Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly

Abstract

Nanocarriers delivering prodrugs are a way of improving in vivo effectiveness and efficiency. For therapeutic efficacy, the prodrug must hydrolyze to its parent drug after administration. Based on the fact that the hydrolysis is impeded by steric hindrance and improved by sufficient polarity, in this study, we proposed the PTX-S-S-VE, the conjugation of paclitaxel (PTX) to vitamin E (VE) through a disulfide bridge. This conjugate possessed the following advantages: first, it can be encapsulated in the VE/VE2-PEG2000/water nanoemulsions because of favorable hydrophobic interactions; second, the nanoemulsions had a long blood circulation time; finally, the concentrated glutathione in the tumor microenvironment could cleave the disulfide bond to weaken the steric hindrance and increase the polarity, promoting the hydrolysis to PTX and increasing the anticancer activity. It was demonstrated in vitro that the hydrolysis of PTX-S-S-VE was enhanced and the cytotoxicity was increased. In addition, PTX-S-S-VE had greater anticancer activity against the KB-3-1 cell line tumor xenograft and the tumor size was smaller after the 4th injection. The present result suggests a new way, use of reduction, to improve the in vivo anticancer activity of a prodrug for nanocarrier delivery by unshielding the ester bond and taking off the steric block.

Formulation and preclinical evaluation of a toll-like receptor 7/8 agonist as an anti-tumoral immunomodulator

“…Water exclusion by the bulky lipophilic α-tocopherol is another possible reason for the less favorable hydrolysis site closer to the lipid. A similar hydrolysis pattern was shown by Fu et al, as their prodrugs using succinate as the linker hydrolyzed to release the free parent drug, and the hydrolysis was favored by decreased steric hindrance and increased polarity [33].…”

Conjugation of Paclitaxel to Hybrid Peptide Carrier and Biological Evaluation in Jurkat and A549 Cancer Cell Lines

“…Both values are higher than IC 50 for free PTX, which is usually expected between 2 and 10 nM, but IC 50 can be significantly higher for prodrugs, than the free form of the drug. 21 While the measured IC 50 for Jurkat cells falls within expected range for a PTX prodrug utilizing drug carrier, the IC 50 for A549 cells is very high. Liebmann et al measured IC 50 for A549 cells for free PTX to be 4.1 nM.…”

“…The succinate linker between the COL-CPP and PTX was chosen as it was previously shown to easily hydrolyze and release the cargo from other carriers. 21 Jurkat cells showed IC 50 of 27 (±2) nM, and A549 cell lines showed IC 50 of 7.5 (±0.9) μM. Both values are higher than IC 50 for free PTX, which is usually expected between 2 and 10 nM, but IC 50 can be significantly higher for prodrugs, than the free form of the drug.…”

“…After folding in the triple helical conformation, the peptide forms a nanoparticle that carries three PTX molecules. 21 Scheme 2. Synthesis of PTX-COL-CPP a a Peptide sequence shows lysine modification site.…”

Evaluation the synergistic antitumor effect of methotrexate–camptothecin codelivery prodrug from self‐assembly process to acid‐catalyzed both drugs release: A comprehensive theoretical study

“…Instead of using any nanocarrier‐based drug delivery system, carrier‐free (self‐delivery) prodrugs have drawn many pharmacists attention due to their biocompatibility and simple structure . The term “prodrug” refers to a pharmacologically inactive compound that is converted to active drugs by a nonenzymatic process (e.g., hydrolysis) or metabolic biotransformation . There are several types of prodrugs such as carrier‐linked and bipartite that contain an active drug and a carrier, but on the other hand, mutual prodrugs (codrug) consist of multiple drugs chemically attached together.…”