Prodrugs is a compound through enzyme or nonenzymatic action in the body to release active matter. It has less active or inactive in vitro. Mostly, prodrugs are simple chemical derivatives. It can convert into active parent drugs by one or two chemical or enzymatic catalysis.
Using prodrug modification to optimize the lead compound can improve the bioavailability of the drug, increase the stability of the drug, reduce toxic side effects, and promote the long-acting of the drug. In tumor treatment research, some researchers have designed and synthesized some anti-tumor prodrugs, which can greatly improve the shortcomings of most chemotherapeutic drugs currently in clinical use, such as high toxicity, non-selectivity, and poor physical properties.
The main types of anti-tumor prodrugs currently developed are as follows:
1.Liposome prodrugs
The optimization of lead compounds through prodrug design requires three conditions. Firstly, according to the properties of biologically active drug molecules, carry out chemical modification for the treatment needs. Secondly, after entering the body, it must be restored regardless of whether the action of enzymes is required. And the prodrug itself does not show biological activity.
Proliposomes are useful for rebuilding liposomes. In the development of solid preparations, the membrane materials, medicinal materials, and solid carriers that constitute liposomes can be made into dry forms such as granules or powders by appropriate methods. They usually have good flow properties and will can dispersion or dissolved into the liposome solution by adding water before use.
In the development of tumor drugs, liposome prodrug systems have the advantages of being able to stay in the blood for a longer time, reducing the toxicity of the drug, increasing the aggregation of the drug at the target, and improving the efficacy of the drug.
Combining prodrugs with liposomes helps to improve the encapsulation rate and lipid-drug ratio of liposomes. Also avoids the instability of prodrugs in the body, making it easier to achieve targeted delivery of prodrugs.
This new drug delivery method that combines drug molecules with liposome-forming molecules provides a new way for drugs that are difficult to be encapsulated in liposomes, such as hydrophilic drugs, to achieve high encapsulation efficiency.
2.Capecitabine anti-tumor prodrug
Capecitabine (CAP) is thymidylate synthase (thymidylate synthase, TS) inhibitor. It is a prodrug that uses a chemical method to transform fluorouracil (FU) into a chemical structure. It contains carbamate structural energy to rapidly absorbed by the intestinal mucosa in the form of complete molecules.
CAP is an oral fluoropyrimidine nucleoside analog with a targeted effect. It can be selectively activated in tumor tissues to produce high concentrations of active cytotoxic substances, thereby improving the tolerance of tumor patients and maximizing anti-cancer activity. Because it does not show biological activity, it avoids many adverse reactions caused by oral FU.
3.Water-soluble curcumin prodrugs
Synthesize a polyethylene glycol-loaded, biodegradable curcumin (Cur) prodrug to solve the water solubility of Cur and enhance the curative effect. In addition, it lays the foundation for the development of new Cur preparations. Method Using monomethoxy polyethylene glycol as a carrier and amino acid as a linking arm, the cur prodrug was synthesized; The structure of the synthesized product was identified by ultraviolet spectroscopy and nuclear magnetic resonance spectroscopy; its solubility in water was directly observed by direct observation Measure; finally, analyze its anti-tumor activity and characteristics in vitro by MTT method. Results The experiment successfully synthesized Cur prodrug with a simple method, high synthesis rate, and good water solubility. It can be released slowly to have an anti-tumor effect, showing a good application and development prospect, and it is worthy of further research and development.
4.Paclitaxel prodrugs
At present, the development of paclitaxel prodrugs is mainly to improve its water solubility, overcome the problem of the low solubility of paclitaxel in water. At the same time reduce drug toxicity and improve anti-tumor activity. Studies have found that paclitaxel prodrugs have the characteristics of no need for anti-allergic pretreatment, short intravenous drip time, high MTD, good curative effect, and low toxicity, which can better solve the poor water solubility of paclitaxel and polyoxyethylene castor oil (Cremophor EL). It has obvious advantages in pharmacokinetics, pharmacodynamics, and toxic and side effects, and its clinical application prospects are good.
5.Enzyme-activated anti-tumor prodrugs
According to the tools for activating prodrugs, prodrugs can be divided into two types: targeted enzyme prodrugs and targeted biofilm carrier prodrugs. Targeted enzyme prodrugs and the corresponding targeted enzymes constitute the enzyme activated prodrug system, which has remarkable anti-tumor efficacy.
Avirulent drugs can translates into cytotoxic drug by input exogenous enzymes (ADEPT)of tumor location or enzymes expressed in tumor cells (GDEPT)with interaction.The prodrugs used in these two strategies are anti- Metabolites and alkylating agents.
At present, the use of enzymes synthesized by tumor tissue itself to activate prodrugs, compared with the use of artificially introduced enzyme-activated prodrug antibody-directed target enzyme prodrug therapy and gene-directed target enzyme prodrug therapy, eliminating many steps of artificial addition. This therapy shows great advantages.
The enzyme-activated anti-tumor prodrug system can improve the targeting of anti-tumor drugs, and the prodrug activated by the enzyme expressed by the tumor tissue itself overcomes many shortcomings of the artificial introduction of exogenous enzymes. It is a drug with wide developing prospects.
6.Hydrogen peroxide-mediated anti-tumor targeted prodrugs
Cancer cells overproduce a series of reactive oxygen species (ROS) during aerobic metabolism, including hydrogen peroxide. ROS plays an important role in the metastasis, apoptosis, proliferation and angiogenesis of cancer cells.
Due to the decrease of growth factors related to cancer cell metastasis, the level of hydrogen peroxide in the cell increases. Studies have shown that the boronic acid and boronic ester bonds of aryl or phenyl groups can be easily broken by hydrogen peroxide. The fluorescent part is used to monitor the position of the drug in the cell, especially in the lysosome, to reflect the transport conditions of the drug in the cell.
Hydrogen peroxide-mediated antitumor targeting prodrug is a novel therapeutic diagnostic Prodrug 7. Prodrug 7 is a drug for the treatment of metastatic tumors, which contains a borate bond triggering part, a fluorescent part (coumarin) and the chemical treatment component 7-ethyl-10 hydroxycamptothecin (SN-38).
Studies have found that after the drug enters the body, it reaches a high level of hydrogen peroxide. And cancer cells, hydrogen peroxide cuts the borate bond and releases 7-ethyl-10-hydroxy-camptothecin and the fluorescent part, which works.
7.The folate receptor-mediated anti-tumor targeting prodrug
Folate receptor (FR) is overexpressed on the surface of most human tumor cells but is rarely expressed or even not expressed on the surface of normal cells.
This makes it possible to use FR-mediated anti-tumor drugs to target FR-positive tumor cells, thereby reducing the toxic and side effects of traditional anti-cancer drugs on normal cells. In addition, prodrugs are used in many fields. Such as overcoming drug medication barriers, enhancing chemical and metabolic stability, increasing the absorption of oral or topical administration, enhancing the permeability of the blood-brain barrier, extending the duration of action, improving bioavailability, and reducing adverse reactions. It has become an effective strategy and is widely accepted.