Coadministration of Polymeric Conjugates of Docetaxel and Cyclopamine Synergistically Inhibits Orthotopic Pancreatic Cancer Growth and Metastasis

Abstract

Purpose The aim of this study was to determine whether co-administration of hedgehog (Hh) pathway inhibitor cyclopamine (CYP) and microtubule stabilizer docetaxel (DTX) as polymer-drug conjugates, methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylenecarbonate-graft-dodecanol-graft-cyclopamine) (P-CYP) and methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propyl-ene carbonate-graft-dodecanol-graft-docetaxel) (P-DTX) could synergistically inhibit orthotopic pancreatic tumor growth in NSG mice. Methods P-DTX and P-CYP were synthesized from mPEG-b-PCC through carbodiimide coupling reaction and characterized by 1H–NMR. The micelles were prepared by film hydration and particle size was measured by dynamic light scattering (DLS). Cytotoxicity, apoptosis and cell cycle analysis of P-DTX and P-CYP were evaluated in MIA PaCa-2 cells. In vivo efficacy of P-DTX and P-CYP were evaluated in NSG mice bearing MIA PaCa-2 cells derived orthotopic pancreatic tumor. Results P-CYP and P-DTX self-assembled into micelles of <90 nm and their combination therapy efficiently inhibited the proliferation of MIA PaCa-2 cells, induced apoptosis and cell cycle arrest at M-phase more efficiently than P-CYP and P-DTX monotherapies. Furthermore, the combination therapy of P-CYP and P-DTX significantly reduced Hh component expression compared to P-CYP alone as determined by Western blot analysis. Lastly, the combination therapy induced greater inhibition of orthotopic pancreatic tumor growth in NSG mice compared to their monotherapies. Conclusion Combination of polymer conjugated anticancer drug (P-DTX) with polymer conjugated Hh inhibitor (P-CYP) enhanced pancreatic cancer cell killing, apoptosis as well as in vivo tumor growth inhibition with no obvious toxicities.

NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products

“…Protein HOS is stabilized by weak hydrogen bonding, electrostatic and hydrophobic forces, which are solvent dependent, and, consequently, formulation differences affect HOS [ 6 , 7 , 8 , 9 ]. In addition, proteins can be chemically modified either purposely, e.g., pegylation, or unintentionally, e.g., oxidation, which could introduce variability to protein HOS [ 10 , 11 , 12 ]. All these factors and the accompanying sensitivity to solution conditions necessitate characterizing the protein chemistry and HOS with minimal perturbation to the formulation by ideally using DPs [ 13 ].…”

Lysine-mediated hydroxyethyl starch-10-hydroxy camptothecin micelles for the treatment of liver cancer

“…Recently, the construction of drug delivery systems based on nanotechnology to load and deliver chemotherapy drugs is the most commonly used technique. Among a variety of approaches, polymer-drug conjugated micelles are a well known and widely exploited technique because it can improve the defect of the properties of the coupled drug by virtue of the properties of the polymer used (Sarika et al, 2015;Almawash et al, 2018;Zou et al, 2018;Lubtow et al, 2019;Shi et al, 2019). For example, Lv prepared a bottlebrush conjugate by attaching 10-HCPT and methoxypolyethylene glycols (mPEG) into the polyester backbone (Lv et al, 2019).…”

Сигнальний шлях Hedgehog: від механізмів трансдукції до пошуку протипухлинних засобів

“…Числен ні дослідження показали його роль також за злоякісного росту (ембріо нальні пухлини мозочка, медулобласто ма, рак передміхурової залози, легенів, молочної залози та ін. ), що викликали зацікавленість до цієї сигнальної систе ми як мішені для пошуку підходів до лікування раку [3][4][5][6][7].…”

“…За ці дослідження вчені отримали Нобелівську премію в 1995 році разом з генетиком Едвардом Б. Льюїсом [5]. Було показано, що втрата функціональ ного фенотипу НН призводила до того, що ембріони покривалися зубцями, невеликими точковими виступами, що нагадували шипучки їжака [7]. Цей сигнальний шлях одержав назву «шлях їжака».…”

“…Два з них -пустельний їжак (DHH) та індій ський їжак (IHH) були названі за видом їжаків, а звуковий їжак (SHH) був названий ім'ям Sonic Hedgehog (SHH), як головного героя відеогри SEGA, їжака Соніка [4,5,8]. Назва була розроблена Робертом Ріддломпост доктором лабораторії Tabin після того, як він побачив Sonicкомікс, який його дочка привезла з Англії [6,7].…”