Keyword: Monoclonal antibodies, nanoparticles, precision medicine, chemotherapy
Targeted chemotherapeutics is the major challenge of the cancer biology, and precision medicine approach, but with the discovery of target specific proteins like monoclonal antibodies and small peptides, with the combination of nanoparticles as the vehicles for drug transport to the tumor cells, it has broadened the use of this in cancer therapy. Because of the very small size of the nanoparticle, it has miscellaneous and multipurpose functions, like a combination of diagnosis and therapy i.e. theranostics. Conjugating these nanoparticles with monoclonal antibodies it can prompt effective targeting, by the release of these nanoparticles at the disease site, due to antibodies, it will minimize off-targeting and adverse side effects on the body.
The major challenge of targeted therapy is to deliver the therapeutic compound to the target site. In general, to find a method for precise drug delivery and eradicate the tumor cells sparing the normal cells is the demand for precision medicine 1-3. The conventional approach of prescription of drug and use has un-conditionally limited the effect of many novel and helpful drugs, causing poor absorption, adverse side effects to the body. This limitation and major drawbacks can be overcome by applying the controlled drug delivery system. Modern research in the field of cancer therapy is now addressing this problem by using nanoparticles as the delivery vehicle 4-6. Nanoparticles are 100 to 10,000 times smaller than the human cells but their size is comparative with the size of enzymes and receptors. Due there size they can enter the most of cells and can move out of the blood vessels, because of their ability it makes them a good vehicle for most of the chemotherapy- drugs.
In this review, we will discuss the recent works have been done by utilizing this smart tool for treating cancer by targeted cancer therapy.
Cancer and current therapy:
Cancer is a disease, which involves uncontrolled cell division and resistance to cell death. The abnormal cell growth is called tumor, except blood cancers, where these cells migrate through lymph systems and enter to the bone marrow. The disease arises because of the mutation and malfunction of proto-oncogenes and tumor suppressor genes that check and control the abnormal cell proliferation, differentiation. These controlling genes control the abnormal cell processes by producing inhibitory signals for the cell growth and cause cell apoptosis. Alterations in these oncogenes and tumor suppressor genes are considered as the main reasons for tumour development and progression 7-9.
Conventional therapy for cancer includes surgery and radiotherapy for benign cells, but these methods proved in-effective when cancer has spread all over the body. The use of anti-cancer drugs, chemotherapy, hormone and immunotherapy are the current choice for the treatment of metastatic cancers 10.
Chemotherapeutic drugs are primarily toxic compounds that inhibit the fast proliferation of the cancer cells but they are not only inhibiting the cancer cells growth but also normal cells like the cell related to hair follicles, bone marrow and gastrointestinal tract layer maintenance cells which leads to the many undesirable side effects on the body 10. Many other combinatory and adjuvant therapy are included in the cancer treatment, but this all works was not helped as they have to, then in late 1990 monoclonal antibodies therapy opened a new door of use of targeted therapy 10. The main aim of targeted therapy to block the specific pathways or critical factors or proteins that are involved in the tumour growth and progression, these targets are present in normal tissue also but are found expressed higher in cancer cells or changed in tumor cells. The monoclonal antibodies can target a specific protein in the cancer cells, so that host immune cells recognize these cells and target them 11. First targeted therapy cancer approved in 1997 was Rituximab was also the first monoclonal antibody available for cancer treatment 12. Because of the target specificity of this proteins, antibody drug conjugates combine the targeting properties of these proteins with the cytotoxicity of drugs, can help in selective accumulation of anticancer compound in the tumor cells. The example of this is a HER2-targeting antibody trastuzumab conjugated to the cytotoxic compound DM1 (mertansine, a maytansine derivative), used for the treatment of HER2-positive metastatic breast cancer 13, not only this but several interesting cytotoxic peptide conjugates are under clinical trials only problem is the short half-lives, that need to be solved 14. So combining this targeting molecule with nanoparticles can open a bigger opportunity for cancer therapy.
Nanoparticles and Nanobiotechnology:
Nanoparticles are synthesized purposely engineered in the lab, that is measured in the size of nanometer (nm) size (10-9), size, surface charge and other surface properties of Nano-materials will govern their physiological fate. For cancer therapy, it is important to effectively in design the nanomaterials as many restrictions imposed by the tumor cells physiology. Different physiological barriers imposed by primary tumors, organ already affected by metastasis and other factors like tumor internal environment that makes the use of one nanoparticle for all difficult. Although nano-particle based therapeutics for cancer therapy face many unique challenges like they have to pass the diverse physiological barriers and face ever-changing disease states, expression levels different molecular targets etc.
Nanoparticles, drug delivery and importance:
Nanoparticles construction was done by a variety of materials like ceramic, polymers, lipids, and metals. This structure contains organic or inorganic elements usually metal as a core 15.
The structure of nanoparticles has very diverse size and shapes, which includes sphere, shells, tubes, fullerenes, emulsions, and liposomes. Therapeutic drugs are united to the nanoparticles by entrapment, surface attachment, or encapsulation.
Nanoparticles a vehicle for drug delivery may be biodegradable, so when it is used for drug targeting, it is degraded and metabolized and does not accumulate in the body and neither causes any adverse cellular toxicity. This is important since the accumulation of high levels of non-biodegradable particles may have toxic side effects on the body.
Nanoparticles and targeting:
The drug delivery by nanoparticles can be either an active or a passive process. Passive delivery of nanoparticles refers to transport through leaky tumor capillary fenestrations into the tumor internal part and inside the cells by passive diffusion 16. Active targeting of drug delivery to the target site by molecular recognition, the approach includes coupling of the ligands to the nanoparticles, so that it binds and interact with the receptor at the target tumor or normal site. Likewise, a specific antibody coupled to a nanoparticleswill binds to the antigenic target site, active targeting is the binding of folate to PEGylated particles for interaction with the folate receptor is an example of active targeting. Overexpression of folate receptors on many cancer cell surface serves as a higher binding affinity for the nanoparticlesfolate bound protein than that of for free folate 17. The folate-conjugated complex undergoes receptor-mediated endocytosis that is lysis of the target due to nanoparticle tagging, as below Figure 1 describe the mechanism.
Not only treatment but if we attach a nanoparticle that can emit some singles we can solve the diagnosis approach also, that means “One stone two birds kills” approach or theranostic in modern terminology.
Figure 1: Approach of nanoparticles as drug discovery vehicle and targeting using specific ligands.
Conclusions and future perspectives:
Due to the increase in the number of fatality or cure of cancer, using conventional chemotherapy is not satisfactory. Adverse Side effects, problem-related to the formulation, retention of drug in the body that is pharmacodynamics and pharmacokinetics, the resistance of cancer cells towards the chemotherapy, toxicity to healthy cells also are major fallbacks of using conventional chemotherapy which makes necessary for a more precise or selective therapy.
The specificity, selectively and targeted therapy can only be achieved by targeting specific pathway, factors and key signalling molecules, that by using the new biological approached like monoclonal antibodies, fragment peptides, drugs which are a blocker to specific targets etc. In targeted therapy, the drugs can deliver by using the nanoparticles as a vehicle and specific target can be located by using the monoclonal antibodies that are specific for the proteins or receptors of the cancer cells.
But this research has to be done in making this complex stable in the body and more target specific there are many new goals to be addressed.