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Vascular-confined multi-passage discoidal nanoconstructs for the low-dose docetaxel inhibition of triple-negative breast cancer growth

Alessia Felici; Alessia Felici; Daniele Di Mascolo; Anna Lisa Palange; Paolo Decuzzi; Luca Bono; Arunkumar Pitchaimani; Simone Lauciello; Miguel Ferreira; Andrea Armirotti

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<oai_dc:dc xmlns:dc="" xmlns:oai_dc="" xmlns:xsi="" xsi:schemaLocation="">
  <dc:creator>Alessia Felici</dc:creator>
  <dc:creator>Alessia Felici</dc:creator>
  <dc:creator>Daniele Di Mascolo</dc:creator>
  <dc:creator>Anna Lisa Palange</dc:creator>
  <dc:creator>Paolo Decuzzi</dc:creator>
  <dc:creator>Luca Bono</dc:creator>
  <dc:creator>Arunkumar Pitchaimani</dc:creator>
  <dc:creator>Simone Lauciello</dc:creator>
  <dc:creator>Miguel Ferreira</dc:creator>
  <dc:creator>Andrea Armirotti</dc:creator>
  <dc:description>AbstractTaxane efficacy in triple negative breast cancer (TNBC) is limited by insufficient tumor accumulation and severe off-target effects. Nanomedicines offer a unique opportunity to enhance the anti-cancer potency of this drug. Here, 1,000 nm × 400 nm discoidal polymeric nanoconstructs (DPN) encapsulating docetaxel (DTXL) and the near infrared compound lipid-Cy5 were engineered. DPN were obtained by filling multiple times cylindrical wells in a poly(vinyl alcohol) template with a polymer mixture comprising poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) diacrylate (PEG-DA) chains together with therapeutic and imaging agents. The resulting "multi-passage" DPN exhibited higher DTXL loading, lipid-Cy5 stability, and stiffness as compared to the conventional "single-passage" approach. Confocal microscopy confirmed that DTXL-DPN were not taken up by MDA-MB-231 cells but would rather sit next to the cell membrane and slowly release DTXL thereof. Empty DPN had no toxicity on TNBC cells, whereas DTXL-DPN presented a cytotoxic potential comparable to free DTXL (IC50 = 2.6 nM ± 1.0 nM vs. 7.0 nM ± 1.09 nM at 72 h). In orthotopic murine models, DPN accumulated in TNBC more efficiently than free-DTXL. With only 2 mg/kg DTXL, intravenously administered every 2 days for a total of 13 treatments, DTXL-DPN induced tumor regression and were associated to an overall 80% survival rate as opposed to a 30% survival rate for free-DTXL, at 120 days. All untreated mice succumbed before 90 days. Collectively, this data demonstrates that vascular confined multi-passage DPN, biomimicking the behavior of circulating platelets, can efficiently deliver chemotherapeutic molecules to malignant tissues and effectively treat orthotopic TNBC at minimal taxane doses.</dc:description>
  <dc:subject>European Commission</dc:subject>
  <dc:subject>Electrical and Electronic Engineering</dc:subject>
  <dc:subject>General Materials Science</dc:subject>
  <dc:subject>Condensed Matter Physics</dc:subject>
  <dc:subject>Atomic and Molecular Physics, and Optics</dc:subject>
  <dc:title>Vascular-confined multi-passage discoidal nanoconstructs for the low-dose docetaxel inhibition of triple-negative breast cancer growth</dc:title>
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