalability and reproducibility, flame spray pyrolysis, and produce calcium phosphate (CaP) ...[more]

PMID: 32290273

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Project description:Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting the upper and lower motor neurons in the motor cortex and spinal cord. Abnormal accumulation of mutant superoxide dismutase I (SOD1) in motor neurons is a pathological hallmark of some forms of the disease. We have shown that the orderly progression of the disease may be explained by misfolded SOD1 cell-to-cell propagation, which is reliant upon its active endogenous synthesis. Reducing the levels of SOD1 is therefore a promising therapeutic approach. Antisense oligonucleotides (ASOs) can efficiently silence proteins with gain-of-function mutations. However, naked ASOs have a short circulation half-life and are unable to cross the blood brain barrier (BBB) warranting the use of a drug carrier for effective delivery. In this study, calcium phosphate lipid coated nanoparticles (CaP-lipid NPs) were developed for delivery of SOD1 ASO to motor neurons. The most promising nanoparticle formulation (Ca/P ratio of 100:1), had a uniform spherical core-shell morphology with an average size of 30 nm, and surface charge (?-potential) of -4.86 mV. The encapsulation efficiency of ASO was 48% and stability studies found the particle to be stable over a period of 20 days. In vitro experiments demonstrated that the negatively charged ASO-loaded CaP-lipid NPs could effectively deliver SOD1-targeted ASO into a mouse motor neuron-like cell line (NSC-34) through endocytosis and significantly down-regulated SOD1 expression in HEK293 cells. The CaP-lipid NPs exhibited a pH-dependant dissociation, suggesting that that the acidification of lysosomes is the likely mechanism responsible for facilitating intracellular ASO release. To demonstrate tissue specific delivery and localization of these NPs we performed in vivo microinjections into zebrafish. Successful delivery of these NPs was confirmed for the zebrafish brain, the blood stream, and the spinal cord. These results suggest that CaP-lipid NPs could be an effective and safe delivery system for the improved delivery of SOD1 ASOs to motor neurons. Further in vivo evaluation in transgenic mouse models of SOD1 ALS are therefore warranted.

Dataset Information

Flame-Made Calcium Phosphate Nanoparticles with High Drug Loading for Delivery of Biologics.

Publications

Flame-Made Calcium Phosphate Nanoparticles with High Drug Loading for Delivery of Biologics.

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