Organic Materials as Smart Nanocarriers for Drug Delivery

Russia

Series Preface: Pharmaceutical Nanotechnology

Alina M. Holban, University of Bucharest, Bucharest, Romania

Due to its immense applicative potential, nanotechnology is considered the leading technology of the 21st century. The science and engineering of nanometer-sized materials is currently employed for the development of numerous scientific, industrial, ecological, and technological fields. Biology, medicine, chemistry, pharmacy, agriculture, food industry, and material science are the main fields which have benefited from the great technological progress developed in nanoscience.

In the pharmaceutical field, nanotechnology has revolutionized traditional drug-design concept and the art of drug delivery. The idea of a highly specific nanoscale drug for the targeted therapy of diseases is now considered a feasible treatment for severe health conditions.

Some scientists believe that the pharmaceutical domain has been reborn by the important contribution of nanotechnology. The field of pharmaceutical nanotechnology has the potential to offer innovative solutions for diagnosis, therapy, and prophylaxis domains. Application of nanotechnology tools in pharmaceutical research and design is likely to result in moving the industry from a blockbuster drug model to personalized medicine. The current main focus of clinicians is to treat patients individually, not their general diagnosed diseases, which are usually difficult to diagnose or incorrectly diagnosed. There are compelling applications in the pharmaceutical industry where suitable nanotechnology tools can be successfully utilized. By designing and modifying drugs at nanoscale, pharmaceutical nanotechnology could be useful not only for the development of completely new therapeutic solutions, but also to add value to existing products. This possibility opens perspectives of success for pharmaceutical companies in existing markets, but also for new markets.

Scientists have manifested an impressive interest on the field of pharmaceutical nanotechnology research in recent years. However, we face today a true dilemma of data unavailability, due to the multitude of existing information which can be highly inaccurate and contradictory. This is because of the lack of an efficient model for sorting the plethora of nanotechnology tools and information that exists, and strategically correlate those with potential opportunities into different segments of pharmaceutical research and design.

This series is trying to cover the most relevant aspects regarding the great progress of nanotechnology and its impact in the pharmaceutical field and to highlight the currently emerging trend of pharmaceutical nanotechnology towards the personalized medicine concept.

The 10 volumes of this series are structured to wisely offer relevant information regarding basic concepts and also to reveal the newest approaches and perspectives in pharmaceutical nanotechnology.

Nanoscale Fabrication, Optimization, Scale-Up and Biological Aspects of Pharmaceutical Nanotechnology, introduces the readers into the amazing field of nanoscale design. Also, this volume facilitate understanding of the biological requirements of nanostructured pharmaceutical formulations for obtaining advanced drugs.

In Design and Development of New Nanocarriers, the most recent progress made on the field of nano-delivery is discussed. Modern nanostructured drug carriers employ innovative solutions for the detection and treatment of various diseases in a personalized and efficient manner.

Design of Nanostructures for Theranostics Applications, highlights the impressive impact of nanotechnology in the development of combined diagnosis and therapy concept: theranostics.

Design of Nanostructures for Versatile Therapeutic Applications, offers a dynamic solution for immune modulation, treatment of diseases by natural-based products and infection control, while employing nanostructured solutions to achieve top results.

Nanostructures for the Engineering of Cells, Tissues and Organs: From Design to Applications, is a highly investigated and debated field; tissue engineering, is dissected through this volume. Here is shown how nanotechnology has advanced research and applications in the manipulation and engineering of cells and tissues in vitro.

Organic Materials as Smart Nanocarriers for Drug Delivery, deals with the specific world of organic nanomaterials, revealing their wide applications, types, and advantages in drug delivery.

In the volume entitled: Inorganic Frameworks as Smart Nanomedicines, the main focus is to discuss the variety and properties of inorganic nanostructures for therapy and drug delivery in the context of improved personalized medicine.

Lipid Nanocarriers for Drug Targeting, deals with recently developed lipid nanostructures and the advances made in drug targeting.

Drug Targeting and Stimuli-Sensitive Drug Delivery Systems, dissects smart stimuli-responsive nanosystems employed to specifically detect various biochemical conditions and control the release of drugs.

Fullerens, Graphenes and Nanotubes: A Pharmaceutical Approach, reveals major findings made on widely applied drug-design nanosystems, namely fullerens, graphenes and nanotubes. The impact of these nanostructures in pharmaceutical research is highlighted.

All 10 volumes are nicely illustrated and chapters are organized into a logical manner to be accessible to a wide audience. The series is a valuable resource of new and comprehensive scientific proof on the intriguing and emerging field of pharmaceutical nanotechnology, which could be of a great use for scientists, engineers, pharmaceutical representatives, clinicians, and any non-specialist but interested user.

Preface

Organic materials as smart nanocarriers for drug delivery

This book offers an up-to-date overview on organic materials presented as smart nanocarriers for drug delivery. Different types of nanocarriers (such as natural polymers, synthetic polymers, dendrimers etc) are dissected and their potential to be utilized as vehicles for therapeutic agents is presented. The volume highlights the importance of smart nanocarriers in the administration of drugs, by enhancing the efficacy of therapeutic agents, significantly reducing toxicity, and associated side effects. The contributors present numerous in vitro and in vivo procedures for drug and gene delivery.

The book, Organic materials as smart nanocarriers for drug delivery, contains 16 chapters, prepared by outstanding researchers from Italy, Russian Federation, Portugal, Canada, Nigeria, México, Malaysia, Turkey, Jordan, India, and France.

Chapter 1, Metal organic frameworks (MOFs) as expanding hybrid carriers with diverse therapeutic applications, prepared by Sarwar Beg et al., provides an overview of various types of MOFs, their characterization and applications in diverse disciplines of biomedical sciences, with particular focus on drug delivery and theranostics. It also highlights the stability and toxicity issues of MOFs, along with their market potential.

Chapter 2, Natural and semisynthetic polymers in pharmaceutical nanotechnology, prepared by Isra Dmour et al., highlights the different classes of natural polymer-based nanocarriers and their chemical modification, advantages, pharmaceutical applications, and limitations as nanosystems. The various methods used in cross-linking of natural polymers are also discussed. A special insight is given on the release kinetics exhibited by natural polymers and the modern advances in engineering polymeric nanocarrier for tailoring specific cargo and drug targeting to certain biological function.

Chapter 3, Current perspectives on drug release studies from polymeric nanoparticles, prepared by Ayhan Savaser et al., present recent progress of commonly used methods for polymeric nanoparticle drug release studies and explain it from the view point of nanoparticle characteristics, dissolution medium, apparatus and biomedical applications.

Chapter 4, Polymeric nanofibers for controlled drug delivery applications, prepared by Gayatri C. Patel et al., highlights the applications and importance of electrospun nanofibrous scaffolds in various fields of biomedical research, ranging from drug delivery to wound healing.

Chapter 5, Polymeric hydrogels for contact lens-based ophthalmic drug delivery systems, prepared by Asadullah Jahangeer et al., reviews the literature on ocular delivery using contact lenses, their classification and manufacturing process, and recent advances on drug delivery techniques using such lenses.

