Nanoparticle Drug Delivery

Polymer mediate transport of the Hsp90 inhibitor LB76, a polar resulting cyclic peptide, produces an Hsp90 cellular phenotype Marwa N. Rahimi, Henry G. Foster, Shegufta N. Farazi, Robert Chapman*, and Shelli R. McAlpine* Chem Commun, V55, p4515-4518 2019 DOI:10.1039/C9CC00890J

LB76 is a cyclic peptide that shows great promise as a selective heat shock protein 90 (Hsp90) inhibitor. However despite strong binding to and inhibition of Hsp90 in cell lysate its polar structure prevents it from crossing the cell membrane. We have developed a pH responsive polymer nanoparticle that effectively encapsulates LB76 from solution without need for purification. The nanoparticle releases the molecule upon crossing the cell membrane. Treatment of human colon cancer HCT116 cells with nanoparticle laden with LB76 produce the typical phenotype associated with Hsp90 inhibition, providing evidence of a therapeutically active payload.

Real time monitoring of peptide delivery in vitro using high payload pH responsive nanogels Shegufta Farazi, Fan Chen, Henry Foster,Raelene Boquiren, Shelli R. McAlpine and Robert Chapman *Polym. Chem.V11, p425-432 2020, DOI: 10.1039/C9PY01120J

Nanogels are attractive delivery vehicles for small hydrophilic cargo, such as peptides, but there is a limited understanding of how the structure of both the nanogel and cargo affect the drug loading and release properties, particularly in biological environments. We have used Förster resonance energy transfer(FRET) to study the loading and release behaviour of a series of hydrophilic charged peptides (SNKAY, SNKKY and SNDDY) in a set of pH-responsive methacrylic acid (pMAA) core crosslinked nanogels that were prepared through miniemulsion polymerisation from a PEGMEMA–DMAEMA–tBuMA terblockcopoylmer. Our nanogels show an extremely high loading capacity of the positively charged peptides (400–800 wt% in the best cases), absorbing them from solution at pH 7.4 without any need for purification. At pH values below 6, the peptide is rapidly expelled from the nanogel due to the collapse of the core and protonation of the positively charged inner shell. By combining FRET with fluorescence lifetime imaging microscopy (FLIM), we were able to monitor this in vitro and found that most of the drug is released within the first 10 min after cell uptake.

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Nanoparticle Drug Delivery

Shelli R. McALpine, PhD., Visiting Professor at University of California, Irvine and Handling Editor Bioorganic Chemistry (Elsevier) mcalpine@uci.edu, www.coachingstemmacademics.com