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Enzymes for Prodrug-Activation in Cancer Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
A prodrug is a compound with low or no pharmaceutical activity which is metabolized after administering to the active drug. Prodrug activation in many cases is achieved by enzyme-mediated processes. The design of prodrugs is an important field in the development of pharmaceuticals and has found application in many therapeutic areas. The aim is to circumvent some disadvantageous pharmacodynamic or pharmacokinetic properties of active drugs which means to improve their physicochemical and biological properties, together, if required, with their target selectivity (particularly important in chemotherapy to avoid severe side effects). Prodrugs also occur naturally and may be isolated from the plants, animals, or microorganisms; one of many examples is mevastatin, a cholesterol-lowering agent (competitive inhibitor of HMG-Coenzyme A (HMG-CoA) reductase) isolated from Penicillium citinium or P brevicompactum; mevastatin is activated by in vivo hydrolysis of the lactone ring to the corresponding open hydroxy-acid form. For a review of natural products as sources of prodrugs, see Padmavathy and Saravanan (2017).
Carriers for Brain Targeting
Published in Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani, Nanocarriers for Brain Targeting, 2019
Md. Sahab Uddin, Mst. Marium Begum
Biotechnology-based products and small molecule drugs cannot cross BBB. In addition, majority of the small molecule drugs (>98%) fail to cross BBB. But if the barrier is overcome, then there is possibility of effective treatment of several diseases of CNS. Various scientific possibilities have been tried for this purpose such as prodrugs, intracerebral injection, use of implants, disruption of BBB, etc. Prodrugs are special types of drugs which undergo a chemical or enzymatic biotransformation to convert to active drug to produce therapeutic action in the body. Lipophilic compounds are used in formulations of prodrugs so that can easily pass through BBB (Rautio et al., 2008). For this, lipophilic esters and other hydrophobic compounds which are important elements of prodrugs have been studied for formulations. Carrier-mediated prodrug transport (endogenous transporters), receptor-mediated prodrug transport (macromolecular delivery), and gene-mediated enzyme prodrug therapy are examples of sophisticated prodrug approaches (Pavan et al., 2008; Rautio et al., 2008).
Glossary of scientific and technical terms in bioengineering and biological engineering
Published in Megh R. Goyal, Scientific and Technical Terms in Bioengineering and Biological Engineering, 2018
Prodrug is a medication that is administered in an inactive or less than fully active form, and then it becomes converted to its active form through a normal metabolic process, such as hydrolysis of an ester form of the drug. A prodrug is a precursor chemical compound of a drug. Instead of administering a drug, a prodrug might be used instead to improve how a medicine is absorbed, distributed, metabolized, and excreted (ADME).
Self-assembled amphiphilic copolymers–doxorubicin conjugated nanoparticles for gastric cancer therapy with low in vivo toxicity and high efficacy
Published in Journal of Biomaterials Science, Polymer Edition, 2022
Xiaoqi Qian, Chenmei Xia, Xia Chen, Qianqian Li, Dong Li
Histological examinations of tumors and primary organs were conducted to verify the treatment effectiveness and analyze the NP’s in vivo systemic toxicity. For example, in the TUNEL experiment in Figure 8, treatment with NP therapy resulted in a substantial rise in apoptotic cell death among cancer cells. Furthermore, the apoptotic impact caused by mPEG-PCL(2K)@DOX-NPs was equivalent to that induced by free DOX. Nanotherapies for anticancer therapy in vivo were shown to have greater therapeutic efficacy when compared to those acquired by conventional methods such as TUNEL labeling of tumor sections and growth inhibition. After treatment with nanotherapies, H&E examination showed no cell death or necrosis in the main organs, supporting the safety profile in vivo (Figure 8). Covalently conjugated polymeric prodrugs combined with nanotherapies exhibited high curative efficacy with slight toxicity.
Self-assembling porphyrin conjugate-carboplatin(IV) prodrug nanoparticles for enhancing high efficacy nasopharyngeal cancer and low systemic toxicity
Published in Journal of Biomaterials Science, Polymer Edition, 2022
Renjie Su, Xiangwen Zhang, Qianhua Peng, Wenbin Wang
Although cancer treatment's backbone, chemotherapy undergoes limitations, for instance, poor water solubility and tumour selectivity, foremost to systemic toxicity, which dramatically reduces treatment efficacy [1]. The development of drug delivery methods spanning liposomes, polymers, and inorganic nanomaterials to enable regulated drug release and tumour drug accumulation has been the subject of many studies [2–4]. Rather than traditional medications, prodrugs are being used to lower systemic toxicity and activate therapeutic drugs in response to stimuli. High loading efficiency, low/no carrier-induced immunogenicity, and inherent biodegradability are advantages of prodrug- self-assembly systems developed specifically for this purpose [5–7]. In addition, regulated tumour-selective drug release is ensured by incorporating prodrugs delivery frameworks, which persist inactive up to triggered by the tumour environment [8].
Transition metal complexes incorporating lawsone: a review
Published in Journal of Coordination Chemistry, 2022
Freeda Selva Sheela Selvaraj, Michael Samuel, Arunsunai Kumar Karuppiah, Natarajan Raman
Ruthenium(II) complexes with lawsone and lapachol with bipyridyl and diphosphine ligands (10) were assayed for their anticancer properties against breast (MCF-7 and MDA-MB-231) and prostate (DU-145) cancer cell lines. Both complexes showed significant activities. The lapachol complex was found to possess high selectivity for triple-negative breast cancer (TNBC) and induced cell death by apoptosis by forming ROS. Again, a ruthenium complex with the formula trans-[Ru(law)(PPh3)2(N-N)]PF6 (23) (Figure 9) inhibited the proliferative activity and exhibited higher selectivity against lung cancer cell lines A549. The complexes possess higher cytotoxicity than the free ligands [47]. Another ruthenium(II) complex incorporating lawsone, diphosphine and N-N donor ligands (10) was active against prostatic cancer cells DU-145. The activity of the complexes was proposed to be caused by cytotoxicity through the generation of ROS and apoptosis induction. The activity presented by the complexes was 34 times higher than cis-platin [48]. The copper complex of 3-(3′-methyl phenyl azo) (11) lawsone caused cell damage of human breast cancer cell-line (MCF-7) and presented highest cytotoxicity through the production of ROS [51]. Copper complexes of 3-(2-R-phenylhydrazono)-naphthalene-1,2,4-triones (12) were evaluated for their in vitro antitumor properties against SF-295, HCT-8, MDAMB-435 and HL-60 cancer cell lines. The complexes were more active than the proligands. The observed cytotoxicity is attributed to the generation of free radicals [52]. Ruthenium complexes with 2-hydroxymethylidene-indene-1,3-dione ligands derived from the phenyliodonium ylide of lawsone (15) were screened for their anticancer potential against the human ovarian cancer cell lines (OVCAR-5, SKOV-3, UWB1.289 and UWB1.289 + BRCA1). Complexes showed significant cytostatic and cytotoxic effects towards all four cell lines [55]. Bioreductive prodrugs have capability to operate even in hypoxic conditions which remain as the hindrance for cancer therapies. With this perspective, cobalt(III) complexes of dimerized lawsone were examined to design prototypes for bioreductive prodrugs. This perspective has delivered favorable outcomes but still the mode of action is unknown. The complex was observed from CV studies to undergo redox cycling which is the characteristic of a prodrug to achieve hypoxic selectivity. A very similar study has been carried out with cobalt(III) complexes (21) (Figure 8) [64, 65].