Chapter 6, Palm-based nanoemulsions for drug delivery systems, prepared by Mohd Basyaruddin Abdul Rahman et al., summarizes the recent studies conducted on the development of palm-based nanoemulsions, physicochemical characterization in contributing to drug efficacy, and in vitro permeation studies.

Chapter 7, Strategies for the design and synthesis of pincer based dendrimers. potential applications, prepared by Hugo Valdés et al., give a recent overview about the development of metallopincer dendrimers and describe the potential applications of more compact metallopincer species in medical research, therapeutics and other fields.

Chapter 8, Nanogels: an emerging trend for drug delivery, prepared by Anupama Setia et al., focuses on different types of nanogels along with the synthetic procedures, drug loading capacity, mechanism of drug release, and recent applications in drug delivery.

Chapter 9, Lipid-based nanoparticles for dermal drug delivery, prepared by Ulya Badilli et al., gives an overview of lipid-based nanoparticles as dermal drug delivery systems, preparation techniques, and in vitro/in vivo characterization methods for lipid nanoparticles and their assay. Analytical studies related to drug-loaded lipid nanoparticles, their characterization, and quantitation are also discussed.

Chapter 10, Lipid-based nanoparticles for cancer diagnosis and therapy, prepared by Narahari N. Palei et al., discusses the development of lipid-based nanoparticulate systems that offer improved chemotherapeutic delivery through increased solubility and sustained retention times is an area of intense focus, cancer therapy.

Chapter 11, Lyotropic liquid crystal nanoparticles: a novel improved lipidic drug delivery system, prepared by Gautam Singhvi et al., focuses in detail on the various phases of lyotropic liquid crystals and potential materials of composition, their phase transition behaviour with respect to various factors, knowledge of which would in turn help the reader in selecting the method of preparation, and suitable characterization techniques. In addition, potential problems and possible future research directions for industrial scale-up and translation from bench-to-bed are highlighted.

Chapter 12, Vesicular carriers as novel nano- drug delivery formulations, prepared by Chukwuemeka C. Mbah and Anthony A. Attama discusses vesicular carriers as an important group of lipid-based nanocarriers, and show their utility in the delivery of bioactives and other therapeutic substances.

Chapter 13, Gemini surfactant-based systems for drug and gene delivery, prepared by Amal Makhlou et al., summarises and discusses the effect of structural modifications on the performance of gemini surfactant delivery systems and correlates the in vitro characteristics to the in vivo results in drug and gene delivery.

Chapter 14, Self-assembled quaternary ammonium surfactants for pharmaceuticals and biotechnology, prepared by Lucia Ya et al., discusses the properties and applications of self-assembled quaternary ammonium surfactants for the delivery of peptides and proteins, genes, and antimicrobials. Particular emphasis was given to a the Gemini quaternary ammonium surfactants, evidencing their properties, comparing to monomer counterparts, and highlighting their particular characteristics (e.g., low critical micellar concentration, antimicrobial activity) that make them surfactants of choice for targeted drug delivery.

Chapter 15, Cyclodextrin-based nanoparticles, prepared by Valentina Oliveri et al., focuses in particular on the nanoparticles based on cyclodextrin polymers. Some successful examples for their application in vivo will be discussed. Among these, the most relevant systems are based on the Cyclosert delivery platform, designed specifically to overcome some limitations in the systemic transport of drugs and Rondel platform, engineered to deliver genes. Both these systems are currently in Phase II clinical development.

Chapter 16, Cyclodextrin nanosponge-based systems in drug delivery and nanotherapeutics: current progress and future prospects, prepared by Riyaz Ali Osmani et al., is taking note of potential benefits and drug delivery efficiency offered by cyclodextrin nanosponge-based systems. Recent approaches, outcomes, and current progress have been thoroughly covered in this chapter for their applications in the field of drug delivery and therapeutics.

Chapter 1

Metal–organic frameworks as expanding hybrid carriers with diverse therapeutic applications

Sarwar Beg¹, Atul Jain², Sumant Saini², Teenu Sharma², M. Saquib Hasnain³, Syed Sarim Imam⁴, Imran Kazmi⁴, Mahfoozur Rahman⁵, Sohail Akhter⁶,⁷ and Bhupinder Singh²,    ¹Jubilant Generics Limited, Noida, India,    ²Panjab University, Chandigarh, India,    ³Shri Venkateswara University, Gajrola, India,    ⁴Glocal University, Saharanpur, India,    ⁵SIHAS, SHUATS, Allahabad, India,    ⁶Jamia Hamdard, New Delhi, India,    ⁷Centre de Biophysique Moléculaire-CNRS UPR4301, University of Orléans Rue Charles Sadron, Orléans, France

Abstract

Metal–organic frameworks (MOFs) have gained much attention and proliferate as porous nanoscaled hybrid polymer–metal composites. These polymeric nanomaterials possess innumerable applications such as gas storage, gas/vapor separation, sensor, catalysis, imaging, luminescence, drug delivery and biomedical applications. The structure of MOFs is characterized by an open framework that can be porous. MOFs consist of transition-metal cations, polydentate organic linkers, and metal ions linked through coordination bonds. The unique physical and chemical characteristics of MOFs are attributed to both their organic and inorganic component. This unique blend of properties makes them suitable for application in the field of material science, biology, and nanotechnology-based drug delivery. Biodegradability, excellent porosity, high loading capacity, and ease of surface modification are the major advantages offered by them. Accordingly, this chapter provides a an overview of various types of MOFs, their characterization and applications in diverse disciplines of biomedical sciences, with particular focus on drug delivery and theranostics; highlighting the stability and toxicity issues of MOFs, along with their market potential.

Keywords

Metal organic frameworks; transition metal; drug delivery; theranostics; biosensors; biodegradability; hybrid polymer–metal composites

