Receptor-based targeting of engineered nanocarrier against solid tumors: Recent progress and challenges ahead
Introduction
The absorption of drugs in cancer cells from the simple nanocarrier is circumscribed owing to the confined dissolution and drug release, which in turn produces toxic effects and multi-drug resistance along with the adverse effects like nausea, vomiting, temporary loss of physical strength, and energy, neuropathy, and finally organ failure [1]. The non-engineered nanocarriers (NCs) such as vesicular carriers (e.g., ethosomes, liposome, noisome and transferosome), nanoparticle (polymeric, silicon, metallic), carbon-based nanocarriers lacks site-specificity, cell recognition and substantial targeting potential. Further differences in size, shape, dimension, drug payload and loading, and their targetability in pathologic cells, EPR effect, clearance from the macrophagic systems (MPS), biological stability are the critical parameters which further restrain the effective therapy in cancer disease [2].
The surface tailoring of nanocarrier is a prime requirement for tumor targeting as the world engrossed in the modern method of medication focusing on designing the high precision and person specific drug therapy, also called as the personalized medicines for delivering drugs to the target diseased cells without harm to the normal cells [3].
In general, the passively targeted nanocarrier release major part of therapeutics to neighboring cells of tumor and gets accumulated due to the EPR effect. The prominent fenestrations across endothelial cell borders with rapidly growing blood vessels of the tumor tissue passively permits the entry of NCs to the leave circulation within tumors and accumulate in the neighboring cells without harming the normal cells. In this perspective, ligand-receptor based active targeting approach is highly desirable for achieving effective concentration of the therapeutic molecules such as chemical agents, biologicals like proteins, peptides, theranostic agents like mRNA and genes to the target site [4,5].
The engineered NCs are effective therapeutic systems in tumor targeting of the drug and diagnostic aids. During nanocarrier fabrication their surface can be modified with targeting ligands such as aptamer, proteins, carbohydrates, peptides, antibody, and affibodies. The engineered NCs could efficiently target the tumor cells by recognizing specific receptor on the tumor cells surface. The question to be arising here is how to clarify the surface modified nanocarrier could maximize payload delivery to the specific site of the tumor tissues? The same to be answered as the ligand-receptor interaction and their binding maximize the internalization of payload preventing loss of therapeutics via systemically administered nanomedicine in liver and spleen. Preferably, the ideal nanocarrier would be able to deliver their warehouse to the target site within therapeutic window due to better retention and adept penetration of therapeutics and capable of organically cleared from body to overcome the nano-toxicity for long period of accumulation [6,7].
The bioengineered nanocarrier adorned with targeting ligand-based therapeutic approach could be effective potential in targeting of therapeutics to specific cells/tissues by circumnavigating the shortcomings associated with the plain NCs without having any surface modifications. The bioengineered NCs could be developed with improved biopharmaceutical characteristics, thus useful in cancer targeting [8].
The appropriate selection of targeting ligand for specific receptor can attenuate the EPR effect and avoids unspecific cell uptake which is helpful in drug development process for tumor targeting therapeutics and maximal cellular internalization. The nanomedicine internalization can be maximize or minimize depending upon the receptor localization within the tumor or endothelial cells [9].
In the perspective of active tumor targeting, the tumor microenvironment (TME) is an important key domain for designing any nanocarrier for effective drug targeting. In contrary to the normal cells, TME differs in terms of vacularization, uncontrolled cell division, pH, hyperplasia and tissues perfusion, orientation of cell component, oxygenation and metabolic states. These condition produces hypoxia, induces angiogenesis, acidosis, oxidative stress, and resulting metastasis. The oxygen, nutrient supply in solid tumor largely depends upon simple diffusion process from the nearby cells, and in the fast growing state of tumor cells, the inadequate supply of oxygen and nutrient makes deficient of them resulting in hypoxia. The hypoxic condition triggers a set of physiological response in the cells and to cope up with them hypoxia-induced factor-1 activates, leading eventually in energizing vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF-alfa), and platelet derived growth factor (PDGF). The growth, progress and invasion of tumor are multistep complex biological phenomena occurring in tumor microenvironment (TME) [10,11].
Exploiting acidic microenvironment of tumor, Li and associates developed self-targeting nanodrug with 2.98-fold higher cellular uptake and 27.3% tumor suppression ability [12]. Targeting of tumor microenvironment with multimodal theranostic metallic nanoparticles of pemetrexed showed promising result in biomimetic targeted therapy in cancer [13]. Similarly dual responsive polymeric nanoparticles facilitates the cell internalization of plasmid DNA, T-cell mediated antitumor effect and longer survival in B16F10-bearing mice [14].
