Nano-based Drug Delivery System for Hacking Colon Cancer Cells

Brief on Colorectal cancer

Cancer is a major cause of fear of death in both the developed and the developing country and also a leading public health problem. Colorectal cancer is the fourth most cancer detected worldwide, although significant progress in therapy still leads to significant mortality and mobility. The American cancer society surveyed that about 1 in 23 women and 1 in 21 men will develop colorectal cancer during their lifetime. Colorectal cancer is the major reason for morbidity and mortality. In line with other cancer, the major reason behind the colorectal cancer mortality is its malignancy. Wherecolorectal cancer patients have the chances of 90 per cent survival rate for five years before entry into the Duke E stage, but once it initiate the chances of survival falls to 12 per cent. The lifestyle factors such as high lipoid western diet; smoking and alcohol use have direct action to trigger the polyp growth in colorectal cancer.

Several studies considered for the genotypic, phenotypic and progression of colorectal cancer. The surgery, chemo and radiotherapy are most relevantly used treatment strategy but each of them arises with the predetermined side effect. Chemotherapy with the use of cytotoxic drugs such as 5-fluorouracil, oxaliplatin and irinotecan are commonly used alone or in combination but arises with various side effects. 90 per cent of the therapy failure in patients is mainly due to the phenomena called as the drug resistance and when we are considering with the case of colorectal cancer, P glycoprotein (P-gp) which belongs to a family of ABC transporter protein plays a major role and the other factors include; decreased therapeutic concentration of the drugs inside the cancer cells, toxicity to the normal cells, the unwanted effect of the chemotherapeutic agent, recurrence of cancer and the difficulty to address the cancer cells during the metastatic stage. For the betterment of the cancer patients, these strategies need to be evaluated and should be addressed [1].

Lipid-based Nanoparticles for colon cancer

Over the past 50 years, various nanoparticles of varied size shape and chemical nature showed with high efficacy in encapsulating several anticancer cargoes, including antibiotics, siRNA and chemotherapeutics. These first-generation chemotherapeutic nanoparticles reach the cancer cells by using the assist of the EPR effect shown by the lymphatic and vascular drainage of the cancer cells; this generated the extravasation and accumulation of the nanoparticle within the cancer cells and enhancing the therapeutic efficacy. Liposome-based technologies are traditional methods used and the first approved human used nanocarriers by the US FDA. Build up with the bilayers of phospholipids with an external or internal aqueous phase backing the encapsulation of both the lipophobic and lipophilic drugs. The polymeric nanoparticles are also effectively used and are found to be more stable as compared to that of the liposomes with a strong platform that can encapsulate both the lipophobic and lipophilic drugs.

The use of the nanoparticles for the early diagnosis and of the monitoring of the efficacy of the therapy is also well known which can improve the specificity and sensitivity of colorectal cancer diagnostics.The recent trend in Nanomedicine covers the use of the combination therapy of cytotoxic agent entrapped within the targeted nanocarriers, which aid in the site-specific drug delivery and allows a sustained release, could even alter the elimination cycle and increase the efficacy [2].

With the initiation of the research work a combination strategy of the drugs in which the first-line chemotherapeutic drug (5-FU) and other is a natural P-gp inhibitor (overcoming drug resistance) encapsulated in a Nano droplet for the Management of colorectal cancer came up with a positive result [3].The selection of the natural inhibitors should be in such a way that it can have a dual mode of action, as a chemosensitiser and also as a chemotherapeutic agent. These natural agents are used from ancient times as a remedy for various agents and are reported to be safe [4]. The access for these agents is easy and economical as well. The encapsulation of this dual drug in the Nanocarriers especially by using the Self-Nano emulsifying drug delivery system is also affordable. Considering the formulation aspects the Nanoparticles are mainly composed of lipids and these lipids are also having a specific mode of action on the cancer cells.

Lipids have various deals for the treatment of colon cancer. Lipids can be used for the target-specific action of the drug to the colon cancer cells, to alter the MDR related issues and during the metastatic stage of cancer. Since the metastasis of the cancer cells mainly originates through the lymph nodes this approach may have the potential to treat metastasis malignancy as the transport of the lipids mainly take place through the lymph nodes. For the rapid proliferation, cancer cells utilise and metabolise a high quantity of lipids compared to that of the normal ones. They mostly utilise the fatty acids as a source of energy and as a precursor for various biological processes. This is meant to be a kind of stealth mechanism where the lipids are considered as an energy source to the cancer cells which is helpful for targeting the drug specifically to the cancer cells thereby the degree of toxicity to the normal one could be reduced. This lipophilic pro-drug approach releases the lipids by cleavage, leaving behind the parent drug then gets eventually distributed into the tumor cells to elicit its cytotoxic effect. When one of the fatty acid is replaced with the drug molecule then the drug can enter into the triglycerides (TG) deacylation-reacylation pathway. TG hydrolyses to 2-monoglyceride (2-MG) and free fatty acid in the lumen of the gastrointestinal tract, where the monoglyceride get absorbed into enterocytes and will get reacylated to form TG. TG will then be incorporated into lipoprotein, followed by its accumulation into the lymphatic system. This drug conjugates will utilise lymphatic transport for its lymphatic drug targeting and enhance drug absorption. The function of the lymphatic system for the transport of dietary lipids from the intestine to the lymphatic capillaries facilitates the lipid drug combination to efficiently use this pathway and to integrate into the enterocytes and enter into the lymphatic capillaries and hence to overcome the first pass metabolism exhibited during the oral administration of the drug [5].

