Nanotechnology: A boon in cancer therapy: Review

There is an irregular and uncontrolled cell division in cancer and is accompanied by an invasion of local tissues and metastasis in distant organs [1]. Cancer is the foremost cause of death despite advanced treatment modalities. [2]. In the present era, radiotherapy and chemotherapy are the primary treatment modalities to eradicate solid tumors. However, chemotherapy harms normal cells also along with cancer cells. [3,4]. The most usually used chemotherapeutic agents, such as paclitaxel and doxorubicin, kills normal rapidly dividing cells in the body along with cancer cells due to the non-selective cytotoxic effect [5].


Introduction
There is an irregular and uncontrolled cell division in cancer and is accompanied by an invasion of local tissues and metastasis in distant organs [1]. Cancer is the foremost cause of death despite advanced treatment modalities. [2]. In the present era, radiotherapy and chemotherapy are the primary treatment modalities to eradicate solid tumors. However, chemotherapy harms normal cells also along with cancer cells. [3,4]. The most usually used chemotherapeutic agents, such as paclitaxel and doxorubicin, kills normal rapidly dividing cells in the body along with cancer cells due to the non-selective cytotoxic effect [5].
Pharmaceutical nanotechnology is a recent technology being used to study the structure,property, and behavior of materials under several hundred nanometers in size [6]. Nanotechnology can solve the problems of current chemotherapeutic agents due to its large surface area in nanosize technology. The nano vehicles with sizes (10-200 nm) are ideal for intracellular endocytic uptake and high drug loading. Thus, it can kill the tumor tissues in a more precise way [2,7]. These artifi cially synthesized nanomaterials can be used to attain safe and effective cancer treatment due to higher therapeutic effi cacy because of the high chemotherapy drug load.Nanoparticle anticancer drug delivery system is benefi cial in intracellular infi ltration and hydrophobic solubility. Nanotechnology affects drug circulation time, reduces non-specifi c uptake, and decreases the toxic effect of anticancer drugs. They act specifi cally against tumor cells and spare normal cells.
Recently, the synthesis of multifunctional theragnostic nanosystems is being done, which can diagnose cancer and screen therapeutic response by imagining the body's tumor legions [8,9]. Soon, the combination of nanotechnology and biological sciences will transform the whole concept of cancer management. This review highlights the ideas of the drug carrier mechanism of nanoparticles, tumor neo-angiogenesis, and enhanced permeability and retention.

Role of Nanotechnology in tumor management by affecting its physiology
Vascular endothelial pores, heterogeneous blood supply, and heterogeneous architecture are physiological obstacles in cancer treatment. Drug delivery to cancer tissue is an excellent task. In the past, anticancer drugs used to affect cancer cells and normal cells of the body and thus had signifi cant side effects. Nanoparticles have multifunctional character and useful in targeted drug delivery in cancer tissue, and normal

Abstract
In cancer, there is uncontrolled cell division, which results in invasion and metastasis. Carcinomas are a signifi cant cause of mortality worldwide. Recently, radiotherapy and chemotherapy are the primary treatment measures that are being used to destroy cancer cells. However, these modalities kill normal cells of the body, along with the destruction of cancer cells. This non-specifi c action is harmful to the whole body, which results in the loss of hairs, anemia, and weakness in the body. Pathological features of tumors and their abnormal neo-angiogenesis also reduce the effi ciency of conventional cancer treatment. Nanoparticles (NPs) have been considered outstanding cancer-targeting vehicles due to their small size, ability to load various drugs and large surface area, and increased absorption of conjugates. They are designed and developed to take advantage of a malignant tumor's morphology and characteristics, benefi ts of leaky tumor vasculature, specifi c cell surface antigen expression, and rapid proliferation. The recent nanoscale vehicles include liposomes, polymeric nanoparticles, magnetic nanoparticles, dendrimers, and nanoshells; lipidbased NPs have been used as conjugates.

Angiogenesis of cancer
There is always neo-angiogenesis from the tissues' pre-existing vascular network during infl ammation, tissue regeneration, and tumor cell proliferation. Excessive or abnormal angiogenesis is common cancer [11,12]. Due to the rapid growth of tumors, they require a fast microvascular network for their development. Due to the hypoxic microenvironment, pro-angiogenic factors like Vascular Endothelial Growth Factor (VEGF) in tumor get stimulated [13,14]. Vascular endothelial growth factor (VEGF), also named as Vascular Permeability Factor (VPF), has been shown to excite the proliferation, migration, and invasion of endothelial as shown in Figure   1a  There is enhanced action of drugs on cancer cells with minimum drug toxicity [19].This EPR phenomenon is for tumor tissues, not for the average healthy tissue in the neighbourhood of cancer. EPR is enhanced by various vascular mediators, such as angiotensin II (AT-II), bradykinin, prostaglandin, and Nitric Oxide (NO) [20]. There is increased systemic blood pressure and increases blood fl ow volume, which enhances   Paclitaxel is a water-insoluble anticancer drug [28], so great diffi culties are preparing its stable solution for effective anticancer therapy [29]. The nanovesicles, such as polymeric micelles and liposomes, bind fi rmly with such insoluble anticancer drugs. The bioavailability and therapeutic effi cacy of these drugs get improved due to encapsulation in these nano vehicles. Compared to these small molecule drugs that are cleared rapidly by renal clearance, nano vehicle-incorporated drugs stay longer in the bloodstream. A suffi cient quantity of drugs can reach the target tissue [30]. As the nano vehicles can fi rmly compress cytotoxic drugs in the interior, they have high levels of power over drug toxicity and release profi les, thus reducing drugs' toxicity to healthy tissues. They also protect anticancer drugs from premature metabolic degradation. A new nanomaterial class response to external triggers like temperature, pH, and light can release anticancer drugs in the specifi c tumor for better effi cacy [31,32].

