Nanoformulation design and therapeutic potential of a novel tubulin inhibitor in pancreatic cancer

JOURNAL OF CONTROLLED RELEASE

卷:329

Article

Bhattarai, Rajan Sharma¹  Kumar, Virender¹  Romanova, Svetlana¹  Bariwal, Jitender¹  Chen, Hao²  Deng, Shanshan²  Bhatt, Vijaya R.³  Bronich, Tatiana¹  Li, Wei²  Mahato, Ram, I¹ 

[1] Univ Nebraska Med Ctr, Dept Pharmaceut Sci, 986025 Nebraska Med Ctr, Omaha, NE 68198 USA

[2] Univ Tennessee, Dept Pharmaceut Sci, Hlth Sci Ctr, 881 Madison Ave, Memphis, TN 38163 USA

[3] Univ Nebraska Med Ctr, Div Hematol Oncol, Div Internal Med, Fred & Pamela Buffett Canc Ctr, Omaha, NE 68198 USA

关键词: Pancreatic cancer;    Nanoparticles;    Tubulin inhibitor;    Lipid-drug conjugate;   

DOI  :  10.1016/j.jconrel.2020.09.052

来源: Elsevier

【 摘 要 】

Successful treatment of pancreatic cancer remains a challenge due to desmoplasia, development of chemoresistance, and systemic toxicity. Herein, we synthesized (6-(3-hydroxy-4-methoxylphenyl)pyridin-2-yl) (3,4,5-trimethoxyphenyl)methanone (CH-3-8), a novel microtubule polymerization inhibitor with little susceptible to transporter-mediated chemoresistance. CH-3-8 binding to the colchicine-binding site in tubulin protein was confirmed by tubulin polymerization assay and molecular modeling. CH-3-8 disrupted micmtubule dynamics at the nanomolar concentration in MIA PaCa-2 and PANC-1 pancreatic cancer cell lines. CH-3-8 significantly inhibited the proliferation of these cells, induced G2/M cell cycle arrest, and led to apoptosis. CH-3-8 is hydrophobic with an aqueous solubility of 0.97 +/- 0.16 mu g/mL at pH 7.4. We further conjugated it with dodecanol through diglycolate linker to increase hydrophobicity and thus loading in lipid-based delivery systems. Hence, we encapsulated CH-3-8 lipid conjugate (LDC) into methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol) (mPEG-b-PCC-g-DC) polymeric nanoparticles (NPs) by solvent evaporation, resulting in a mean particle size of 125.6 +/- 2.3 nm and drug loading of 10 +/- 1.0% (w/w) while the same polymer could only load 1.6 +/- 0.4 (w/w) CH-3-8 using the same method. Systemic administration of 6 doses of CH-3-8 and LDC loaded NPs at the dose of 20 mg/kg into orthotopic pancreatic tumor-bearing NSG mice every alternate day resulted in significant tumor regression. Systemic toxicity was negligible, as evidenced by histological evaluations. In conclusion, CH-3-8 LDC loaded NPs have the potential to improve outcomes of pancreatic cancer by overcoming transporter-mediated chemoresistance and reducing systemic toxicity.

【 授权许可】

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