The use of the lipids in the Nano formulation can be selected based on the pH and temperature specificity. The colon cancer cells elicit a temperature range higher and lower pH than the normal cells. The targeting of the colonic region can be made available by coating with a pH sensitive polymer or by using homing devices.The major reason for the coating of the Nanoparticles with the coating material is to reduce the degradation of the lipids in the gastrointestinal tract. The lipids have the ability to get breakdown from the mouth to the small intestine; hence the effective delivery of the lipids to the colorectal region is necessary.

When the nanoparticles are combined with the chemotherapy drugs, a substantial reduction in the tumour growth is observed than when chemotherapy is used alone. The nanoparticles efficiency is studied more prompt for the cure of the various disorders. The effective use of the nanoparticles for colon cancer is described in short below.

Nanomedicine hacking the six responses

Challenges associated with the treatment failure can be handled by incorporating nanotechnology connecting with the effective therapeutic formulation. The richness and inventively of the

Nanoparticles for the management of colorectal cancer cells are mentioned below:

1. Degradation: Nanoparticles might preventthe enzyme and metabolic degradation and the unsuitable environment, nevertheless protection against early clearance from the body.
2. Size: Due to their size, nanoparticles can interact upon the intracellular and the cell membrane and hence have an immense property to deal with the drug resistance part.
3. Targeting:  Nanomedicine facilitates active and/passive targeting by taking the asset of the leaky microvasculature of the tumor cells, therewith improving the bioavailability of the chemotherapeutic agents, reduce the adverse effects and increase in the therapeutic concentration of the chemotherapeutic agent within the cancer cells. Passive targeting by making use of the enhanced permeation and retention (EPR) effect.
4. Drug Loading: Enormous drug loading efficacy, improved chemotherapeutic effect.
5. Tumor marker: Nanoparticles can target the Carcinoembryonic antigen which is the tumor marker for colorectal cancer.
6. Administration: Nanomedicine can be effectively administered by inhalation, via rectal route, oral route or systemic route; these ways of administration are well adapted for the treatment of gastrointestinal diseases which includes colorectal cancer which helps in improving the patients comfort and compliance [1].

Targeted Nanoparticles for colorectal cancer

• The evolution of therapeutic modalities using nanoparticles as a drug delivery system became one of the most dazzling approaches for cancer therapy.
• Surface modification of nanoparticles using the ligands for cancer cell targeting has yield a new generation of nanoparticles.
•  Targeted nanoparticles might take improvement of differentially conveyed molecules on the surface of tumor cells, providing an adequate release of cytotoxic drugs.
• Nevertheless, the use of contrast agent came up with disadvantages such as rapid clearance; low tissue specificity and nonspecific extracellular distribution, the use of the targeted nanoparticles modify such contrast agents to enhance the specificity and sensitivity for the diagnosis of colorectal cancer [2].

Future Perspective

The upcoming future of definite-targeted Nano formulation includes the most efficient combination for colorectal cancer is just around the corner due to the auspicious assets in the field of research and a trend should be followed which initiate in the increase in the marketing of the Nanomedicine for the management of the colorectal cancer and other ailments.

Reference

[1] Kotelevets L, Chastre E, Desmaele D, Couvreur P. Nanotechnologies for the treatment of colon cancer: From old drugs to new hope. International journal of pharmaceutics. 2016 Nov 30;514(1):24-40.
[2] Cisterna BA, Kamaly N, Choi WI, Tavakkoli A, Farokhzad OC, Vilos C. Targeted nanoparticles for colorectal cancer. Nanomedicine. 2016 Sep;11(18):2443-56.
[3] Karthika C, Sureshkumar R. Can curcumin along with chemotherapeutic drug and lipid provide an effective treatment of metastatic colon cancer and alter multidrug resistance?.Medical hypotheses. 2019 Nov 1;132:109325.
[4] Tran S, DeGiovanni PJ, Piel B, Rai P. Cancer nanomedicine: a review of recent success in drug delivery. Clinical and translational medicine. 2017 Dec 1;6(1):44.
[5] Karthika C, Sureshkumar R, Shivasaraun U, Vasanthi C, Nethravathi P. Plasma Glycoprotein Efflux Induced Resistance: Implications, Mechanism, Inhibitors, and Novel Strategies to Overcome. Asian Journal of Pharmaceutics. 2018 Oct 1;12(4):261-71.