Ligand Decorated Theranostic Nanomedicines

A novel therapeutic approach against tumor targeting

Md. Habban Akhter ,  Assistant Professor, Faculty of Pharmacy DIT University Dehradun, India

Md. Shivli Nomani ,  Principal Bihar College of Pharmacy, India

Md. Qayamuddin ,  Assistant Professor, School of Pharmaceutical Sciences, MVN University, Palwal, India

The use of nanomedicines in cancer therapy has been extensively focused in preclinical study and clinical application in past few decades. In spite of the fact, majority of nanomedicine based on the biocompatible lipidic nanocarrier with employing simple fabrication technique and their worldwide utility is circumscribed owing to failure in targeting capability, poor specificity, and low target concentration of therapeutics and thus, lacks significant clinical vantage over systemic therapy. However, the receptor based targeting of ligand activated functional nanocarrier to specific receptor in tumor endothelial cells, perivascular and stromal cells utilising combinatorial peptide potentially enhanced drug concentration inside tumor cells. The receptor proteins such as GRP78, IL-11Rα and EphA5 are over-expressed state in tumor cells and present opportunities for delivering therapeutic target. The peptides binding to the specific cell surface receptor likewise apoptotic peptides, imaging agents, and or chemotherapeutics could actively deliver to suppress the cancer growth in vivo without causing harm to healthy cells. The review shortly shed light on some of receptor over-expressed in tumor cells and ligand decorated functional nanocarrier targeting to tumor cells for plausible therapeutic efficacy in cancer.

Introduction

The drug absorption in cancer cells from the conventional dosage form is limited due to poor dissolution, toxic effect, and drug resistance along with debilitating adverse effects such as nausea, vomiting, temporary loss of physical strength, and energy, neuropathy, and finally organ failure. The simple nanocarriers made from diverse material likewise, polymeric (nanoparticles), lipidic (vesicles, nanostructure lipid carrier), and metallic of different shape, size, payload capacity, drug release capability, biostability, bio-distribution, retention in the body as well as clearance from the body further impose constraint for therapeutic efficacy towards cancer therapy. For example, size of nanocarrier play vital role in determining the significant to specific site, particle <5 nm cleared in urine and size >100 nm acquitted from reticuloendothelial system. The particle size >200 nm becomes difficult to penetrate the different strata of skin. Similarly, the biocompatible nanocarriers decorated with specific ligand based therapeutic approach effectively circumvent the pitfalls in conventional therapy in delivering chemotherapeutic agents. Preferably, the ideal nanocarrier would be able to deliver their payload to the target site within therapeutic window due to good penetration and retention and should be capable of organically cleared from body to overcome the nano-toxicity from long period of accumulation. Combining the features of simple nanocarrier functionalised nanocarrier could be developed with improved biocharacteristics and thus the nanomedicine therapy in cancer targeting would be clinically efficacious [1-4].

For simple nanocarrier targeting, the majority of the drug passively transported and accumulated non-specifically nearby the cancer tissue due to Enhanced Permeation and Retention (EPR) effect. The large fenestrations at endothelial cell borders, several loose pericyte along rapidly growing blood vessels of tumor tissue passively permits the nanocarrier to the leave circulation within tumors and accumulate to the neighboring cells non-specifically could be a major barrier in effective drug delivery. So due to lack significant concentration of payload to the target site by means EPR effect or passive targeting approach, ligand-receptor based active targeting is highly desirable for effective concentration of therapeutics such as chemotherapeutics, proteins, peptides, imaging agents, plasmid, SiRNA, or genes to the target site [5, 6].

The phase display binds with receptor has been identified for peptide in vivo which can enrich the targeting moieties by ligand binding for efficient cell internalisation. The appropriate selection of targeting peptides could circumvent the EPR effect and unspecific cell uptakes are helpful in drug development process for tumor targeting therapeutics and cell internalisation. The nanomedicine internalisation can be maximise or minimise depending upon the receptor localisation within the tumor or endothelial cells [7]

Deshpande et al. reported that nonspecific targeting are minimised using DOX loaded targeting liposomes for treatment of brain tumor [8]. The phase display technique using targeting peptides enhanced the DOX internalisation in human breast cancer or pancreatic adenocarcinoma cells [9]. For instance, the peptide or anti-body targeting moiety binds with interleukin-11 alpha receptor (IL-11Rα), or 78-kDa Glucose-Regulated Protein (GRP78) receptor over-expressed in breast or prostrate tumor. The tumor-targeting peptides derived from luteinising hormone binds with membrane-disrupting lytic peptides to effectively inhibit human breast and prostate xenograft tumor growth and metastases [10].