Chapter Outline

1.1 Introduction 2

1.2 Classification of Metal–Organic Frameworks 5

1.3 Synthesis Approaches of Metal–Organic Frameworks 6

1.4 Physicochemical Characterization of Metal–Organic Frameworks 6

1.5 Classification of Metal–Organic Frameworks 8

1.5.1 Amorphous Metal–Organic Framework Structures 8

1.5.2 Crystalline Metal–Organic Frameworks Structures 9

1.5.3 Nanoscale Structures of Metal–Organic Frameworks 9

1.5.4 Structure of Biometal–Organic Frameworks 10

1.5.5 Luminescent Metal–Organic Framework Structures 11

1.6 Surface Modification of Metal–Organic Frameworks 11

1.6.1 Polymer-Grafted Metal–Organic Frameworks 12

1.6.2 Peptide-Functionalized Metal–Organic Frameworks 13

1.6.3 PEGylated Metal–Organic Frameworks 13

1.7 Applications of the Metal–Organic Frameworks 13

1.7.1 Chemical Catalysis 13

1.7.2 Storage of Various Gases 15

1.7.3 Biosensors 15

1.7.4 Drug Delivery Carriers 18

1.7.5 Cancer Therapy 20

1.7.6 Delivery of Biomolecules 21

1.7.7 Cellular Trafficking 21

1.7.8 Antibacterial Properties 21

1.7.9 Photodynamic Therapy 22

1.7.10 Computer Modeling 22

1.7.11 In Vitro Activity 23

1.7.12 Diagnostic Agents 23

1.8 Biodegradability and Stability 24

1.9 Toxicity and Safety Consideration 25

1.10 Industrial Scalability and Market Potential 26

1.11 Conclusions 26

References 26

1.1 Introduction

Metal–organic frameworks (MOFs) are porous crystalline nanomaterials or coordination polymers, first discovered by Robson in 1989. They consist of a three-dimensional collection of inorganic and organic linkers associated by rigid bi- or multipodal organic linkers (Eddaoudi et al., 2001; Spokoyny et al., 2009; Beg et al., 2016). Since the discovery and knowledge of several applications of MOFs is expanding, the whole scientific world is taking interest in the modification and advancement of MOFs for nanobiomedical, catalysis, separation, magnetism, storage, luminescence, drug delivery, photo sensitive, and other applications (Cui et al., 2012; Zhang and Xiong, 2012). This has led to the need for the synthesis of a new porous coordination polymer, resulting in the formation of a new generation of chemical entities for this purpose (Allendorf et al., 2009; Keskin and Kizilel, 2011). MOFs are considered new generation hybrid inorganic–organic materials, which can also be classified on the basis of dimensionality and order of organic and inorganic molecule participating in the synthesis. Table 1.1 highlights the different types of hybrid nanoporous material based on their dimensions.

Table 1.1

However, MOFs act as a single molecule with entirely unusual physiochemical properties. Additionally, because of the presence of specific dimension, order of arrangement, and dimensionality of the metal ion and organic linker, MOFs emerge as the advance type of coordination complexes with high level of porosity and surface modification abilities (Tranchemontagne et al., 2009). Table 1.2 lists the key structural differences between the coordination polymers and MOFs.

Table 1.2

SBU, strategic building unit.

Usually, MOFs show a high degree of robustness in their framework structure, with a highly flexible nature and have capabilities for chemical alteration during incorporation of the metal ions with the organic linkers. A wide range of MOF structures are available, with a high degree of adaptability in their chemical composition, thus offering excellent surface modification (helpful in the biomedicine applications), high surface area (for efficient loading of cargo), and large pore sizes (facilitates wrapping of various types of pharmaceuticals and theranostic agents) (Sun et al., 2012). Regarding structure, MOFs possess high molecular weight, supramolecular crystalline solid structures with well-defined geometry, wherein the inorganic component is connected with the organic part in the form of struts (Furukawa et al., 2013). The inorganic (polar) component includes metals, transition metals, or groups of metals, while organic (nonpolar) component includes hybrid carbon materials. Several inorganic metals (e.g., iron, zeolite, silica, copper, etc.) and organic ligands (e.g., phenolates, sulfonates, polycarboxylates, phosphonates, imidazolates, etc.) have been investigated for preparing MOFs (Horcajada et al., 2012a). The comprehensive detailed list of various metal ions and organic linkers which are used in the synthesis of MOFs has been described in scientific reports. Fig. 1.1 summarizes the various organic linkers which are commonly used in synthesis of MOFs (Allendorf et al., 2009; Furukawa et al., 2013; Canivet et al., 2011; Cho et al., 2006; Dau et al., 2012; Mori et al., 2005; Rieter et al., 2007; Zimpel et al., 2016). The arrangement and orientation of Lewis-base sites, combined with the organic linkers, decides the group of metal ligands with well-defined geometries (James, 2003; Kurmoo, 2009; Horcajada et al., 2012a). Moreover, the electronic valency of metal ions which are used in the MOFs chemistry may be typically mono-, di-, tri-, or tetravalent ligands (Czaja et al., 2009). The mixing of metals ions and organic ligands can build up different molecular modifications and engineering of MOFs, with a broad variety of physicochemical properties for diverse applications in biomedical and nanotechnology fields. Since MOFs are used abundantly, this chapter intends to provide an focus in the diverse area such as drug delivery, sensing, biomedical imaging, catalysis, storage of gas, and many more (Furukawa et al., 2013).

Figure 1.1 Chemical structure of various MOFs.

1.2 Classification of Metal–Organic Frameworks

The structural and functional classification of different types of MOFs is based on the various approaches involved during synthesis. MOFs, as functionalized carriers are classified as: first generation, or primary MOFs; second generation, or modified MOFs; and third generation, or advance MOFs. Primarily MOFs are constituted of inorganic and organic moiety. Modification of MOFs is possible by surface engineering with chemical functionalities. Advanced MOFs contains biomolecules such as ions (cation and anion), pharmaceutical APIs, bioactive, toxins, vaccine, gases, etc. inside their framework cages (Perry et al., 2009). On the basis of strength of the structural frameworks, these can also be categorized as flexible and rigid MOFs. Flexible MOFs are those which can reversibly alter their structural conformation due to subsistence from external physiochemical factors, such as temperature, pressure, and molecular inclusion. Conversely, the rigid MOF frameworks do not acquire any conformation change in the presence of any said external stimuli (Horcajada et al., 2012a). In addition, MOFs can further be classified into two category: crystalline and amorphous MOFs, on the basis of packing of crystal structure as MOFs (Farha and Hupp, 2010). Crystalline MOFs hold a collection of extremely unusual solid porous frameworks units in definite long-range order. The uniform regularity reproducing framework structures offer a patchy porous architecture of crystalline MOFs, which is responsible for beneficial physicochemical characteristics (Davis, 2002). Conversely, amorphous MOFs maintain their fundamental integrity of structural units and interconnectivity among the different homologous units, such as crystalline MOFs, except long-range periodic rearrangement of structural unit with respect to their structural network (Bennett and Cheetham, 2014; Bennett et al., 2010).

1.3 Synthesis Approaches of Metal–Organic Frameworks

The preparation of diverse types of MOFs involves high-end chemical reactions among the inorganic and organic counterparts for attaining the desired structural network. Moreover, as far as the synthesis of MOFs is concerned, especially for biomedical application, the chemistry need to be thoroughly checked to assess the safety of MOFs for biomedical applications (Stock and Biswas, 2011). Multiple synthesis methods have been reported so far for producing a variety of MOFs, where few of the widely employed approaches include hydro/solvothermal synthesis (Cheetham et al., 2006), microwave-assisted synthesis (Jhung et al., 2005), mechano-chemical synthesis (Klimakow et al., 2010), sonochemical synthesis (Huxford et al., 2010), electrochemical synthesis (Joaristi et al., 2012), spray drying (Cao et al., 2016), inverse emulsion, microfluidics-based synthesis (Pan et al., 2011), and many more. Each of the synthesis techniques has it own merits for producing MOFs with different physiochemical properties, functionalization, and scale-up ability. Table 1.3 describes some common synthesis method and their significance in MOFs.

