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Research
Areas > Current Project
Key
words Introduction Goal Results
1. Albumin-binding prodrugs 2. Drug release 3. Multidrug resistance
1. Albumin-binding prodrugs
Despite significant advances in the chemotherapy of several types of cancer, chemotherapy is not effective enough against common solid cancers. Anticancer agents act predominantly by an anti-proliferative mechanism and lack any anti-tumour selectivity. Thus, chemotherapy is frequently associated with severe side effects due to destruction of normal tissues. As a result, the amount of drug that can be administered is usually insufficient to deliver a lethal concentration of anticancer agent at the tumour site. Moreover, the lack of selectivity of cytotoxic drugs dramatically increases the risk of development of cellular resistance by tumour cells. To overcome these major limitations in cancer chemotherapy, many approaches have been investigated in order to enhance the selectivity for the killing of tumour cells. A very promising approach is the development of non-toxic prodrugs that can release the corresponding active drugs predominantly at the tumor site. Most prodrugs can be considered structurally as three part compounds comprising trigger, linker (or spacer) and anticancer drug:
Macromolecular
prodrugs are being intensively studied,
preclinically as well as clinically, in order to reduce the toxicity and
improve the efficacy of anticancer agents.
Due to its preferential tumor uptake in various tumor animal models, endogenous albumin will be used as a drug carrier.
In situ binding of maleimide-based prodrugs to the cysteine-34 position of circulating human serum albumin (HSA) that accumulates in tumor is a preclinically and clinically validated technology of increasing the therapeutic index of anticancer agents.
This macromolecular prodrug concept is based on two features: a) rapid and selective binding of a maleimide functionalized prodrug to the cysteine-34 position of HSA after intravenous administration b) release of the albumin-bound drug at the target site due to the incorporation of a cleavable bond between the drug and the carrier. The
acid-sensitive (6-maleimidocaproyl)hydrazone derivative of doxorubicin [INNO-206, previously DOXO-EMCH] is being studied
clinically:
Release of the albumin-bound drug predominantly at the tumor site can be achieved through the incorporation of an acid-sensitive or an enzymatically cleavable bond between the drug and the carrier:
An acid-sensitive cleavable bond such as the hydrazone bonds can be applied to carry drugs that contain a carbonyl group:
A widely applicable and effective way to liberate the drug effectively at the tumor site is to introduce a self-immolative spacer between the drug and a lysosomally cleavable peptide that is specifically recognized by enzymes, which are over-expressed in solid tumors. The linkers used in prodrug design can be classified, depending on the reaction mechanism involved in the self decomposition of this unit, into two categories:
1.
Elimination process For example, the incorporation of the PABC self-immolative spacer between the peptide and the drug ensures access to the site of cleavage by the lysosomal enzyme. The self-immolative spacer hydrolytically decomposes upon deacylation, spontaneously releasing the free drug:
2. Cyclization
process Furthermore, some prodrugs can be designed to release the active compound by a cyclization reaction as in the case of the ethylenediamine linkers: In addition to radiation therapy and surgery, chemotherapy is an effective method for the treatment of cancers. Despite the great progress in drug cancer treatment, chemotherapy is often not effective enough to cure patients with solid cancers. The amount of drug that can be administered is usually insufficient to deliver a lethal concentration of anticancer agent at the tumor site. Some cancer cells cannot be treated with chemical drugs since they have the ability to become resistant to multiple different drugs. The intrinsic or acquired multidrug resistance is a phenomenon that is responsible in most of the cases for the failure of the chemotherapy. A number of biochemical mechanisms have been described that are responsible for MDR phenotype that include: 1- membrane changes as well as elimination of the drug from the tumor cell through the action of drug efflux pumps (Figure):
2-
defective apoptotic pathways, due to the over-expression of signal transduction proteins such
as the transcription factor NF-kB (Figure):
3- changes in the cellular target of the respective drug, 4- alterations in enzymatic activation and detoxification mechanisms, Consequently, there has been a concerted effort to develop specific modulators that circumvent MDR. Therapeutic strategies that combine a MDR modulator with anticancer agents have many disadvantages: (1) MDR modulators often alter the pharmacokinetic profile of the co-administered anticancer drugs resulting in a considerable dose reduction, (2) systemic toxicity of the MDR modulators, (3) sufficient concentrations of the MDR modulator and the anticancer drug in resistant tumor cell are not achieved simultaneously since the therapy schedule for two pharmacokinetically unrelated drugs remains unpredictable and needs to be assessed empirically, (4)
a lack of tumor targeting for the MDR modulators as well as anticancer
agents.
Therefore,
we are being involved in the development of prodrugs that avoid these
disadvantages and prove more efficacious in the potential treatment of cancer
patients with intrinsic or acquired resistance. |
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