Journal
MOLECULAR PHARMACEUTICS
Volume 14, Issue 11, Pages 3866-3878Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.7b00584
Keywords
pulmonary drug delivery; pressurized metered-dose inhalers; poly(ethylene glycol); doxorubicin; Schiff base; pH sensitive conjugates; lung cancer
Funding
- National Science Foundation (NSF-DMA) [1508363]
- University Grants Commission (UGC), New Delhi, India under UGC [F 5-84/2014 (IC)]
- Direct For Mathematical & Physical Scien
- Division Of Materials Research [1508363] Funding Source: National Science Foundation
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Pulmonary administration of polymer drug conjugates is of great potential clinical significance for treating lung cancer as such regimen significantly increases local drug concentrations while decreases systemic and local side effects. In this work, we demonstrate that nanoparticles prepared with methoxypoly(ethylene glycol) (mPEG)-doxorubicin (DOX) conjugates (mPEG-DOX) that have a pH-sensitive imine bond (Schiff base) can at the same time work as efficient carriers for DOX to kill cancer cells and also as a strategy to directly formulate nanoparticles in propellant-based inhalers. Nanoparticles prepared by precipitation in water had a diameter in the range between 100 and 120 nm. We investigated the effects of molecular weight (MW) of mPEG (1K, 2K, and 5K Da) on the in vitro release kinetics, cellular internalization, and cytotoxicity on in vitro model of lung adenocarcinoma and aerosol characters. It is observed that the DOX released from mPEG DOX nanoparticles was significantly accelerated in acidic environment, pH 5.5 (endosomal/lysosomal pH) in comparison with pH 7.4 (physiological pH), as designed. Release of DOX from mPEG1K-DOX nanoparticles was significantly greater than those from mPEG2K and mPEGSK counterparts. In vitro cytotoxicity of nanoparticles followed the sequence of mPEG1K-DOX > free DOX > mPEG2K-DOX >> mPEGSK-DOX, a trend closely following their rate and extent of cellular internalization. mPEG DOX nanoparticles with mPEG1K and mPEG2K were directly dispersed in. hydrofluoroalkane (HFA), while a trace of ethanol was required to disperse mPEGSK-DOX nanopartides in HFA. These pMDI formulations with high physical stability in HFAs display superior aerosol characteristics conducive to deep lung deposition. The fine particle fractions of these formulations ranged from 40-60%, higher than those of commercial products. Such formulations prepared from nanoparticles of pH-sensitive PEG drug conjugates may also be envisioned to be extended to formulate other hydrophobic drugs for local delivery with propellant-based inhalers to other pulmonary disorders, thus broadening the impact of the proposed strategy.
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