Abstract
Taxane 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.
Highlights
Breast cancer is the most common malignancy in females and the second leading cause of cancer-related deaths [1]
discoidal polymeric nanoconstructs (DPN) were synthetized using a mixture of poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) diacrylate (PEG-DA) polymers. 50 mg of PLGA are dissolved in 1 mL of Acetonitrile and mixed with 6 mg of PEG-DA and 10 mg of DTXL
The DPN were released from the hydrophilic poly(vinyl alcohol) (PVA) templates upon dissolution in deionized water for 3 h under gentle stirring, were collected through centrifugation (3,900 rpm for 20 min) and purified from residual debris and scum layer through 2 μm
Summary
Nanomedicine could play a fundamental role to enhance the therapeutic efficacy of small anti-cancer molecules optimizing their bioavailability, tissue deposition, and cellular uptake while limiting off-site targeting [16,17,18,19]. De-Sheng Liang and colleagues implemented a dual targeting approach including on the same nanoparticle moieties to recognize CD44 molecules, expressed on the cancer cells, and neuropilin receptors, exposed on the tumor neovasculature. Bio-conjugation may not be that intrinsically specific because targeting receptors could be expressed on healthy cells or the moieties’ orientation over the particle surface could be sub-optimal impairing the proper biological recognition Along this line, a recent meta-analysis revealed that active targeting agents yield only modest improvements in intratumor nanoparticle accumulation [38]. The tumor vasculature is tortuous and characterized by lower flow rates as compared to healthy vascular beds This specific hemodynamic conditions and vascular architecture would favor the deposition of nonspherical micrometric particles over more conventional spherical nanoparticles [45,46,47,48]. The therapeutic efficacy and imaging efficiency of DTXL and Cy5-loaded DPN is tested preclinically in mice bearing an orthotopic model of triple negative breast cancer
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