TY - JOUR
T1 - Nanoformulation design and therapeutic potential of a novel tubulin inhibitor in pancreatic cancer
AU - Bhattarai, Rajan Sharma
AU - Kumar, Virender
AU - Romanova, Svetlana
AU - Bariwal, Jitender
AU - Chen, Hao
AU - Deng, Shanshan
AU - Bhatt, Vijaya R.
AU - Bronich, Tatiana
AU - Li, Wei
AU - Mahato, Ram I.
N1 - Funding Information:
All the authors, except Vijaya Bhatt and Wei Li, have declared that no competing interest exists. Vijaya Bhatt reports receiving consulting fees from Takeda, Omeros, Agios, Abbvie, Partner therapeutics, and Incyte, and research funding (institutional) from Jazz, Incyte, Tolero Pharmaceuticals, and National Marrow Donor Program, and drug support for a trial from Oncoceutics. Wei Li is a scientific consultant for Veru, Inc. who licensed the patent portfolio covering tubulin inhibitors, inculding CH-3-8 and QW-296 discussed in this paper, for commercial development. Wei Li also reports receiving sponsored research agreement grants from Veru, Inc. However, Veru, Inc. did not have any input or influence in the experimental design, data collection, and data analyses in this paper.
Funding Information:
The faculty start-up fund supported this work from UNMC and DHHS NE LB506 to Ram I. Mahato and NCI grant R01CA148706 to WL. Vijaya Bhatt is supported by the National Institute of General Medical Sciences , 1 U54 GM115458 .
PY - 2020
Y1 - 2020
N2 - 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 microtubule 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 μg/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.
AB - 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 microtubule 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 μg/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.
KW - Lipid-drug conjugate
KW - Nanoparticles
KW - Pancreatic cancer
KW - Tubulin inhibitor
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U2 - 10.1016/j.jconrel.2020.09.052
DO - 10.1016/j.jconrel.2020.09.052
M3 - Article
C2 - 33010334
AN - SCOPUS:85092165588
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -