Smart Nano-Enabled Drug Carrier in Combating Tumor Development and Progress

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

Md. Shamshir Alam ,  Associate Professor in Department of Pharmacy Practice, MM College of Pharmacy, MM (Deemed to be University), Mullana-Ambala, India

Md. Akram Minhaj ,  Department of Pharmacology, Maulana Azad Medical College and Hospital, New Delhi, India

The era of conventional therapy has now been gradually changed to smarter way of treatment approach based on smart nano-enabled drug carrier in combating tumor disease and progress. Smart nano-enabled drug carrier or smart drug delivery system offers precise drug release at site of target with reduced drug dose, dosing frequency in a controlled way so as the patience compliance achieved which further mitigate the dose related side effect. Smart nano-enabled drug carrier based smart delivery of therapeutics in cancer therapy nowadays is the work of interest and creates a wave among the scientist working in the interdisciplinary area across the world. Smarter delivery of nanocarrier however, achieved golden therapeutic potential and nevertheless a lot of thing entrusted to gain with efforts in future. This critique details in brief about the smart nano-enabled drug carrier in tumor therapies such as smart liposomes, nanoparticles (gold, iron oxide, silica), theranostic nanoparticles, micelles, dendrimers, carbon nanotubes, quantum dots, and also mentioned their nanotoxicity.

Introduction:

The worldwide report of mortality due to lethal disease cancer is common and progressive nowadays. Although nanomedicine advances in tumor biology and medical research in such prognosis is far ahead however, still a potential threat prevalent in the form of lethal diseases in human beings. With the growing apprehension of smart nano-enabled drug carrier and nanomedicine advances in cancer therapy will likely to resolve the problem of neoplastic disease.  The failure of chemotherapy in mitigating wide spread growth of cancer cells, and non-recognition of healthy vs cancer cells is major the set back in this treatment regimen. The growing cancer cells are generally bear mutant gene, and to control the growth such adaptable cells is very difficult with conventional approach. Despite of these the multi-drug resistance which enables the cancer cells to escape the effects of anti-neoplastic agent in this therapy led to the development of nano-enabled drug carrier for targeted therapy. The nano-enabled drug carrier promisingly delivered the drug at the target site. Nanotechnology advances in drug delivery system making the system more easy and reliable for loading therapeutics as conjugate in nano-drug carrier which enables the controlled release therapy for extended time period in accordance with rational drug design and hence patient compliance could be achieved. The nano-enabled drug carrier offers precise and effective release of drug at low dose, give smooth plasma drug profile, minimise dose related side effect, adverse effect, toxicity, and hence often biodegradable and biocompatible with biological system. The marketing of nanomedicine based on nano-enabled drug carrier alike Abraxane, Doxil, DaunoXome, Myocet showed superior therapeutic efficacy in cancer treatments [1].

The concept of magic bullet given by P. Ehrlich for active drug targeting evidently proved their significant role in nanodrug delivery to specific site. The nanocarrier is the building block of nano-enabled smart drug delivery. The nanocarrier should comply the requisite condition for smarter delivery with cells such as biocompatibility, biodegradability, non-toxic, capable of delivering nanodrug to the projected site of application efficiently and keeping healthy cells unharmed. This brief review emphasizes the current application of nanotechnology based nanodrug carrier system which enables the drug delivery to cells, tissues and organs mediated via specific transit pathway (extracellular, intracellular, diffusion, paracellular, intercellular, transcellular) and ligand gated or  receptor mediated cellular entry (vital for efficient nano drug delivery) [2]. The some of the nano-enabled drug carrier hashed out here are smart metallic NPs, smart micelles, dendrimers, smart liposomes, carbon nanotubes, and quantum dots.

Concept of drug targeting
Generally passive and active targeting mode of drug delivery utilising nanocarrier are highly quoted in the literature. The passive mode of drug targeting lacks cell recognition, rather it pours drug in the nearby area of diseased site by a phenomena so-called enhanced permeation and retention (EPR) effect. The extravasation of nanocarriers through inadequately formed leaky microvessels of angiogenic tumour tissue, and pathetic lymphatic drainage as well as the particle size all together contribute EPR effect [3].
 
On the another hand, the active targeting is site specific delivery of nano-enabled drug carrier which are capable of recognising binding site with cell surface receptor. The published writing convey the reports regarding nanodrug binding to the target site by identifying the structural geometry, shape, and size of binding domain together play significant role in efficient delivery of therapeutics. The rigorous understanding of molecular pathways involved in various kinds of tumor development and their progress ought to carry novel message for potential delivery and treatment regimens of nanotherapeutics. The active targeting process associated with functionalisation of nanocarriers (carry multiple groups for identification of cell surface receptors). The surface functionalisation of nanocarrier could be accomplished by conjugation reaction, activation followed by surface attachment of ligand materials such protein, antibody, phage DNA, RNA, etc depending upon the site of target and presence of dominating receptor at specific site. Such functionalised nanocarrier has high affinity to get internalised in tumour cells though different molecular pathways. The scientist adopting active targeting for nanodrug delivery to cancer cells owing worldwide acceptance both in vitro and in vivo and in clinical research study further ascertained the instigated uptake of such carriers into cells [4, 5].

Characteristics of smart nano-enabled drug carrier
The schematic drug carriers lack ability to deliver their content at right concentration, at right place or the target area upon internal or external stimulation. Thus this type of drug carrier can’t be assigned as smart drug carrier. Further, it required surface modification to make them ideal as smart nano-enabled drug carrier for precise and controlled drug targeting.

Most preferably smart nanocarrier should be capable of delivering efficiently nanodrug as well as other component likewise imaging agent, viral DNA, RNA at the site of target, may be accumulated in the vicinity of target for enhance permeation and retention effect, and biologically degraded and finally excreted out from body.

Therapeutic approaches based on Smart Nano-enabled drug carrier in cancer therapy

Smart liposomes:
Liposomes consist of membrane phospholipid of amphiphillic in nature hence called as amphipathic nanocarrier. The main component of membrane phospholipids is fatty acids which is having head as hydrophilic part and tail as hydrophobic part. The self assembly of liposomes bi-layer vesicles (polar and non-polar end) was first of all demonstrated by G. Gregordians in few centuries back by introducing in aqueous medium. The bi-layer of lipid is further divided into two types such as uni-lamellar and multi-lamellar vesicles depending upon the size of liposomes. It can be developed by several methods; thin film hydration, reverse phase evaporation, dialysis and solvent injection methods. The most recent technology implanted the application of supercritical fluid technology for preparation of liposomes. Due to inefficient drug loading, stability problem, short biological half life as well as quick release rate of medicaments smart liposomes are employed.

Smart PEGylated liposomes: It escapes the reticuloendothelial cells an increase blood circulation half life resulting in longer duration of action and prompted therapeutic efficacy of loaded therapeutics.

Smart grafted liposomes: The hyluronic acid-grafted liposome developed by Qhattal and coworkers meant for targeting breast cancer advances. The mean particle size of grafted liposome varied 120–180 nm. The result of his study demonstrated that 120-180 nm of liposomes could easily entered the cells through lipid raft-liaised endocytosis process [6].

Radiolabeled liposomes: The functionalisation of liposomes with radiolabeled ligand are said to be radiolabeled liposomes. The radiolabeled liposomes are used to diagnose the bio-distribution of drug loaded liposomes their release towards tumor site.

Theranostic liposomes: able to carry both imaging as well as therapeutics simultaneously.  . Despite this it is also capable of co-delivery of genetic material along with chemotherapeutic agents [7].

Smart Micelles
The smart micelles consist of amphiphillic block copolymer of having water soluble hydrophilic shell for loading aqueous chemotherapeutic agents and hydrophobic core meant for incorporating water-insoluble anti-cancer agents. It shows the characteristics of self-assembly when in contact with water above critical micelles concentration (CMC) orienting polar heads towards solvent whereas hydrophobic part away from solvent. The hydrophilic shell provides stability to nanosize micelle structure. The size of micelles ranges to 100 nm, which is capable of accommodating high payload, deeper penetration in cancer tissues, uniform long circulation, and bio-distribution making ideal nanocarrier for anti-cancer drug delivery [8].

Grafted micelles Hyaluronic acid grafted micelles fabricated for targeting in breast cancer. The drug delivery system having paclitaxel as chemothepeutic agent and micelles targeted against CDD4 receptor in breast cancer. The system capable of targeting and delivering drug at endosomal pH which is highly desirable for effective targeting. Thus, dual purpose micelles a promising smart nanocarrier for advance targeting of paclitaxel at endosomal pH in breast cancer [9].

Dendrimers: It is a novel polymer with several branches ranges from 10-100 nm in size. It can be differentiated into three parts; a core, branching dendrite and surface loci of active groups.  It has been widely explored due to size tuning, high payload, flexibility, multiple active loci for surface modification, biocompatibility and biodegradability, and reduced clearance from reticuloendothelial system. The different types of dendrimers are quoted in literature such as, PAMAM dendrimer, polylysine dendrimer, oxygen and carbon based dendrimers, silicon, phosphorous and Newkom dendrimers. These dendrimers are highly efficient in delivering nucleic acid, genetic materials, as contrasting agent for imaging and diagnosis of tumor [1].

Metallic nanoparticles:
Gold nanoparticles. It is highly explored metallic NPs for due to nanosize, adjustable surface area to volume ratio, thermal ablation therapy in cancer, surface functionalisation, and easy manufacturing etc. Different types of ligand molecules (folic acid, tranferrin receptor) can be grafted on this nanoparticles depending upon the site of target. Studies reported for gene transfection by gold NPs, heparin labeled fluorescent gold NPs for cancer diagnosis [7].

