Prodrugs for improving tumor targetability and efficiency

Abstract

As the mainstay in the treatment of various cancers for several decades, chemotherapy is successful but still faces challenges including non-selectivity and high toxicity. Improving the selectivity is therefore a critical step to improve the therapeutic efficacy of chemotherapy. Prodrug is one of the most promising approaches to increase the selectivity and efficacy of a chemotherapy drug. The classical prodrug approach is to improve the pharmaceutical properties (solubility, stability, permeability, irritation, distribution, etc.) via a simple chemical modification. This review will focus on various targeted prodrug designs that have been developed to increase the selectivity of chemotherapy drugs. Various tumor-targeting ligands, transporter-associated ligands, and polymers can be incorporated in a prodrug to enhance the tumor uptake. Prodrugs can also be activated by enzymes that are specifically expressed at a higher level in tumors, leading to a selective anti-tumor effect. This can be achieved by conjugating the enzyme to a tumor-specific antibody, or delivering a vector expressing the enzyme into tumor cells.

A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy

“…Both SAHA-S-S-VE and SAHA-S-S-VE/TPGS NPs showed enhanced antiproliferative activities (lower IC 50 values) compared with free SAHA in all the tested cell lines, whereas the NH 2 -S-S-VE showed little toxicity in the given concentration range after 48 h. Among these four cell lines, SAHA-S-S-VE/TPGS NPs revealed the most obvious antiproliferative activity (P,0.01, compared to free SAHA) in HepG2 cell line. The enhanced cytotoxic might be due to one or two of the following mechanisms: 1) the lipophilic nature of SAHA-S-S-VE (higher log P; Table 2) might facilitate intracellular uptake 11,14,51 and 2) when the concentration of SAHA-S-S-VE/TPGS NPs was higher than the CAC, part of the self-assembled SAHA-S-S-VE/TPGS NPs might keep intact for the low GSH concentration in the cell culture medium, 38 which resulted in the greater cellular uptake through the endocytic pathway and higher cytotoxic efficiency. 1 Besides, the GSH-insensitive SAHA-O-VE appeared to have a significantly lower proliferation inhibitory efficacy than SAHA-S-S-VE, which might be resulted from the slow release of SAHA.…”

“…Prodrug approach provides a remarkable tool to improve the therapeutic efficacy and to reduce the toxic side effects of the anticancer agents. [11][12][13] In this work, prodrug strategy combined with the SMND system was reported for solid tumor therapy.…”

Biotin-conjugated tumour-targeting photocytotoxic iron(III) complexes

“…The choice of three different cell lines for this study is based on the facts that (i) hepatocyte HepG2 cells overexpress SMVTs depending on biotin availability, (ii) HeLa cells present highly proliferative growth models usually found in cancerous tissues, and (iii) HEK293 represents a transformed non-cancerous cell line, which possesses SMVTs similar to normal cells. Although most of the cancer cells are well known to possess overexpressed SMVTs, enterocytes (representative cell line, Caco-2) and hepatocytes are largely involved in biotin uptake and regulation [51]. Complex 2 showed a dose-dependent decrease in cell viability in the HepG2 cells with an IC 50 value of 5.1 µM upon pre-incubation of the complex with the cells for 12 h in the dark followed by photoexposure with visible light (figure 2).…”

Prodrug Applications for Targeted Cancer Therapy

“…The details of these advances have been documented in several recent reviews (2)(3)(4)(5)(6). Here, our aim is to present a unified view of the prodrug concept in targeted cancer therapy.…”