Table 1.3

Besides the previously discussed methods, the straightforward method of preparing MOFs involves the chemical reaction between the inorganic and organic components (e.g., metal nitrates, sulfates or acetates) (Czaja et al., 2009; Farha and Hupp, 2010). In general, throughout the synthesis of MOFs, the method tends to become hindered by low prophecy of the geometrical network and inaccurate orientation of the ligands in/onto the coordination position during the ring-opening polymerization reaction, using many types of ligands in various concentrations (James, 2003; Pichon and James, 2008). Nevertheless, current modern research in the development and assessment of morphology, crystalline structure, and geometry of the MOFs shows perfection in evaluation for improving their application in term of porosity and surface distinctiveness by modifying with organic and inorganic subunits to contribute rigid surfaces (Carlucci et al., 2000). Advanced method of producing MOFs creates ultra-porous MOFs with appropriate surface modification properties, which helps in drug delivery for various diseases. Furthermore, surface modification of MOFs has been shown as an influential parameter for improving the functionality of the active sites of the subunit by generation of catalytic sites. This leads to further significant improvement in their material characteristics for various nanobiomedical applications (Lei et al., 2014).

1.4 Physicochemical Characterization of Metal–Organic Frameworks

MOFs have multiplicities in their combination and geometrical arrangement, due to the availability of different organic or inorganic structural units that leads to somewhat tricky geometrical identification, and characteristics. Currently, a variety of analytical techniques have been reported in scientific literature for evaluating and characterizing different parameters of MOFs (Bennett and Cheetham, 2014; Bennett et al., 2010). Out of diverse available techniques, Powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR), Differential scanning calorimetry (DSC), X-ray, neutron total scattering, and helium pycnometry are some of the most commonly used methods for the characterization of MOFs. PXRD is categorized as an evergreen price reliable evaluating method in characterizing the crystalline nature and phase purity of a broad range of MOFs, while FTIR and Raman spectroscopy methods are used for interpretation of the functional group involved in the MOFs, due to vibrational modes within the functional groups across crystalline and amorphous products. Being a physical material, sorption site, along with revealing information from the Bragg and diffuse scattering in the MOFs can also be obtained from neutron total scattering and X-ray techniques. Helium pycnometry is used for measuring the density of the crystalline and amorphous MOFs (Orellana-Tavra et al., 2015). DSC is useful for evaluating the effect of heat flow on induced amorphization of the MOFs. Apart from these, other techniques, such as pair distribution functions analysis, excitation attenuated fluorescence spectroscopy, X-Ray attenuated neutron emission scattering and positron annihilation lifetime spectroscopy are also useful in characterizing the order of porous materials. These characterization techniques are useful in identifying and evaluating the type and nature of various defects in the MOF structures (Gagnon et al., 2012). Overall, these characterization techniques are also helpful in detection other vital characteristics of the MOFs, including porosity, density, bulk volume, pore size, topology, structural and constitutional properties, along with thermal and mechanical stability (Keskin and Kizilel, 2011).

1.5 Classification of Metal–Organic Frameworks

1.5.1 Amorphous Metal–Organic Framework Structures

Amorphous MOFs hold the fundamental subunit and therein connectivity of their crystalline counterparts, although they are devoid of any long-range regular arrangement. A systematic arrangements of different MOFs components change the result pattern of X-ray diffraction, which is dominated by broad humps due to diffuse scattering, that are indistinguishable from one another (Orellana-Tavra et al., 2015). Amorphous MOFs possess different exciting opportunities for various practical application, such as drug delivery, either as novel hybrid coordination polymeric functional materials themselves or facilitating other available processes although the domain is largely unexplored (total MOF reported structures amounts to nearly 30) (Bennett and Cheetham, 2014; Orellana-Tavra et al., 2015; Bennett et al., 2010). These materials are simply defined as the network combinations containing inorganic metal ions linked by the organic ligands (generally carboxylate or nitrogen-based functional groups). The literature reports have demonstrated exploration of imidazole frameworks with various metals, such as zeolite, nickel, zinc, cobalt, cupper, palladium, platinum, sodium, etc. Practically, the amorphous MOFs are prepared from the crystalline frameworks by applying stress, such as temperature and pressure (Bennett et al., 2010; Cheetham et al., 1999; Cheetham et al., 2006). The stress generated due to the application of energy causes deformation in the lattice geometry and increases amorphization in the structures. Recently, literature reports have revealed the application of an electric discharge method for collapsing the metal-binding carboxylate groups in the framework to produce amorphous structures (Bennett and Cheetham, 2014). Moreover, the comminution approach, using a ball mill, has also been reported for producing the amorphous MOFs. It has been observed that the degree of amorphization tends to be useful in drug delivery applications for tailoring the release rates of the drugs. The recent application of amorphous MOFs has been reported by Orellana-Tavra et al. (2015) for delivering calcine, using Zr-based UiO-66 MOF, and they observed superior drug release control for more than 30 days vis-à-vis their crystalline counterpart, with drug release control only up to 2 days (Orellana-Tavra et al., 2015).

1.5.2 Crystalline Metal–Organic Frameworks Structures

Crystalline MOFs represent the solid network of metal ions which are interconnected through various organic ligands in an broad range. The arrangement of MOFs subunits within the skeleton is extremely regular and possesses a long-range order (Bennett and Cheetham, 2014; Bennett et al., 2010). The MOF structures with crystalline appearance are synthesized by solvent-free methods (Pichon and James, 2008). Usually, metal acetate and organic pro-ligands are mixed and ground in a ball mill, and subsequently the crystals are precipitated through the salting out mechanism. An instance of solvent-free synthesis includes Cu3(BTC)2 MOFs, synthesized via hydrothermal approach (Braga et al., 2007; Lucena et al., 2013). Recently, the advancement in solvent-free preparation of MOF films and composites by chemical vapor deposition method has produced end products with high yield (Stassen and De Vos, 2016). These techniques have also been applied for the synthesis of ZIF-8 MOFs (Betard and Fischer, 2012).

1.5.3 Nanoscale Structures of Metal–Organic Frameworks

MOFs within the nano range (nano-MOFs) have now been emerging as an innovative class of MOFs, with exciting applications in various fields of drug delivery. Nano-MOFs shows high surface area, porosity, exclusive size-dependent optical property, luminescent, electromagnetic and storage properties, compared to that of the normal MOFs (Della Rocca et al., 2011; Tamames-Tabar et al., 2014). These display a high degree of variety in their composition, structure, properties, and show high dispersibility and biocompatibility properties. These MOF structures are of nano size dimensions, or at times present in the nanoparticulate structures. Nano-MOFs can be prepared by adding of inorganic nodes to modify the functional properties of MOFs, without altering their coordination characteristic. Furthermore, the approach of ligands anchoring with various functional groups present over the external surface is also used as an alternative approach for chemical grafting of the biomolecules (Cohen, 2012). This ligand tagging helps in exploration of their specific drug delivery and bioimaging for cancer treatment (Doherty et al., 2014). The nano-MOFs are prepared by two different strategies: i.e., top-down approach (by reducing the particle size) or bottom-up approach (by synthesizing the nanosized MOFs). In this regard, the fundamental understanding of the growth mechanism and kinetics of nano-MOFs tends to facilitate the development of a variety of MOFs with nanoscale dimension, as versatile hybrid nanomaterials for biomedical applications (Haque et al., 2010; Della Rocca et al., 2011). In the classic approach, during the synthesis of nano-MOFs, both the solutions were mixed together to allow particle nucleation and growth. Furthermore, nanoprecipitation was achieved for collecting MOF nanoparticles in the solvent system, containing individual precursors that remained soluble within them. Nano-MOFs provide an interesting opportunity for designing novel theranostic nanomedical devices. Della Rocca group prepared nano-MOFs loaded with cisplatin for tumor targeting and specifically achieved 75% loading in the Pt(NH3)2Cl2(succinate)2 MOFs with spherical morphology of around 50–60 nm diameter (Della Rocca et al., 2011).

1.5.4 Structure of Biometal–Organic Frameworks

MOFs are not biocompatible in nature, probably due to the lack of biodegradability and toxicity related to metal ions and organic linkers. Biocompatible MOFs have attained a lot of importance in the past decades. Attempts, therefore, have been taken towards bioengineering of MOFs to produce bio-MOFs. These can be synthesized by two different approaches: trapping of biomolecules within the porous cavities of MOFs, or by incorporating the biomolecules (e.g., drugs, toxins, gases, anionic or cationic ligands, organic ligands) within the MOF structure during the synthesis process (McKinlay et al., 2010, 2014; Miller et al., 2010). Recently, a series of biomolecules have also been used to produce bio-MOFs, which includes amino acids, peptides, nucleotides, cyclodextrins, etc. (Forgan, 2014). Like other MOF structures, bio-MOFs possess diverse drug delivery and biomedical applications. A report published by McKinlay group discussed the application of selection of biomolecules as linker or bioactive metals as the inorganic counterparts for the synthesis of bio-MOF, where the developed MOFs have applications in bioimaging as a theranostic tool (McKinlay et al., 2010, 2014). In an another report, the bio-MOFs constructed from anionic metals have shown better absorption of the cationic drugs, leading eventually to high drug-loading efficiency and controlled drug release profile from the pores of MOFs. Huxford et al. (2010) observed cationic charge triggered drug release from the MOFs loaded with anionic drugs (Huxford et al., 2010). As far as the drug release is concerned, from MOFs loaded with drug molecules in the porous cavity, the porosity of particles is considered as one of the rate-governing factors for controlling release rate of drugs. Ideally, the synthesis of bio-MOFs containing therapeutically active molecules as a part of the structural framework are produced with minimum number of synthetic steps for attaining maximum drug payload by avoiding toxicity profiles. Furthermore, synthesis of bio-MOFs depends on the selection of high quality and low toxic solvents to generate the MOFs with biodegradable and biocompatible nature. within the MOF include drugs such as bisphosphonates, cisplatin, vitamin B3, nicotinic acid, and many more, which have been employed for bone repair, anticancer applications, and providing nutritional value for the purpose. The coupling therapeutic molecules with MOF has been reported in many literature reports, which include bisphosphonates, cisplatin, vitamin B3, nicotinic acid, and many more, for bone repair, anticancer action and providing nutritional value (Miller et al., 2010). Moreover, the usage of metal ligands as a part of the MOF structure has lately been investigated. These include Ca, Mg, Ag, Zn, and Fe as a part of the MOF structure for potential applications in biomedicine.

1.5.5 Luminescent Metal–Organic Framework Structures

MOFs exhibit a broad range of luminescent properties, due to their various combinations between the metal ion and the organic linker (Rieter et al., 2007; Allendorf et al., 2009). There are the some MOF varieties which are especially explored for their functional luminescence properties. The available scientific literature reports on luminescent MOFs have demonstrated their suitability as light-emitting devices for imaging applications (Cui et al., 2012). Highly porous and mesoporous nature of luminescent MOFs provides high drug loading capacity for the different biological molecules such as anticancer drugs or gases. Luminescent MOFs contain open metal sites or functional Lewis-basic and/or acidic sites on the linkers, which helps in provides controlling the interaction with biological system and release into the environment (Olivera-pastor et al., 2012).

1.6 Surface Modification of Metal–Organic Frameworks

Surface modification or functionalization is a vital aspect of drug delivery. It reduces the interaction time with the biologic medium to perk up the stability of nanoparticles, and also enable drug crossing across the various physiological barriers present inside the body, thereby providing the accessibility of targeted delivery. Functionalization of MOFs is a newer area of research for attaching therapeutic biomolecules/ligands on the surface. Different chemical, physical, or adsorption approaches have been utilized for surface modification of the MOFs, with the help of specified lipid, polymers, amino acid, biomolecules, ligands, etc. (Mantion et al., 2008a). Functionalization or surface engineering of MOFs aids in increasing water solubility and stability, high drug loading, decreased protein binding, bypassing the reticuloendothelial system, etc. (Huxford et al., 2010). Moreover, alteration of MOFs surface also shifts the degradation pattern, thus increasing the premature release profile of the loaded drug molecules in a controlled pattern. Fig. 1.2 depicts the synthesis scheme of nano-MOFs surfaces, functionalized with different ligands. Despite numerous merits, only limited reports are available on surface functionalization of MOFs for drug delivery applications. The key reason behind limited investigations could be attributed to their complex molecular structure and chances of toxicity to biological systems of the body. Recently implementation of silica coating was used to manage the stability of MOFs (Sun et al., 2013).

Figure 1.2 Schematic steps of synthesis of multifunctional MOFs.

1.6.1 Polymer-Grafted Metal–Organic Frameworks

Polymerization of MOFs includes modification using silica on the surface and/or encapsulation of the silica particles within the MOF framework (Della Rocca et al., 2011). The surface-coating of silica offers good biocompatibility, enhanced water dispersibility, and ease of further functionalization, owing to the presence of silyl groups on the silica surface (Rieter et al., 2007). Moreover, water dispersibility can also be improved by surface modifications with hydrophilic polymers, such as polyvinyl pyrrolidone. The polymer tends to bind with end groups of the MOFs at their vacant sites via electrostatic attraction with the particle surface, or covalent attachment with the bridging ligands for providing shielding effect for the purpose (Lu et al., 2012). The surface coating with silica or polymers is usually carried out during the synthesis of MOFs or post-synthesis of MOFs via conjugation approach. Besides silica, other polymeric moieties have been employed for surface engineering of the nano-MOFs. For instance, polysaccharides like dextran, fluorescein, biotin, and chitosan are employed for attaining superior efficacy over the simple MOFs structures for improving solubility, cellular adhesion, and contrast imaging (Tanabe et al., 2008). The instance of polymer functionalization includes conjugation of thiol end groups of the polyvinyl pyrrolidone with the framework of Gd3þ MOFs. The polymer coating slows down the release of Gd3þ ions and helps in providing controlled release action to the framework structure (Lu et al., 2012). Another example demonstrates the combined use of both silica and polymer functionalization approaches to stabilize the MOFs, which helps in augmenting the water solubility and dispersibility. Moreover, literature shows higher drug encapsulation efficiency for cisplatin, and superior tumor targeting potential with silica-coated iron terephthalate MIL-101 nano-MOFs (Mocniak et al., 2015).

1.6.2 Peptide-Functionalized Metal–Organic Frameworks

Peptide-functionalized MOFs are analogous to general MOFs which are bioinspired, where an organic linker is replaced by peptide (Keskin and Kizilel, 2011). The first peptide-based MOF (MPF) was prepared from an oligovaline peptide family and, because of the presence of infinite structural variety of different available peptides, shows a wide range of synthesis of new MPFs in the near future (Mantion et al., 2008b,a). Peptide functionalization of MOFs has been investigated for in vitro imaging and tumor targeting using various fluorescence dyes (Jung et al., 2010). In different recent studies, researchers use rhodamine, Arginylglycylaspartic acid (RGDfK), and angiogenic peptides for targeting the cancer cells (McKinlay et al., 2010, 2014).

1.6.3 PEGylated Metal–Organic Frameworks

Surface functionalization of the MOFs using different molecular weight polyethylene glycol (PEG) provides stealth properties (Horcajada et al., 2008), and offers diverse advantages for biomedical applications, especially in alteration of solubility, hydrophilicity and stability of the carrier, increased blood circulation time of the nanocarriers, tumor targeting, and diagnostic imaging (Tamames-Tabar et al., 2014), PEG-coating of iron-carboxylate nano-MOFs shows controlled interface of MOFs and increases the circulation half-life of loaded drug molecules in a system, from several hours to weeks (Horcajada et al., 2012b).

1.7 Applications of the Metal–Organic Frameworks

Applications of MOFs have been highlighted in Fig. 1.3, which indicates their diverse applications in various fields.

Figure 1.3 Diverse applications of MOFs in biomedical sciences.

1.7.1 Chemical Catalysis

Chemical catalysis is a phenomenon where minute quantities of external substances (also called as the catalysts) are used to increase the rate of reaction by decreasing the activation energy required for initiation of a chemical reaction. An ideal catalyst can alter the rate of a thermodynamically feasible reaction, however the thermodynamic equilibrium remains constant (Opanasenko et al., 2013; James, 2003). Depending upon the type and phase of chemical reaction, the catalysts used may be solids, liquids, or gases, and are categorized as heterogeneous or homogeneous (Luz et al., 2010). Use of MOFs as catalysts in different chemical reactions have demonstrated several folds improvement in reducing reaction time (Czaja et al., 2009; Dhakshinamoorthy et al., 2012; Dhakshinamoorthy and Garcia, 2014). In a chemical reaction, a catalyst may act as classic catalyst support, active center, secondary building unit as active center, or active center introduced by post-synthesis modification. Table 1.4 lists some pros and cons of different catalysts for the synthesis of organic compounds (Dhakshinamoorthy et al., 2012; Dhakshinamoorthy and Garcia, 2014). Table 1.5 describe different examples related to various applications of catalyst. In general, metals as metal salts or its transition metal complexes are broadly used as homogeneous catalysts in various organic reactions, with recovery as the main limitation because they may decompose during the reaction (Luz et al., 2010). To surmount those restrictions, heterogenized homogeneous catalysts were developed by researchers.

Table 1.4

Table 1.5

1.7.2 Storage of Various Gases

A large amount of MOFs are reported for their gas storage and separations, which can be considered as the most biomedical applicable areas (Mori et al., 2005). Their storage capability is due to high surface-to-pore volume within the void space of the materials (Dau et al., 2012). During synthesis of MOFs, unsaturated metal sites remain unoccupied, known as open metal sites, which are available to attach guest molecules after activation (Keskin and Kizilel, 2011). The adsorption capacity of the particular MOF depends upon the prior composition, which can be increased by means of interpenetrating networks, or insubstantial hybrid component with minor cavities, such as magnesium formate (Cheetham et al., 1999, 2006). Some example of MOFs include NU-100, MOF-210, MOF-5, M-CPO-27, MOF-200, MOF-177, NOTT-140, Zn(MeIM)2, (ZIF-8), and HKUST-1; they have shown their applicability in the storage of different medical gases, such as nitric oxide, hydrogen, nitrogen, and hydrogen sulfide (Ma and Zhou, 2009).

1.7.3 Biosensors

A biosensor is a self-contained integrated analytical device used for the detection of analytes or biological samples, even outside the body, with a physicochemical detector. The device changes the biological response into an electrical signal (Fig. 1.4) (Lei et al., 2014). Biosensors have innumerable uses benefits due to their ability to smartly solve numerous analytical challenges. Hence, these have diverse uses in various fields such as defense, environmental monitoring, security, food technology, drug delivery, medical imaging and other industrial applications (Kirsch et al., 2013). Development of a MOF-based biosensor device is primarily based on application area and the principle of detection, because they show outstanding capability, such as magnetism, photostability, light sensing, and luminescence in biosensing due to the presence of a variety of combinations (Lei et al., 2014). Some characteristic features of an ideal biosensor includes: (1) highly specific biocatalyst must be used for the analyses; (2) the interaction between reactant and the reagent should be independent of external factor; (3) electronic signal should be accurate, precise, reproducible, and should be in the analytical range; (4) in the case of invasive monitoring, the probe must be small, biocompatible, sterile, and nonimmunogenic; and (5) the device should be of low cost, small, transportable, and easy to handle (Kirsch et al., 2013). Moreover, the fundamental properties of MOFs include pore size, coordination capability, or bonding facility in the framework responsible for biosensing applications (Chen et al., 2013).

Figure 1.4 Mechanistic applications of MOFs in biosensing.

1.7.4 Drug Delivery Carriers

MOFs have been broadly examined as drug delivery carriers in the past decade for delivering drug molecules to the desired sites. Although high numbers of carriers have been reported, MOFs gained much recognition due to their porous structure containing voids, which provides high drug-loading capacity and controlled drug release profile (Filippousi et al., 2016). A broad range of drug molecules with hydrophilic and hydrophobic nature can be incorporated in the MOFs. Based on the loading approaches discussed earlier, drugs can be encapsulated in the MOF cavity and/or tethered with the framework structure (Keskin and Kizilel, 2011; Della Rocca et al., 2011). Fig. 1.5 shows the drug-loading strategy in MOFs. The covalently conjugated drug molecules with the MOFs shows higher capacity for controlled drug release action over the drugs adsorbed in the cavity, or over the MOFs surface at desired site (Horcajada et al., 2012a). Table 1.6 highlights the applications of various MOFs in drug delivery.

Figure 1.5 Covalent and noncovalent drug loading in MOFs.

