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Genetically Encoded Stealth Nanoparticles of a Zwitterionic Polypeptide-Paclitaxel Conjugate Have a Wider Therapeutic Window than Abraxane in Multiple Tumor Models
journal contribution
posted on 2020-03-09, 12:36 authored by Samagya Banskota, Soumen Saha, Jayanta Bhattacharya, Nadia Kirmani, Parisa Yousefpour, Michael Dzuricky, Nikita Zakharov, Xinghai Li, Ivan Spasojevic, Kenneth Young, Ashutosh ChilkotiSmall-molecule
therapeutics demonstrate suboptimal pharmacokinetics
and bioavailability due to their hydrophobicity and size. One way
to overcome these limitationsand improve their efficacyis
to use “stealth” macromolecular carriers that evade
uptake by the reticuloendothelial system. Although unstructured polypeptides
are of increasing interest as macromolecular drug carriers, current
recombinant polypeptides in the clinical pipeline typically lack stealth
properties. We address this challenge by developing new unstructured
polypeptides, called zwitterionic polypeptides (ZIPPs), that exhibit
“stealth” behavior in vivo. We show
that conjugating paclitaxel to a ZIPP imparts amphiphilicity to the
polypeptide chain that is sufficient to drive its self-assembly into
micelles. This in turn increases the half-life of paclitaxel by 17-fold
compared to free paclitaxel, and by 1.6-fold compared to the nonstealth
control, i.e., ELP-paclitaxel. Treatment of mice bearing highly aggressive
prostate or colon cancer with a single dose of ZIPP-paclitaxel nanoparticles
leads to near-complete eradication of the tumor, and these nanoparticles
have a wider therapeutic window than Abraxane, an FDA-approved taxane
nanoformulation.
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nonstealth controlZwitterionic Polypeptide-Paclitaxel Conjugatesuboptimal pharmacokineticsMultiple Tumor Models Small-molecule therapeuticsZIPP-paclitaxel nanoparticlesGenetically Encoded Stealth NanoparticlesAbraxanepolypeptide chainFDA-approved taxane nanoformulationlack stealth propertiescolon cancerzwitterionic polypeptidesTherapeutic Windowreticuloendothelial systemdrug carriers
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