The World Health Organization (WHO) has already emphasized the urgency in designing new antimicrobial molecules, because conventional antibiotics have shown a high propensity to develop antibiotic resistance(27). Another global concern is the rise in the incidence of cancer. (28). There are many natural and synthetic peptides, with both antimicrobial and anticancer activity (29). However, only a small number are used in clinical trials. This is mostly due to the challenges associated with the development of these peptides as pharmaceutical drugs, such as proteolytic degradation, and nonspecific binding (13, 30).
For preventing of degradation, nanoparticles have been developed for encapsulation (31). Another challenge associated with the development of these peptides as pharmaceutical drugs, is synthesis costs. Coprisin is an insect defensin-like peptide from which a synthetic peptide, called CopA3, was synthesized(32). CopA3 displayed antimicrobial activity and inhibited the growth of pancreatic and hepatocellular cancer cells. This is an example of a synthetic peptide based on a naturally occurring substance that exhibits inhibitory activities against microbes and has potential use as a novel anti-cancer agent.
Previous reports indicated that natural defensins purified from human neutrophils have strong antimicrobial and anticancer activity in comparison to synthetic and commercial types (9, 25, 33). A major source that recently has been introduced for purification of natural HNP1-3 is leukocyte reduction filters (LRFs) that used in blood banks to prepare leukoreduced blood products (25, 33). A large number of neutrophils that trapped in leukofilters allowing purify large amount of ?-defensins that can be used in the pharmaceutical industry. It should be noted that the production of defensins by synthetic methods not only is expensive, but also limited due to their composition and the presence of three disulfide bridges.
Therefore, the extraction of defensins from neutrophils of blood donors is a safe and economic source.
On the other hand, defensins are cations and therefore bind electrostatically to the anionic targets of specific microbes. This target specificity for lipopolysaccharide has been proposed for use in anti-endotoxin treatment for patients with gram-negative sepsis. The appearance of resistance to these antimicrobial peptides is rare because they can inhibit or kill bacteria at micro molar concentrations (34). Moreover, the membrane of tumor cells is different when compared to normal cells(35, 36). Cancer cell membranes generally exhibit a net negative charge due to overexpression of anionic molecules such as phosphatidylserine (PS) (37). It’s reported that neutrophil derived ?-defensins, given in mice at the time of inducing peritonitis, led to a diminished inflammatory exudate. In addition, mice infected with pathogenic Salmonella enterica serovar Typhimurium showed a reduced bacterial load and serum TNF? levels upon administration of exogenous ?-defensin. Hence, neutrophil-derived ?-defensins were able to affect profound changes in the inflammatory environment while also serving as effective antimicrobial peptides(38).
In the present article, our hypothesis is application of defensins-based nanoparticles conjugated with two mAb for targeting invasive T cells and bacteria in ATL patients. The controlled delivery to target sites would enable the use of higher doses of defensins for increasing therapeutic efficacy. For drug delivery efficiency, it is necessary that the antigens and receptors are overexpressed or even expressed only in malignant cells (39). Most target antigens are shared between normal and malignant T-cells(40) rendering specific targeting of tumor T-cells challenging. The CCR7+ cell is significantly higher in patients with aggressive ATL than those with indolent ATL and non-ATL. These patients are refractory to ZDV+IFN and chemotherapy (17).
In conclusion, this hypothesis for ATL patients represents a field for more investigation on this topic. Progress in this area could open up new applications in treatment strategies.
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