A paclitaxel prodrug with bifunctional folate and albumin binding moieties for both passive and active targeted cancer therapy

Abstract

Folate receptor (FR) has proven to be a valuable target for chemotherapy using folic acid (FA) conjugates. However, FA-conjugated chemotherapeutics still have low therapeutic efficacy accompanied with side effects, resulting from complications such as short circulation half-life, limited tumor delivery, as well as high kidney accumulation. Herein, we present a novel FA-conjugated paclitaxel (PTX) prodrug which was additionally conjugated with an Evans blue (EB) derivative for albumin binding. The resulting bifunctional prodrug prolonged blood circulation, enhanced tumor accumulation, and consequently improved tumor therapeutic efficacy.Methods: Fmoc-Cys(Trt)-OH was coupled onto PTX at the 7'-OH position for further synthesis of ester prodrug FA-PTX-EB. The targeting ability was investigated using confocal microscopy and flow cytometry. The pharmacokinetics of this bifunctional compound was also studied. Meanwhile, cell viability was evaluated in normal cells and three cancer cell lines by MTT assay. In vivo therapeutic effect was tested on FR-α overexpressing MDA-MB-231 tumor model.Results: Compared with free PTX, the FA-PTX, PTX-EB and FA-PTX-EB prodrugs increased circulation half-life in mice from 2.19 to 3.82, 4.41, and 7.51 h, respectively. Pharmacokinetics studies showed that the FA-PTX-EB delivered more PTX to tumors than FA-PTX and free PTX. In vitro and in vivo studies demonstrated that FA-EB-conjugated PTX induced potent antitumor activity.Conclusion: FA-PTX-EB showed prolonged blood circulation, enhanced drug accumulation in tumors, higher therapeutic index, and lower side effects than either free PTX or monofunctional FA-PTX and EB-PTX. The results support the potential of using EB for the development of long-acting therapeutics.

Conjugate of Doxorubicin to Albumin‐Binding Peptide Outperforms Aldoxorubicin

“…High‐yield recombinant synthesis of albumin and albumin fusions requires a specialized yeast expression system that is not readily available to most researchers . To address these limitations of the ex vivo albumin approach, drugs can, alternatively, be conjugated to albumin‐binding moieties that bind albumin in vivo . The small size and lower viscosity of these albumin‐binding drug conjugates compared to albumin conjugates and fusions can also provide for easier formulation and administration.…”

Antitumor Activity of 1,18-Octadecanedioic Acid-Paclitaxel Complexed with Human Serum Albumin

“…Harnessing human serum albumin (HSA) as a drug carrier in oncology is an established strategy aimed to improve dosing, safety, and efficacy. 1−4 HSA is the most abundant serum protein with myriad functions, including a central role in metabolic pathways as a transporter of long-chain fatty acids (LCFAs) and hydrophobic molecules, both natural and synthetic. 5−7 Recently, HSA and its endogenous ligands have gained interest for their roles in dysregulated metabolism tied to tumor growth.…”

Tumor Microenvironment–Responsive Peptide-Based Supramolecular Drug Delivery System

“…However, such measurement is challenging because of the lack of a feasible analytical instrument or methodology to reveal the structural transitions of peptide-based DDSs in vivo . Inspired by other nanomedicine research (Shan et al, 2018 , 2019 ), some potential strategies are expected to solve this thorny problem, including high performance liquid chromatography measurement of plasma level of the loaded drugs, detection of specific overexpressing proteins/micromoles in the blood, and development of harmless tracer/probe. This research direction needs more efforts in the future.…”