The first US-FDA approved nanomedicine, a PEGylated liposomal preparation of Doxorubicin credited to orthobiotech for the treatment of various cancers in 1995 greatly influenced the development of nanomedicines in cancer therapy. Several nanomedicine based products on active targeting strategy has been approved and many are under clinical phase. Few examples are Kadcyla, an antibody−drug conjugate, trastuzumab emtansine (T-DM1) indicated for HER2 positive breast cancer [https://www.cancernetwork.com/her2-positive-breast-cancer/fda-approves-t-dm1-kadcyla-her2-positive-breast-cancer]; monomethylauristatin E−brentuximab (SGN-35) an antibody drug conjugate indicated for lymphomas Perjeta [https://www.cancernetwork.com/articles/fda-approves-pertuzumab-perjeta-her2-positive-breast-cancer]; Perjeta, an antibody−drug conjugate of Pertuzumab indicated for HER2 positive breast carcinoma [https://www.perjeta.com]; Ontak, bind with interleukin receptor and receptor mediated endocytosis of fragment A of Diptheria toxin released in cytosol and prevents protein synthesis indicated in cell lymphoma [https://www.accessdata.fda.gov]; Gendicine® a recombinant adenovirus (p53 type) indicated in head and neck squamous cells carcinoma [15]; Rexin-G® retrovirus derived gene indicated for solid tumors [16].
Section snippets
Protein corona, opsonization in biological system
Despite the advances in the NC based drug delivery in the past few decades with promising biomedical utility and cancer therapy, yet the challenges remain unaddressed in clinical application. The literature search shows plentiful research on NC-based on preclinical and clinical study. However, we still far away communicating their application in clinical utility. The ignorance or lack of information about NC interaction with the component of biological environment could be one of the reasons
Tumor microenvironment hallmarks
The tumor microenvironment is a highly complex and heterogeneous (irregular geometry and architect) make the tumor cells deprived of oxygen and nutrients, leads to inflammation, and thus creates dense extracellular matrix and later developed demoplasia due to collagen deposition and cell stiffness. The demoplasic phase further induces invasion, rapid cell division and metastasis. In such microenvironment precise drug targeting is challenging because some cells receives plentiful nanocarrier and
Overcoming EPR based obstacles: role of active targeting
The barriers in the way of EPR based targeting could be restricted by receptor based or active targeting. The different targeting ligands have affinity for specific receptor located on the cell surface receptor is protein, peptide, carbohydrate, small molecules, and aptamers [[42], [43], [44], [45]]. They specifically bind with nanocarrier surface during surface modification process. The engineered nanocarrier has potential to identify and binds with target cell through ligand-receptor
Challenges related to nanocarrier fabrication
There is an aberrant change has seen in the field of drug delivery sciences and their application in medical health care due to radicalization of nano-engineering of biomaterials over the last few decades. On the basis of the current data of clinical approval of nanomedicine it is a big hurdle for the formulators to face critical challenges pertaining to the physicochemical characteristics of NC such as (particle shape size, elasticity, the surface design, surface of charge, storage stability,
EGFR directed tumor targeting
The epithelial growth factor receptor (EGFR) was first discovered by Stanley Cohen and received Nobel Prize in field of physiology/medicine. Afterward several growth factors receptor and their family have been discovered [112].The solid tumor has substantial level of growth factor receptors. The broad family of EGFR receptor is EGF and assigned to receptor tyrosine kinase (RTK) type I. The squamous cancer of head and neck region, renal, pancreatic, colon, brain cancer, breast cancer and ovarian
Location and selection of receptor
Before active targeting one must ensure that location of receptor either on the surface or inside the cancer cell which greatly affected the therapeutic efficacy and potency of targeting drug conjugate. For instance, targeting the intracellular receptor viz., retinoid receptor the targeting moiety should be nonspecifically permeable to the cell membrane to access them. On the contrary, the cell surface receptors viz. urokinase receptor provides ample opportunity for specific targeting [181].
The
Conclusions
We have discussed the recent progress in the field of receptor based active targeting and potential challenges hereunder to cope up for maximum therapeutic efficacy of NC. EPR based NC targeting however achieved not the expected percentage of drug retention in targeting domain argued by xenograft model. To cope up EPR based drug targeting limitation active targeting approach is preferred nevertheless it also grimaces several critical challenges to internalize the therapeutics maximally in the
Declaration of competing interest
Authors declare no conflict of interest.
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