Strategic Theranostic nanomedicine in cancer therapy

The simple nanocarrier covers a wide variety of nanoparticles for delivering therapeutic cargos including lipid based (liposomes, niosomes, ethosomes), iron oxide, gold, silver, carbon based such as graphene molecule, carbon nanotubes, polymer nanoparticles, quantum dots, Dendrimer, hydrogel based delivery systems, and silica-based nanoparticles. The specific characteristic of each nanocarrier has been exploited for ideal delivery of therapeutics. The metallic nanocarrier has advantage of inherent contrasting agents whereas in other types of nanocarrier the imaging agents have to be incorporated during the preparation technique [11, 12].   

Magnetic nanoparticle

The iron oxide nanoparticles are very much of interest because of precise drug delivery to target region by the use of magnet. It has multimodal theranostic use and is abide by FDA as theranostic agent. Nonetheless, the limited biodegradability of these nanoparticles has constraint in frequent application due to accumulation in body organs. The iron oxide nanoparticle slowly decomposed in biological system and often show significant retention in vital organs of the body such as liver, kidney, lungs and spleen after 90 days of application. Iron oxide nanoparticles recently developed for Photodynamic Therapy (PDT) therapeutic modality in various types of cancer alternative to conventional therapeutic system. The nanoparticle functionalised with targeting ligand such as fibronectin-mimetic peptide and then encapsulate with second generation PDT drug (Pc4). Thus, the targeted iron oxide nanoparticle has great potential both as Magnetic Resonance Imaging (MRI) agent and PDT drug clinically [13].

Abedin and associates worked on magnetic NP for photo-thermal ablation therapy of breast cancer. They developed gold decorated magnetic core–shell nanoparticle of size approximately 60 nm. The surface of the nanocarrier was positively charged with certain polymer for efficient internalisation within cells. The in vitro characterisation revealed a good nanothermal ablator and MRI contrasting agent and breast cancer investigation indicated high cytotoxicity due to high intracellular uptake triggered by NIR laser [14, 15].

Gold nanoparticle

The gold nanoparticles have potential interest to work MRI agent or in PDT therapies, due to biocompatible and no significant toxicity and no adverse effect. Although, it accumulates in liver, and spleen for month after injection. Use of gold nanoparticles as therapeutic nanocarrier is limited due to poor biodegradability in biological fluid and low payload per particle.

Eyvazzadeh et al. developed a multimodal nanoplateform as MRI contrast agent and nano-heater for photothermal therapy by combining the iron oxide nanoparticles and surface plasmon resonance aided gold nanoparticles. The developed core-shell gold coated nanoparticle was synthesised and in vitro characterised like MRI contrast agent along with light-responsive agent for PDT therapy in cancer. The nanoparticles were further characterised by UV-visible spectroscopy, Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and zeta potential analysis. The optimised particle showed hydrodynamic diameter of 33 nm. The cytotoxicity such nanoparticle was investigated in epidermal carcinoma of a human mouth and showed concentration dependent cytotoxicity. The data showed the potential utility of dual function nanoparticle as MRI contrast agent and photosensitiser for photothermal therapy in cancer [16, 17].

Mesoporous silica nanoparticles

The silica NPs is Generally Regarded as Safe (GRAS) by FDA. Silica NPs are characterised by high surface area to volume ratio owing to periodic uniform sized mesopore of diameter varying 2 to >20 nm engrafted within an amorphous framework of silica particle and the particle size of mesoporous silica nanoparticles varies in between 20 to 250 nm. The mesoporous silica available in varying in shapes such as rod like, spherical, and toroid. By tuning the abundant silane group thorough coupling chemistry, the pore size can be altered to accommodate large payload is a distinct advantage besides approved by FDA.   

The first inorganic based ultrasmall hybrid NP recognised as silica NPs for the treatment of metastatic melanoma is under clinical trial phase I. The NP as labeled with Positron Emission Tomography (PET) and surface modified with peptides and having a dye Cy5for molecular targeting. The pharmacokinetics, clearance, radiation dosimetry and safety profile of silica particle were investigated by computerised tomography and PET post i.v. administration in patients. Findings was consistent, stable and distinct as well as well traced in vivo, nano-toxicity, adverse effect was not attributed to the particle and further suggested safe application of silica NP in diagnosis of human cancer [18].

