Poly(amidoamine) Dendrimer-Doxorubicin Conjugates: In Vitro Characteristics and Pseudosolution Formulation in Pressurized Metered-Dose Inhalers

Molecular Pharmaceutics
Qian Zhong, Sandro R P da Rocha

Abstract

Lung cancers are the leading cause of cancer death for both men and women. A series of PEGylated poly(amidoamine) dendrimer-based doxorubicin (DOX) nanocarriers (G3NH2-mPEG-nDOX) were synthesized and their chemistry tailored for the development of novel pseudosolution formulations in propellant-based metered-dose inhalers (pMDIs) with enhanced aerosol characteristics. A pH-labile bond was used to conjugate DOX to dendrimer for controlled intracellular release. We employed a two-step PEGylation strategy to cover a range of DOX loading and PEGylation density. We investigated the impact of pH, PEGylation density, and DOX payload on the release of DOX from the conjugate. We also determined the cellular internalization of the conjugate, the intracellular release kinetics of DOX from the conjugate, and their ability to kill human alveolar carcinoma cells (A549). The acid-labile conjugates sustained the release of DOX in acidic medium, and also intracellularly, as determined by nuclear colocalization studies with confocal microscopy. Meanwhile, DOX was retained in the conjugate at extracellular physiological conditions, indicating their potential to achieve spatial and temporal controlled release profiles. We also observed that the ki...Continue Reading

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Citations

Aug 24, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Livia Palmerston MendesVladimir P Torchilin
Oct 20, 2018·ChemistryOpen·Rita B RestaniAna Aguiar-Ricardo
Sep 5, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Adriana Aurelia ChisAdina Frum
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Aug 5, 2017·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Qian ZhongSandro R P da Rocha
Mar 14, 2018·Chemical Reviews·Farzad SeidiDaniel Crespy

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