**3. Ligands for cancer targeting**

*Advances in Precision Medicine Oncology*

caused by chemotherapeutic drugs [3]. The rapid clearance from the body can be seen when the drug was administered in a higher tolerable dose, which ultimately leads to higher toxicity [4]. During targeted therapy, the drug could be modified to target biological transduction pathways and cellular factors. It also targets angiogenesis and apoptosis inducing molecules [5]. In recent years, several studies have been designed to investigate the effects of nanosized medicines inoperative targeting and diagnosis of cancer cells. Nanoparticles can possibly entrench drugs, theranostic agents, and genes [6]. It was also observed from the various research findings that, nanoparticular approach while drug targeting improves drug tolerability and bioavailability [7]. In formulation drug delivery, anchoring, fabricating, protection of payload from getting degradation by enzymes are possible [8]. The anchored nanoparticles can able to deliver a higher dose into tumor cells while bypassing the normal cells. The modified scaffold integration of nanoparticles facilitates biodistribution of specific drug delivery, which conjugates with ligands and eventually binds with tumor biomarkers [9]. Paul Ehrlich recently suggested a magic bullet, where two different targetings are possible with consistent therapeutic action [10]. In recent research articles and patents, it was often observed that many pharmaceutical carriers such as liposomes, micelles, polymeric nanoparticles designed from natural or synthetic sources were used to target chemotherapeutic medicaments in different cancer cells [11]. Many nanoparticles have passed phase II of the clinical trials stage. This suggests that effective active and passive targeting is possible, due to which greater specificity while selecting cancer target is achieved [12]. Nowadays, conjugation of antibodies, peptides, small chemical entities are versatile in delivering anticancer agents in the form of nanoparticle composite [13]. However, tumor targeting is not an easy job! Scientists are targeting tumors in three different mechanisms; (a) Where nanoparticles were pre-exposed with leaky vasculature of tumor cells and encountered with the reticuloendothelial system (RES) or enhanced permeability and retention (EPR) effects [14]. However, (b) active targeting is more advantageous, as inactive targeting, uncontrolled cell proliferative targeting of tumors, and pH and temperature-dependent targeting is possible. In physical targeting (c) pathological conditions such as pH and temperature play a key role. Nevertheless, targeting the tumor side also depends on the size of the nanoparticles. The nanoparticles, which are less than 7 nm, come under hydrodynamic diameters, easily passing through renal excretion [15]. The nanoparticles that are larger than 100 nm are eventually cleared from the circulation by the phagocytic system [16]. The nanoparticles' surface charge also plays a pivotal role, as the particles' cationic charge helps to facilitate internalization [17]. Sometimes surface addition of poly (sarcosine) and poly (ethylene glycol) [18] enhances the circulating half-life of the particles, on the other hand, preventing nanoparticles from getting engulfed by the reticuloendothelial system; by which accumulation of a certain amount of nanoparticles on the outer surface of the cancerous tissue is possible. To make nanoparticles more advanced, hooking ligands onto the nanoparticles' body

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facilitates internalization into cancer cells.

To target cancerous cells, it is essential to target molecular aberrations. Effective

nanoparticular therapy for cancer targeting relies on the ability to targets such genetic alterations to provide significant clinical benefits [19]. Nowadays, scientists are more focused on targeting p53, ALK PIK3CA, KRAS, G-NAQ, MET, BRAF, EGFR, CKIT genes, and certain pathways, i.e., PI3K/Akt/mTOR, etc. [20].

**2. Molecular targets in cancer**

Ligands are a prerequisite for cancer. Recently, immunotoxin has obtained clinical approval from USFDA, and more than 100 ligand-targeted therapies are under clinical trials [21]. Newly developed phase-display techniques allow selective targeting with higher affinity. The bispecific antibodies and fusion proteins have been used for therapeutic purposes. Mostly the nanoreservior systems viz., niosomes, and polymeric nanoparticles are most suitable for ligand-based targeting [22]. However, pharmacokinetic behaviors and bio-distribution understanding of the molecules are still unknown. The principles of Ligands for cancer targeting can also be applied to the targeted delivery of gene medicines such as antisense oligonucleotides [23].