Table 1.6

Various factors influence the drug delivery capabilities of MOFs, including the physiochemical properties of MOF subunits (metal ion and organic linker) and drug molecules, pore size, three-dimensional arrangements, which facilitate the fitting of drugs inside the carrier molecules for competent delivery to the desired site. Unlike other nanocarriers, which tend to release the drug molecules with burst effect, the drug release mechanism from MOFs includes slow and controlled liberation of the drugs by matrix degradation (Jung et al., 2010). In one instance, the iron-containing BioMIL-1 MOFs showed higher loading for nicotinic acid, up to 75%, compared to the native MOF structures and exhibited controlled drug delivery application (Miller et al., 2010). The study portrayed the variable drug release profiles of metronidazole from Ni-CPO-27 and HUKUST-1 MOFs, where HUKUST-1 indicated pronounced controlled release characteristics (McKinlay et al., 2010, 2014).

Besides direct drug delivery applications of MOFs, literature reports have demonstrated the development of various MOF formulations in the form of tablets, pills, films, patches, etc. for increasing their patient compliance (Horcajada et al., 2006). These formulations have been reported in literature for exploring their specific drug delivery applications. Besides these conventional formulations, utility of nanoparticle formulations of MOFs have lately been investigated for drug delivery applications. The details regarding various techniques employed for incorporating drugs and therapeutic agents into the MOF have been discussed in Section 1.5.3. The loading of drugs in MOFs is achieved in situ during synthesis or post-synthesis phase. The approach of encapsulation of drug molecules involves noncovalent interactions, while functionalization involves covalent binding with the surface of MOFs. Combined use of these techniques has been practiced for attaining multimodal drug delivery and imaging, with the help of MOF-based delivery systems (Della Rocca et al., 2011). Interestingly, the noncovalent approach has been found to possess high drug-loading capacity for MOFs, as is evident in the case of drugs such as ibuprofen and cisplatin, with controlled drug release profiles and lack of any burst effect (Morris et al., 2014). Moreover, the use of mesoporous silica and zeolite in MOF structures has shown to produce robust frameworks with the advantage of a lack of burst release effect (Davis, 2002).

1.7.5 Cancer Therapy

Applications of MOFs in cancer therapy have been extensively explored for accomplishing the desired targeted action for prolonged periods of time. The nanosized MOFs are useful in treating diverse human cancers (Rodriguez-Ruiz et al., 2015; Lucena et al., 2013; Lu et al., 2014). Applications of Fe3O4–UiO66 MOFs for delivering an anticancer agent (i.e., doxorubicin) shows that enhanced biopharmaceutical properties, including controlled drug release behavior up to 6 weeks, greater anticancer activity on HeLa cells, and significant decrease in the tumor volume (Zhao et al., 2016). Taylor and coworkers reported the application of Mn-containing nano-MOFs (i.e., Mn(1,4-BDC)(H2O)2 and Mn3(BTC)2(H2O)6) coated with silica shell for the delivery of RGDfK peptide and Rhodamine B dye, revealed superior antiangiogenic properties on HT-29 cells by upregulation of Rvβ3 integrin gene (Taylor et al., 2008b,a). In another report, the utility of nano-MOF in ovarian cancer has been explored, where combination of cisplatin, combined with siRNA, showed promising results in reducing growth of ovarian cancer cells during cellular cytotoxicity, uptake, and apoptosis studies (Doherty et al., 2014). Likewise, the nano-MOFs of Gd have shown enhanced anticancer activity against FITZ-HAS endothelial sarcoma cell line model, by increasing cellular apoptosis of Rvβ3 gene expression (Rowe et al., 2009).

1.7.6 Delivery of Biomolecules

The applications of MOFs are galore beyond drug delivery. Hence, these have gained wider attention in for delivery of biological molecules such as DNA, RNA, siRNA, etc. (Keskin and Kizilel, 2011). Recent instances of MOFs used for biomedical applications include utility of high porosity nano-MOFs encapsulated with chemotherapeutic agents, with pooled Multi-drug resistance (MDR) gene silencing siRNA for action against the drug resistant ovarian cancer cells. In another case, the approach of delivering prodrug of cisplatin by encapsulation within the MOF structure, with siRNA, has been employed to provide improved anticancer action. In this context, MOF helps in protecting the siRNA from ribonuclease degradation in the body, as well as enhancing cellular uptake. It promotes escape from endosomal enzymes for silencing MDR genes, leading eventually to enhanced chemotherapeutic efficacy (He et al., 2014a). Conjugation of MOFs with enzymes has been studied in the literature. Cui and associates discussed the applications of MOFs for immobilization of CAL-B enzyme by conjugation on its surface (Liang et al., 2015).

1.7.7 Cellular Trafficking

The role of MOFs in cellular trafficking has been investigated in the past few years. As intracellular pH plays a vital role in regulating the cellular functioning, the MOFs have application in modification of the cellular vesicle trafficking, altering the metabolism and signaling process for the treatment of diseases (He et al., 2014a,b). In this regard, MOFs can be used for real-time sensing and monitoring of pH changes in the cells. Consequently, MOFs have high importance in understanding physiological and pathological processes, and rational design of intracellular drug delivery systems. Instances of MOFs used in intracellular delivery include: covalent conjugation of fluorescein isothiocyanate with UiOnano MOF, which tends to guide the dye, for efficient localization in the cells via pH-sensing properties and endocytosis mechanism (He et al., 2014b; Lucena et al., 2013). This indicates nanosensor behavior of MOFs for efficient cellular trafficking of the drugs and other biomolecules.

1.7.8 Antibacterial Properties

Antibacterial action has been observed with MOFs belonging to M-CPO-27 family, containing Mg, Cu, Fe, Mn, Co, Ni, or Zn as metals and 2,5-dihydroxyterephthalate as the organic linker. Among these metals, MOFs containing Ni and Zn have shown promising antimicrobial activity (McKinlay et al., 2014, 2010). The antibacterial properties of MOFs are attributed to the presence of metal ions, which easily internalize inside the bacterial cell wall and alter the synthesis of proteins. For instance, McKinlay et al. prepared HKUST-1, MOF-199 and CuBTC MOFs, which have shown promising antibacterial action against E. coli. The reports have also demonstrated that Ag-containing MOFs proved to be the better antibacterial agents over the conventional disinfecting agents, with wide spectrum action and lack of resistance over the plain Ag ions (Lu et al., 2014). Moreover, the potential for delivering antibacterial agent, metronidazole, where the Ni-COP-27 MOF indicated drastic augmentation in the antibacterial activity of the drug against Pseudomonas aeruginosa and Staphylococcus aureus (McKinlay et al., 2014, 2010).

