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Microenvironment‐responsive nanoparticle platform for anticancer drug delivery.
Author(s) -
Wlodarczyk Marek Tadeusz,
Dragulska Sylwia,
Poursharifi Mina,
Cheng Ying,
Martignetti John,
Mieszawska Aneta
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09257
Subject(s) - chemistry , drug delivery , plga , prodrug , hela , folate receptor , linker , paclitaxel , peg ratio , cancer cell , biophysics , pharmacology , biochemistry , cancer , in vitro , medicine , organic chemistry , biology , finance , computer science , economics , operating system
Chemotherapy is a leading method of anticancer treatment. However, most of the chemotherapy agents have high systemic toxicity, poor bioavailability and solubility, which limit their clinical dose and decrease therapeutic outcomes. Nanoparticle (NP)‐based drug delivery systems have a potential to address these problems. We describe the formulation of a pH sensitive NP platform suitable for anticancer drug delivery. The NP’s core is composed of polylactic‐co glycolic acid (PLGA) conjugated to a platinum‐based drug. The NP’s corona is composed of a targeting ligand against Mucin 1 – a protein overexpressed on some epithelial cancer cells, and a pH‐sensitive pegylated phospholipid shell that provides high water solubility of the NPs. PLGA is biodegradable, biocompatible, and is FDA approved. The pH sensitive coating is achieved with a hydrazone linker that connects phospholipids with hydrophilic polyethylene glycol (PEG). Hydrolysis of the PEG‐hydrazone‐phospholipid occurs faster at slightly acidic environment (pH 6.8), which is characteristic of a tumor. The purpose of PEG cleavage is to unshield the targeting ligands on the NPs and facilitate fast NPs uptake by the cancer cells through receptor‐mediated endocytosis. The DNA aptamer is used as targeting ligand against Mucin 1, and the NP was tested in ovarian cancer model where Mucin 1 was found to be highly overexpressed. Our platform has been tested in both chemo naïve and chemo resistant ovarian cancer cell lines, including A2780, CP70, ES2, TOV21G, OV90. The NPs uptake and biological activity was high in all cells tested, and the results were compared to carboplatin, a free drug analogue. Also, preliminary in vivo studies demonstrated efficient NPs accumulation within the tumor tissue. The NP design is flexible and can easily be extended to delivery of other anticancer agents, or to the treatment of different tumor types. Support or Funding Information Supported by NIH Grant