Paramagnetic NPs. The smart SPIONs developed by micro-emulsion, thermal decomposition, co-precipitation, sono-chemical, and microwave assisted techniques. It is a member of the nanocarriers’ family which has theranostic characteristics and can be detected by external magnetic field [10].

Smart carbon nanotubes. It is a allotropes of carbon, with seamless cylindrical tube of either single walled or multi-walled highly efficient for surface functionalisation, PEGylation, pH and enzyme dependent drug release. Carbon nanotubes are a promising nanocarrier for the delivery of aptamers, plasmid DNA, siRNA, and antisense oligonucleotides [11].

Smart quantum dots. It is fluorescent nanocarriers of semiconducting nature which are composed of hundreds to thousands number of atoms. A neurotoxin quantum dot conjugate developed from snake venom to target boundaries of neoplasm marked by UV-irradiation [12].

Conclusion
Smart nanocarrier play significant role in modern science era and in biomedical application. This nanocaeer has won limitations associated with conventional therapy in cancer. Whilst critical challenges still ahead of this journey for promise therapeutic modalities in tumor development and their progress. The nanotoxicity is of great concern for successful delivery and hence to critically considered during evaluation stage.    

References
1. Md. Habban Akhter, Saima Amin. Nanocarriers in advanced drug targeting: Setting novel paradigm in cancer therapeutics. Artif Cells, Nanomed, and Biotech. 2017;46:873-884.
2. Md. Habban Akhter, Saima Amin. An investigative approach to the treatment modalities of squamous cell carcinoma. 2016. Curr drug deliv. 2017; 14:597-612.
3. Md. Habban Akhter, Javed Ahmad. Epidermal growth factor based active targeting: A paradigm shift towards advance tumor therapy. 2018. Artif Cells, Nanomed, and Biotech. 10:1-11. DOI: 10.1080/21691401.2018.1481863.
4. Md. Habban Akhter. Nanotherapeutic Intervention in Cancer Disease. e-newsletter, November, 2017
5. Md. Habban Akhter. Multifunctional nanocargo in the treatment modalities in tumor microenvironment. e-Newsletter, 2017.
6. Qhattal HSS, Liu X. Characterisation of CD44-mediated cancer cell uptake and intracellular distribution of hyaluronan-grafted liposomes. Mol Pharm. 2011;8:1233–1246.
7. Hossen S, et al. Smart nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: A review. Journal of Advanced Research. 2018. [In Press].
8. Seo S-J, Lee S-Y, Choi S-J, Kim H-W. Tumor-targeting co-delivery of drug and gene from temperature-triggered micelles. Macromol Biosci 2015;15:1198–204.
9. Yanhua L, Chengming Z, Wenping W, et al. CD44 receptor targeting and endosomal pH-sensitive dual functional hyaluronic acid micelles for intracellular paclitaxel delivery. Mol Pharm. 2016;13:4209–4221.
10. Md. Habban Akhter. Nanocomposite of hybrid metal- organic framework in drug delivery and Theranostic application. e-Newsletter, December, 2017.
11. Md. Habban Akhter. Carbon Nanotube: A Drug Delivery Platform in Neurological Disorder. Acta Scientific Pharm Sci. 2018:2;60-61.
12. Md. Habban Akhter. 3D cell culture technique: A next generation tumor research in translational medicine. e-Newsletter Pharma Focus Asia June, 2017.

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. Shamshir Alam

Md. Shamshir Alam is a M.Pharm., Ph.D. in Pharmacy Practice, from Hamdard University, New Delhi, India. Currently working as an Associate Professor in the Department of Pharmacy Practice, MM College of Pharmacy, MM (Deemed to be University), Mullana-Ambala, India. He is actively involved in research and has guided 02 PharmD and 05 M. Pharm. research projects till now. Currently, he has 02 PharmD project guidance to his credit. Major thrust areas of his research interests include Antibiotic resistance, Pharmacoepidemiology and Pharmaceutical care.

Md. Akram Minhaj

Md. Akram Minhaj has completed his graduation and post graduation in Pharmacology from Jamia Hamdard University. He has completed his Doctorate (Pharmacology) on Diabetes Mellitus. He is presently doing Research in the Department of Pharmacology, Maulana Azad Medical College, the University of Delhi in the cadre of Diabetes and related disorder. He is involved in ADR monitoring. He is a recipient of Best Teacher Award and Best English Commentator awards in various Domestic levels Cricket Match. He has received UGC Sponsored fellowship during PG Programme after cracking GATE. Dr.Minhaj has published 22 research papers in various reputed national and international journals. He has added two chapters in a Pharmacology book.

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