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<p>Melanoma is an aggressive malignancy with a five-year survival probability of under 50% in stage 4. Conventional chemotherapeutics, such as Dacarbazine, show an objective response rate of ~ 20%. Cabazitaxel (CBZ), a second-generation taxane, has demonstrated the ability to resist PI3K/Akt and P-gp-mediated resistance, thereby showing high potential for therapeutic response. However, the problems associated with delivery and pharmacokinetics, such as high lipophilicity and molecular weight, limit aqueous solubility and ultimately pharmacokinetics. To address these limitations, CBZ-loaded polycaprolactone nanoparticles (CBZ NP) were prepared using the anti-solvent addition method and optimized by a Central Composite Design (CCD) approach. CBZ NP exhibited a mean size of 170.2 ± 3.12&#xa0;nm, PDI of 0.166 ± 0.01 using DLS and showed spherical morphology in TEM. Nuclear and acridine orange/ethidium bromide staining performed on B16-F10 cells revealed induction of apoptosis (<i>p</i> &lt; 0.001). Cell cycle revealed CBZ and CBZ NP-induced G2/M phase arrest. Scratch, 3D migration, and clonogenic assay demonstrated immense potential as an adjuvant chemotherapeutic platform. 3D spheroid model treated with CBZ NP exhibited a marked reduction in spheroid diameter, accompanied by a 3.89-fold enhancement in cellular uptake relative to free CBZ. HET-CAM assay verified the anti-angiogenic efficacy of the formulation. In silico docking studies showed strong binding affinity for Caspase-3, Bcl-2 and VEGFR-2. Furthermore, western blotting and immunocytochemistry showed an overexpression of caspase-3 and a downregulation of Bcl-2, representing significant apoptosis in the CBZ NP-treated group. Consequently, CBZ NP offered improved delivery and enhanced therapeutic efficacy, highlighting their potential for effective melanoma management.</p> Graphical Abstract <p></p>

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Quality by Design Manoeuvred Cabazitaxel-Loaded Polycaprolactone Nanoparticles for Management of Melanoma: Development, Optimization, In Silico Modeling and In Vitro Studies

  • 期刊论文

  • 发表日期：

    2026年5月18日

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  • Suraj Wagh,
  • Paras Famta,
  • Saurabh Shah,
  • Ganesh Vambhurkar,
  • Rahul Kumar,
  • Anamika Sharma,
  • Giriraj Pandey,
  • Gurpreet Singh,
  • Pooja Khairnar,
  • Anupama Sikder,
  • Abhishek Sharma,
  • Swapnil Shinde,
  • Chandan Pandia,
  • Bishal Samadder,
  • Nitin Pal Kalia,
  • Saurabh Srivastava

摘要

Melanoma is an aggressive malignancy with a five-year survival probability of under 50% in stage 4. Conventional chemotherapeutics, such as Dacarbazine, show an objective response rate of ~ 20%. Cabazitaxel (CBZ), a second-generation taxane, has demonstrated the ability to resist PI3K/Akt and P-gp-mediated resistance, thereby showing high potential for therapeutic response. However, the problems associated with delivery and pharmacokinetics, such as high lipophilicity and molecular weight, limit aqueous solubility and ultimately pharmacokinetics. To address these limitations, CBZ-loaded polycaprolactone nanoparticles (CBZ NP) were prepared using the anti-solvent addition method and optimized by a Central Composite Design (CCD) approach. CBZ NP exhibited a mean size of 170.2 ± 3.12 nm, PDI of 0.166 ± 0.01 using DLS and showed spherical morphology in TEM. Nuclear and acridine orange/ethidium bromide staining performed on B16-F10 cells revealed induction of apoptosis (p < 0.001). Cell cycle revealed CBZ and CBZ NP-induced G2/M phase arrest. Scratch, 3D migration, and clonogenic assay demonstrated immense potential as an adjuvant chemotherapeutic platform. 3D spheroid model treated with CBZ NP exhibited a marked reduction in spheroid diameter, accompanied by a 3.89-fold enhancement in cellular uptake relative to free CBZ. HET-CAM assay verified the anti-angiogenic efficacy of the formulation. In silico docking studies showed strong binding affinity for Caspase-3, Bcl-2 and VEGFR-2. Furthermore, western blotting and immunocytochemistry showed an overexpression of caspase-3 and a downregulation of Bcl-2, representing significant apoptosis in the CBZ NP-treated group. Consequently, CBZ NP offered improved delivery and enhanced therapeutic efficacy, highlighting their potential for effective melanoma management.

Graphical Abstract