Nanocomposite Hybrid Metal-Organic Framework in Drug Delivery and Theranostic application

Md. Habban Akhter ,  Assistant Professor, DIT University, India

Metal-Organic Framework (MOF) comprises of metal ion coupled with organic ligands i.e., polymer-metal nanocomposite, which are a recent advances in chemistry for drug delivery and biomedical application. The MOF is porous structure at nanoscale, uses an innovative biomaterial which has compatible physicochemical properties in the biological system. They are being widely explored worldwide nowadays for potential utility in biological sciences, nanotechnology as well as in novel drug delivery system. Moreover, MOFs have excellent porosity, high entrapment efficiency and drug loading capability. The surface modification of this framework has the special characteristics in targeted therapy in cancer and theranostic application. As such MOFs have limited biodegradability, biocompatibility owing to the presence of metallic ligand and organic linkers. Therefore, the endeavour has been made a few years back to engineer biocompatible and biodegradable nanoporous MOFs.

1. Introduction
MOFs are evolving novel hybrid materials comprised of two component of inorganic and an  organic fraction with diverse physicochemical characteristics. MOFs have  a high degree of porosity, size, tunability, biocompatibility, biodegradability and functionalisation capabilities. Structurally, MOFs resemble metal coordination complexes, and thus they may be considered as new generation hybrid metal-organic framework with coordination complexity [3].

Furthermore, MOFs possess a high degree of robustness, high surface area for payloads, pliable nature, and a high degree of flexibility for surface modification during incorporation of metal ions with the organic linkers. The porous nature of MOFs facilitates entrapment of many pharmaceuticals, chemotherapeutics and theranostic agents. The surface modification capabilities are helpful in receptor-based targeting in cancer therapy.   

As far as the structural investigation is concerned, MOFs are supramolecular (high molecular weight) crystalline solid structures with well-defined geometry, wherein the inorganic component is connected to the organic part by struts. The inorganic metals used are iron, copper, silica, zeolites and organic linkers such as polycarboxylates, imidazolates and phosphanates have  been examined for fabricating MOFs.

Based on synthesis, MOFs  could be classified as (i) Simple MOFs (first generation); (ii) Functionalised MOFs (second generation); and (iii) Smart MOFs (third generation).
The first generation MOF has the basic architect of two components inorganic and organic moiety. The second generation MOFs leads to functionalisation for target-oriented delivery of bioactives.
Whereas, third generation MOFs contain biomolecules such as cations, drugs, bioactives, toxins and gases within their framework.

They can also be classified as flexible MOFs because they respond to conformational alteration in their geometry in presence of external stimuli such a change in temperature, pressure, and or molecular inclusion. By contrast, rigid MOF is resistant to framework alteration in contact with external stimuli. It can also be categorized based on crystalline or amorphous structure of MOFs.

The synthesis of MOF involves chemical reactions between the inorganic and organic parts for getting appropriate structural network. Microwave assisted synthesis, sonochemical technique, solvothermal synthesis, electro-chemical, spray drying are among common techniques of MOFs fabrication.

2. Physicochemical Characterisation of MOFs
The identification and characterisation of MOFs is highly challenging due to structural diversity and material characteristics. However, analytical techniques such as powder and thin film X-ray diffraction, FT-IR, DSC, neutron total scattering, Raman spectroscopy and helium pycnometry are some commonly used techniques for characterization of MOFs. Powder X-Ray Diffraction (PXRD) is an analytical tool that confirmed the presence of crystalline or amorphous nature of MOFs, whereas FT-IR and Raman spectroscopy are used for identifying the functional moieties for inferring the short-range ordering in the MOFs by tracking the vibrational modes within the functional groups across crystalline and amorphous products. The Helium pycnometry is used for measuring the density of the crystalline and amorphous MOFs. The sorption site in the MOFs can be evaluated using neutron total scattering technique and the porous characteristics are estimated by fluorescence spectroscopy.  

3. Nano MOFs for theranostic application
Nano MOFs constitute a novel class with exciting application owing to a high surface area, unique size-dependent magnetic, electric, optical, luminescent property over conventional MOFs. They exhibit a high degree of diversity in their composition, structure, properties and demonstrate high dispersibility and biocompatibility properties.

The ligation approach with specific functional groups for chemical grafting of therapeutics and biomolecules allows exploration of nano MOFs in target-based drug delivery and theranostic application in cancer therapy.  

Nano MOFs are fabricated by optimizing particle size through top-down/bottom-up approach. The typical method of synthesizing nano MOFs involves mixing precursor solution for particle nucleation and growth followed by nano-precipitation for separating MOF particle from the precursor solution. For example, Della Roca and associates developed theranostic nano-device of MOFs with payload (cisplatin) of 75 percent achieved in Pt (NH3)2Cl2(succinate)2 MOFs for specific targeting in the tumor as well bio-imaging.