Polyelectrolyte complex micelles
(Shown in Figure 3) are new nano vehicles that are usually formed by the reaction between anionic macro-molecules and the di-block copolymers and are used for effi cient delivery of charged therapeutic agents [34]. The polyelectrolyte complex micelles are spherical and have an inner core and a hydrophilic outer shell layer. The polyelectrolyte complex micelles can deliver various bioactive macromolecules via the intravenous or intracellular route [35]. Moreover,the different structures and compositions can be used to make them applicable to a wide range of biopharmaceutical applications [6].

Liposomes
(Shown in Figure 3) are spherical with two layers, inner aqueous compartment and outer lipid materials, and are useful for anticancer drug delivery. They have high drug loading capacity and carry water-soluble drugs into their aqueous interior and water-insoluble anticancer drugs into the hydrophobic lipid layer [30]. As liposomes are composed of naturally-derived phospholipids, they are biocompatible with the body and cause minimum antigenic, allergic, and toxic reactions [36]. They are capable of delivering high loads of anticancer drugs to intracellular compartments of tumor cells.
Macrophages in the reticuloendothelial system can engulf the extravasation of NPs in tumor tissues due to the action of AT-II.AT-IIs affects contraction of the smooth muscle layer surrounding the capillary vessels.

Role of nanomaterials in drug delivery in tumors
The nanomaterials provide many unique advantages that are not accessible with other straight anticancer treatments.
First, nanomaterials own a small size similar to biological macromolecules such as peptides, proteins, and nucleic acids, as shown in Figure 3. In measurement, they are many times smaller than the size of a single cancer cell. There is a high intracellular uptake of nanomaterials due to the small size and similarities to biomolecules, and thus can be used for cancertargeted drug delivery [22]. Furthermore, the intracellular nanomaterials react with the biomolecules involved in cancer survival and proliferation [23]. More signifi cantly, nanomaterials can protect themselves from the vascular barriers and biological defence systems of the body. Circulating body macrophages engulf these micro-sized particles comparable in size to those of microbes and thus result in fast clearance of the microparticles from the bloodstream by the reticuloendothelial defence mechanism [19,24]. Well-synthesized nanomaterials of the controlled size can gain entree to many parts of the body via the circulating system, thereby increasing the chances to carry drug load precisely to the tumors.
Second, owing to their enormous surface area relative to their total volume, nanomaterials can carry many therapeutic agents. Due to large surface area, a small size polymeric nanoparticle can carry approximately 2,000 drug molecules [25] in comparison to polymer-drug conjugate, which can carry only nine drug molecules [26]. Such a high drug loading capacity of nanomaterials is advantageous for achieving signifi cant therapeutic effi cacy in cancer therapy. Additionally, NPS offers a chance of surface modifi cation with several targeting moieties (such as small molecules, peptides, or antibodies) for signifi cant cancer penetration. Recently scientists have proved that the multiple attachments of a targeting ligand signifi cantly enhance the ligand-functionalized nano vehicles' intracellular uptake in the specifi c cancer cells. This occurs due to the multivalent binding to the cell-surface receptors [27]. Hence a nanocarrier system with several targeting ligands can easily be used for specifi c uptake by the targeted tumor cells. liposomes due to their large size (50-400 nm). Thus, they can clear them fast and avoid that; they can be incorporated with Polyethylene Glycol (PEG) as an outer layer. This protecting layer prolongs the plasma half-life of liposomes and thus protects them from macrophages. Therefore anticancer drugs stay for a more extended period in the bloodstream, and tumors and act more effectively [19].

Polymer nanoparticles
(Shown in Figure 3

Virus based nanoparticles
There are a few viruses which have a natural affi nity for receptors of malignant cells that could be used for nanotechnology application. The latest technology is used to develop non-infectious, engineered viral nanoparticles for multifunctional nanoscale devices for cancer treatment [39]. CPMV nanoparticles are the smallest virus that can cross intact through the stomach's hostile environment and be taken into the bloodstream via the intestines. So, CMPV nanoparticles could offer a means of administering anticancer drugs and tumor imaging agents orally rather than by injection. Thus, synthetic plant virus particles could prove useful in delivering drugs and imaging contrast agents to tumors because it is possible to attach tumour-targeting molecules to the surface of engineered viral nanoparticles and load various drug-type molecules into the interior of the virus particles. Geneticallyengineered form of the adenovirus was fi xed with a human gene. When delivered into cancerous growth, the virus rapidly multiplies in the cancer cells and kills them. The new adenovirus can target and kill cancer cells selectively without harming normal cells [40,41].

Multifunctionality of NPs is the main advantage in
anticancer drugs therapy as follows: 1. NPs are useful anticancer drug carrier due to large surface area and high absorption rate.
2. NPs loaded with drugs can evade the immune system and cannot be taken away by macrophages. So, less dose of anticancer drugs is needed. Moreover, they can carry many therapeutic drugs due to their high surface-area-to-volume ratio, penetrate the leaky tumor vasculatures, and subsequently deliver the whole drug into tumor tissues via the EPR effect. Thus, nanoparticles deliver a proper dose of anticancer drugs selectively and effectively, sparing the surrounding healthy cells.
Although most of the technologies described above are profi cient and effi cient in cancer treatment, there are still safety concerns regarding nanoparticles' infusion in the human body. A future nanotechnology discovery area comprises the development of a bio-responsive, self-regulatory drug delivery system along with a possibility to obtain a controlled, regulated anticancer drug delivery that kills only cancer cells without any effect on surrounding normal cells.