Carbon nanotubes

The large expose surface area of carbon like structure is attractive due to every atom sufficiently exposed and improved the possibility of ultra-dense surface modification and payload. In addition to the advantages, the major setback of carbon-based structures is their limited biodegradability which results in accumulation in vital organs of the body and systemic deposition further leads to pulmonary problem and immune toxicity. The BioNanofluid comprised of functionalised multi-walled carbon nanotubes for potential receptor based targeting in Papillary Thyroid Carcinoma (PTC) has been investigated by Dotan et al. The nanocarrier has capability to convert external light energy into heat efficiently thus killing specific tumor cells. The BioNanofluid targeted to Thyroid Stimulating Hormone Receptor (THSR) of PTC cells. The laser diode works at 532 nm was illuminated to PTC cell line in set of experiments for fixed duration of exposure. The cell apoptosis monitored with Trypan Blue staining. Findings led to selective ablation of BCPAP, a TSHR-positive PTC cell line and 60 per cent of cells killed 30 second laser exposure on the other hand >70 per cent of cells ablated using Thyrotropin- and Thyrogen-BioNanofluid conjugates, respectively. The results suggested that BioNanofluid platform is potential therapeutic strategy for potent and selective killing of papillary thyroid carcinoma [19].

Graphene sheet:

Graphene sheet is a closely packed 3-dimensional structure of carbon atoms. Because of unparalleled physiochemical and mechanical characteristics, nano-graphene structure poses tremendous interest in biomedical and pharmaceutical applications [20].

Dongzhi Yang et al. developed monoclonal antibody conjugated nano-graphene oxide against Follicle-Stimulating Hormone Receptor (FSHR). This functionalised nano-graphene had particle diameters ~120 nm based on microcopy. Further, radio-labeling enabled nanocarrier for visualisation by PET imaging. The FSHR-targeted, graphene sheet nanoplatform could serve as a significant tool for early detection of metastasis as well as targeting of therapeutics [21].

Conlcusion

The technological advances in the field of biomedical and pharmaceutical sciences led to development of ligand conjugated specific targeting (receptor mediated cellular internalisation) of tumor tissues that left the nearby cells unharmed. The development of metallic nanoparticle, graphene sheet and carbon based nanostructure advances therapeutic approach in cancer therapy. Further investigation in future will provide more insight and better treatment module.   

References:

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21. Dongzhi Yang et al., In Vivo Targeting of Metastatic Breast Cancer via Tumor Vasculature-Specific Nano-Graphene Oxide. Biomaterials. 2016 Oct; 104: 361–371.

Md. Habban Akhter

Md. Habban Akhter has graduated in Pharmacy in 2007 from Jamia Hamdard, New Delhi and received master in pharmacy in Pharmaceutics from Jamia Hamdard, New Delhi in 2009 under the supervision of Javed Ali, Associate Professor at Jamia Hamdard. He had completed doctoral program in Pharmaceutical Sciences in 2016. He had qualified GATE exam conducted by Indian Institute of Technology (IIT), Kanpur, Govt. of India, with percentile of 98.04 in 2007. He has attained and presented several papers in national and international conferences/seminars/symposia. Currently, working as Assistant Professor in DIT University, Dehradun, India.

Md. Shivli Nomani

Mohd Shivli Nomani has more than 12 years of experience in the various departments such as Pharmaceutical Research & development, Education and also guided several projects. He holds bachelor and master (Pharmaceutical Biotechnology) degree in pharmacy from Jamia Hamdard, New Delhi, India, and PhD from SRU, Rajasthan. He received advanced professional training in Protein purification and fermentation technology at Hyderabad. His main area of interest is in formulation development. He has published numerous national and international research papers in reputed journals. He is consultant of Bised Health Care Pvt. In Delhi, India.

Md. Qayamuddin

Md Quamuddin has completed B Pharm and M Pharm from Jamia Hamdard University, New Delhi. Currently, working as an Assistant Professor at School of Pharmaceutical Sciences, MVN University, Palwal, Haryana. He has been teaching for past 7 years and has taught subject like Pharmacology and Human anatomy physiology. He has attended various seminars and conferences and has presented various papers in them. He has several papers in different national and international journals.

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