Bio MOFs can be synthesized by immobilizing biomolecules in the porous cavities or by incorporating bioactives, drugs, and or ligand within MOF structure during the synthesis process. Of late, several biomolecules including amino acid, peptides, cyclodextrin etc. have been utilised to developed bio MOFs in biomedical application. In this regard, McKinlay et al. hashed out the application of suitable biomolecules as linkers while inorganic part comprised of bioactive metals for the synthesis of bio MOFs, where the developed MOFs have been used in bioimaging of cancer cell as a theranostic tool.

4. Surface functionalisation of MOFs
The surface modification of MOFs is a novel area of research for precise cellular/tissue/organ targeting of bioactives. Several approaches have been adopted for surface engineering of the MOFs with application ligand, polymers, bioactive molecules and several others. The surface modification of MOFs helps in improving their water solubility, dispersibility and stability, improving payload, avoiding uptake by the reticuloendothelial system and specific targeting, reducing drug-induced side effects, reduce dosing frequency etc.

Polymer coating techniques also used to alter surface morphology of MOFs for various applications such as it alters surface degradation pattern, modulating drug release in a controlled fashion. Jung, S. et al. recently functionalised MOFs surface using fluorescence dyes for in -vitro imaging and tumor targeting. Similarly, McGuire and Forgan prepared MOFs surface coated with Rhodamine and angiogenic peptides for tumor targeting.

5. Application of MOFs
MOFs have a wide application in drug delivery, bioengineering and biomedical sectors. Some of these are briefly discussed below:

5.1. In drug delivery
MOF has garnered much attention due to the porous nature with a large number of voids spaces that provides high drug loading capacity and a controlled drug-release profile. A wide range of therapeutics whether hydrophilic or hydrophobic and or amphiphilic substances can be entrapped in the MOFs. Based on the loading approaches, the active moiety can be encapsulated in the MOF cavity and/or tethered with the framework structure.

Iron-containing BioMIL-1 MOFs showed higher loading for nicotinic acid up to 75 % as compared with the native MOF structures and exhibited controlled drug delivery. The drug metronidazole achieved pronounced controlled release profile from HUKUST-1 MOFs.

Apart from direct drug delivery approach, literature domain reported several MOFs formulation as tablets, pills, patches and films.
5.2. Delivery of biomolecules
Bimolecular delivery from MOFs has also found a wide application for specific delivery of DNA, RNA, and SiRNA etc. The nano MOFs loaded with chemotherapeutics and functionalized with MDR gene siRNA against drug-resistant ovarian cancer cells have been developed. Nano MOFs, encapsulated with prodrug cisplatin and siRNA, have shown improved therapy in cancer.
5.3. In tumor targeting
Nano MOFs have been extensively explored for targeting several human cancers. The doxorubicin loaded Fe3O4-UiO66 MOFs have demonstrated improved drug delivery and superior anti-cancer activity in Hela cells with a significant reduction in the volume of tumor. There are several other complex nano MOFs with silica coating for peptide delivery; Rhodamine delivery from MOFs revealed superior anti-angiogenic attributes. Nano MOFs have great role in intracellular trafficking by changing metabolism and signaling process in the treatment of many diseases.
5.4. As antiseptics and disinfectants
Some of the metals like Ag possess better antibacterial properties, thus Ag-bearing MOFs proved superior antibacterial activity than conventional antiseptics and disinfectants.
5.5. As biosensor
MOFs possess excellent utility in designing the biosensing devices as diagnostic tools for disease identification. The photosensivity, magnetism, luminescence, and light sensitivity of MOFs allows for excellence in biosensing application.

6. Stability and biodegradation of MOFs
The stability of MOFs has  been estimated by subjecting under different simulated conditions such as in phosphate buffer saline and other media as well as evaluated for defects in the framework structure without any degradation of products. Examples are MOF-100, MOF-5, and M-CPO- 27. The degradation and stability profile MOFs also depends on the physical state (crystalline/amorphous), composition and particle size of MOFs.

7. Conclusion
A breakthrough in nano MOFs with research and study for drug delivery and theranostic application further fueled their importance in the biological field. The issues of stability, biocompatibility, biodegradability, and nanotoxicity are considerable for further applicability. Further studies need to focus on in vitro cell line study, preclinical and clinical evaluation in animal and human models.


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Md. Habban Akhter

Md. Habban Akhter has graduated and master in pharmacy (Pharmaceutics) from Jamia Hamdard, New Delhi in 2007 and 2009 and completed doctoral program in 2016. He had qualified GATE exam conducted by IIT, Kanpur, Govt. of India, percentile 97.04 in 2007. He had honored with JRF by UGC, SRF by DST SERB Govt. of India. His work of interest is novel drug delivery system, nanotechnology- based work, engineered nanoparticles targeting approach in cancer therapy, cell line study, cancer induction in an animal model, and development of xenograft model etc. He published several research and review papers in high impact journal of repute. He has attained and presented many papers at  national and international conferences/seminars/symposia. Currently, working as Assistant Professor at DIT University, Dehradun, India.