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1.
J Control Release ; 373: 277-292, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39019086

ABSTRACT

The Kirsten Rat Sarcoma Virus (KRAS) oncoprotein, one of the most prevalent mutations in cancer, has been deemed undruggable for decades. The hypothesis of this work was that delivering anti-KRAS monoclonal antibody (mAb) at the intracellular level could effectively target the KRAS oncoprotein. To reach this goal, we designed and developed tLyP1-targeted palmitoyl hyaluronate (HAC16)-based nanoassemblies (HANAs) adapted for the association of bevacizumab as a model mAb. Selected candidates with adequate physicochemical properties (below 150 nm, neutral surface charge), and high drug loading capacity (>10%, w/w) were adapted to entrap the antiKRASG12V mAb. The resulting antiKRASG12V-loaded HANAs exhibited a bilayer composed of HAC16 polymer and phosphatidylcholine (PC) enclosing a hydrophilic core, as evidenced by cryogenic-transmission electron microscopy (cryo-TEM) and X-ray photoelectron spectroscopy (XPS). Selected prototypes were found to efficiently engage the target KRASG12V and, inhibit proliferation and colony formation in KRASG12V-mutated lung cancer cell lines. In vivo, a selected formulation exhibited a tumor growth reduction in a pancreatic tumor-bearing mouse model. In brief, this study offers evidence of the potential to use nanotechnology for developing anti-KRAS precision therapy and provides a rational framework for advancing mAb intracellular delivery against intracellular targets.


Subject(s)
Antibodies, Monoclonal , Proto-Oncogene Proteins p21(ras) , Animals , Proto-Oncogene Proteins p21(ras)/genetics , Humans , Cell Line, Tumor , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/chemistry , Bevacizumab/administration & dosage , Bevacizumab/chemistry , Precision Medicine/methods , Hyaluronic Acid/chemistry , Female , Neoplasms/therapy , Neoplasms/drug therapy , Nanotechnology/methods , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/pharmacology , Lung Neoplasms/drug therapy , Mice , Mice, Nude , Drug Delivery Systems/methods , Nanoparticles/chemistry , Nanoparticles/administration & dosage
2.
Drug Deliv Transl Res ; 14(8): 2026-2031, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38796665

ABSTRACT

This note aims to inspire through providing a personal view of the development and potential Drug Delivery Nanocarriers functionalized with polythyleneglycol (PEG). This polymer has been used extensively in Pharmaceutical Technology in a variety of compositions, including polyethylene oxide (PEO)-based surfactants. However, the concept of PEGylation, which started in the 70's, differs from the functionality of a surfactant, already discloses in the 50's. Here, we strictly adhere to the biological functionality of PEGylated nanocarriers intended to have a reduced interaction with proteins and, therefore, modify their biodistribution as well as facilitate their diffusion across mucus and other biological barriers. We analyze how this concept has evolved over the years and the benefit obtained so far in terms of marketed nanomedicines and provide the readers with a prospect view of the topic.


Subject(s)
Drug Carriers , Nanoparticles , Polyethylene Glycols , Animals , Humans , Drug Carriers/chemistry , Drug Delivery Systems , Nanoparticles/chemistry , Polyethylene Glycols/chemistry , Polyethylene Glycols/administration & dosage
3.
Pharmaceutics ; 15(6)2023 May 30.
Article in English | MEDLINE | ID: mdl-37376070

ABSTRACT

The COVID-19 pandemic has made it clear that there is a crucial need for the design and development of antiviral agents that can efficiently reduce the fatality rate caused by infectious diseases. The fact that coronavirus mainly enters through the nasal epithelial cells and spreads through the nasal passage makes the nasal delivery of antiviral agents a promising strategy not only to reduce viral infection but also its transmission. Peptides are emerging as powerful candidates for antiviral treatments, showing not only a strong antiviral activity, but also improved safety, efficacy, and higher specificity against viral pathogens. Based on our previous experience on the use of chitosan-based nanoparticles to deliver peptides intra-nasally the current study aimed to explore the delivery of two-novel antiviral peptides making use of nanoparticles consisting of HA/CS and DS/CS. The antiviral peptides were chemically synthesized, and the optimal conditions for encapsulating them were selected through a combination of physical entrapment and chemical conjugation using HA/CS and DS/CS nanocomplexes. Finally, we evaluated the in vitro neutralization capacity against SARS-CoV-2 and HCoV-OC43 for potential use as prophylaxis or therapy.

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