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pH‐responsive nanoparticles for Pt (II) delivery to ovarian cancer cells.
Author(s) -
Mieszawska Aneta Joanna,
Wlodarczyk Marek T.,
Dragulska Sylwia A.,
Poursharifi Mina,
Chen Ying,
Martignetti John A.
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.s1.02911
Subject(s) - polyethylene glycol , plga , in vivo , chemistry , cancer cell , drug delivery , internalization , ovarian cancer , cancer research , in vitro , cancer , pharmacology , biophysics , cell , nanotechnology , biochemistry , materials science , medicine , biology , microbiology and biotechnology
Platinum‐based agents represent the most widely used chemotherapy against cancer cells. The effectiveness of Pt (II) treatment depends upon two major factors: 1) cellular accumulation and 2) cellular recognition of the platinum‐induced damage leading to cancer cell apoptosis. Limitations of Pt (II) therapy include inappropriate drug activation in the blood compartment and interaction of Pt (II) agents with plasma proteins. Together these factors result in systemic toxicity, decreased targeted cancer cell delivery, and ultimately, leads to treatment failure. To overcome these major limitations, our work has focused on the synthesis of lipid/polymer nanoparticles (NPs) encapsulating Pt (II) therapy. The NP’s core consists of Pt (II) modified poly(lactic‐co‐glycolic) acid (PLGA‐Pt) polymer. The drug payload within PLGA‐Pt NPs is 5 wt. %, and the NPs are 180 nm in diameter with low polydispersity of 0.115. We explore DNA aptamers as active targeting ligands, which are a part of the NP’s coating. The pH‐responsive polyethylene glycol (PEG) masks the targeting ligands at physiological pH but exposes them at tumoral pH conditions. Proof‐of‐priniciple studies in ovarian cancer (OvCa) models demonstrate enhanced internalization of the PLGA‐Pt NPs when targeting surface ligands. The NPs are highly efficacious in vitro , lowering OvCa cell viability better than the clinical Pt (II) analog, and reveal tumor targeting in vivo in an OvCa mouse model. Taken together our results demonstrate a novel method of delivering Pt‐based drugs, which can overcome current clinically‐relevant limitations. Support or Funding Information NIH/NCI1R01CA238539‐01