1.7.9 Photodynamic Therapy

MOF applications in photodynamic therapy have been explored as an efficient technique for application against malignant cancer cells. Because the mechanism of photodynamic therapy involves energy transfer from high to low energy light in the excited state, it generates reactive oxygen species for inducing cellular apoptosis and localized destruction of the diseased tissues by minimal exposure to the healthy tissues (Lu et al., 2014). For instance, chlorin-based nano-MOFs 5,15-di(p-methylbenzoato) chlorin-Universitetet i Oslo (DBC-UiO) have demonstrated significantly improved photophysical properties over the porphyrin-based nano-MOFs (DBP-UiO), owing to their crystallinity, stability, and porosity, thus facilitating efficient apoptosis and immunogenic cell death against colon cancer (Lu et al., 2015). Likewise, zirconium-based nano-MOFs functionalized with Boron-dipyrromethene (BODIPY) have shown efficient generation of reactive oxygen species for killing the cancer cells (Wang et al., 2007).

1.7.10 Computer Modeling

In silico molecular simulations using computer modeling are a valuable technique to balance between the various experimental methods such as infrared, NMR, and X-ray diffraction, for the assessment of all the possible interaction between the drug and the porous host interactions. It is also useful for exploring the active character of the drugs within the space of the porous material, or, in other words, to define nearly all possible option conformation of the drug molecule. For the first time, semiempirical molecular orbital methods were implemented to reveal the possible geometrical conformation, spatial arrangement and expected interaction energy, adsorption mechanism, and the release kinetics of the active molecule, which involves the different elemental components of drug molecules and different zeolite molecules. Characterization of different structure within the various layer and pores of MOFs can also be calculated by using density functional theory (DFT). Molecular dynamics simulations, which are based on generic force, were also implemented to obtain the mobility of drug molecule reside in the MOFs, keeping the physiological body fluid as constant parameter as compare to the drug molecule 203. However, the binding energy between the drug and carrier material can also be calculated by DFT calculations. Monte Carlo simulations, which predict the drug uptake and explain the adsorption mechanism are also playing crucial role in drug delivery. Quantitative structure activity relationship approach is the another quick and more informative computational method implemented that aims at establishing a correlation among the properties and some relevant molecular descriptors that characterize the physicochemical features of the structure. That calculation is based on a large number of molecular descriptors which are further associated to the property of curiosity. Conversely, the earlier DFT method is slow for screening a wide range of structures. Such a molecular strategy has been extensively implemented in pharmaceutical dosage, biology, and heterogeneous catalysis; its application in the field of nanomaterials is relatively new and relics quite limited. In a nutshell, statistical and Quantitative structure-activity relationship (QSAR) approaches using computer modeling, conducted using different sets of experiment, and are potentially very hopeful for evaluating several characteristic properties of porous materials, including their encapsulation and dissolution profile, or their degradation in biological environment (Horcajada et al., 2012a, 2006).

1.7.11 In Vitro Activity

Current research shows a high interest in application of MOFs in nanobiomedical as well as drug delivery (Cai et al., 2015). Cell line studies are the most commonly used experimental methods for in vitro testing of anticancer drugs because these cells closely resemble with characteristic of cancer cells (Wang et al., 2007, 2016). In vitro experiments were carried out to corroborate the activity relationship, and to evaluate the possible restrictions in the exploitation of these advance nanocarriers. In vitro cell line studies are advantageous over in vivo mouse models because the same genotype can have different phenotypes in humans, when compared with transgenic mice (Kesharwani et al., 2012). Cellular studies contribute valuable information related to in vitro cytotoxicity, cell uptake, and permeability, possible interaction among the nanocarrier, and the biological system bypassing the different biological barriers (Horcajada et al., 2012a).

1.7.12 Diagnostic Agents

Currently, innovative nanomaterials (NMs) have become an important area in research and are used in the diagnosis and/or treatment of various diseases (Ferrari, 2005). Carrier systems are applied in diagnosis as a contrast agent, due to their fluorescent, photo stability, luminescent character intended for theranostic imaging (Davis, 2002). Nanomaterials consist of a wide range of materials, from organic (lipid, polymer-based carrier system, natural to synthetic material) to inorganic (quantum dots, metallic nanoparticles, and metal zeolites). Surface-engineered NMs enable to application of diverse molecular imaging techniques, such as magnetic resonance imaging (MRI), computed tomography (CT), single-photon emission tomography, positron emission tomography, ultrasound imaging, and optical imaging methods (Barreto et al., 2011). MOFs are usually prepared in mild conditions, where a wide range of molecular functionalities can be possible to instruct desired properties, applicable for potential applications (Liu et al., 2013, 2016). MOFs were exposed by Lin and coworkers for the first time, signifying the application of nanoscale MOFs for medical imaging (Taylor et al., 2008a). MOFs have the capability to house various chemical moieties as contrast imaging agents, which are broadly investigated in different medical areas for imaging (Liu et al., 2016). Some of the instances of MOFs as imaging tools include: usage of nanoscale MOFs containing lanthanide series elements for their excellent chemical or bio-functional behavior. It has been documented that surface modification of Gd nano-MOFs with isopropyl acrylamide and methacrylate derivatives are suitable for attaining efficient medical imaging (McGuire and Forgan, 2015). Furthermore, surface modification of Gd MOFs with PEG has also shown superiority in contrast imaging properties. Gd-based MOFs as theranostic devices, containing functional polymer chains of glycine-arginine-glycine-aspartate-serine-NH2 and O-methyl acrylate moiety, have also shown improved cellular imaging (Rieter et al., 2007). Likewise, the applications of amino-functionalized iron-carboxylate MOFs have been investigated as novel carriers for the delivery of Br-BODIPY for optical imaging (Wang et al., 2007, 2016). Moreover, the unique luminescence and paramagnetic properties of MOFs are also known to be responsible for their radio contrast effect and photostability, long decay rates, stokes shifts, and narrow emission bands, thus making them suitable for MRI and CT scanning of vital body tissues and organs (Zhao et al., 2016). Gd-, Fe- and Mn-containing MOFs possess excellent properties as MRI contrast agents. Both Gd and Mn MOFs in their nano forms can better serve as contrast agents for MRI. Reports have also demonstrated application of microemulsion of Gd(BDC)1.5(H2O)2 and [Gd(1,2,4-BTC)-(H2O)3]H2O MOFs with improved radio contrast imaging properties (Hatakeyama et al., 2011).

1.8 Biodegradability and Stability

Since MOFs are mostly constructed from metal ions and organic linkers, their biocompatibility, biodegradability, and stability are considered highly critical characteristics for biomedical and healthcare applications. Therefore, MOFs are thoroughly evaluated for these properties, considering their chemical compositions. Several in vitro and in vivo studies have been documented in literature for evaluating the acceptance of MOFs. Some of the MOFs reported with established biodegradability profiles include the series of iron-carboxylate MOFs (e.g., MIL-88A, MIL-88B-4CH3, MIL-100, etc.) (Miller et al., 2010; Keskin and Kizilel, 2011). Biocompatibility of MOFs is attributed to the selection of linker molecules (hydrophilic, hydrophobic, aliphatic and/or aromatic). Similarly, the stability of MOFs is also vital for preventing hydrolytic cleavage of the covalent bonds between the metal and organic linker. It can be tested by treating MOFs under different simulated conditions, such as phosphate-buffered saline and bovine serum albumin, and evaluated