Metal Organic Framework-Mesoporous Silica Nanoparticle Composite for Controlled Drug Delivery

An approach to solve the problem of premature release of cargo from bare MSN

Chandan Adhikari ,  Assistant Professor, Lovely Professional University, India

Drug delivery system composed of mesoporous silica nanoparticles suffers from many drawbacks. Out of many challenges, two major challenges in drug delivery through mesoporous silica nanoparticles, are premature leakage and fast release of the drug molecules. Because of these most of the time efficiency of the drug delivery system become very low. In this work, Mesoporous Silica Nanoparticles (MSN) have been modified using zeolitic imidazole framework through formation of a hybrid system. An anticancer drug Doxorubicin was encapsulated in mesoporous silica nanoparticles. The composite system has enough control on the drug release over the conventional drug delivery through bare mesoporous silica nanoparticles. This phenomenon was explained based on that, the ZIF frameworks act as a shield against the external stimuli and protects the bare silica from contact with the external agent and results in slower drug release. But in case of bare silica due to the absence of this kind of protection, drug release becomes very fast under acidic conditions.

Most of the chemotherapeutic drugs suffer from uncontrolled and non-specificdelivery that lead to lethal effects to the body thus limits their uses.So;severe side effects of chemotherapeutic drugs to the healthy cells is very common and controlleddelivery is very essential for chemotherapeutics. To overcome these adverseeffects of uncontrolled delivery, we need a delivery vehicle which will deliver the drug moleculesin a controlled way with specific target and high efficiency. An ideal Drug Delivery Systems (DDS) should have high biocompatibility, biodegradability, high loadingefficiency, ability to prevent drug leakage, control over the release, high efficiency, less side effectsetc. [1] To achieve these, several DDS have been developed in the last fewdecades including both soft materials as well as hard materials. Liposome, polymerosome, micelle, dendrimer, polymer capsules are few examples of soft DDS and few ofthese have already been approved by FDA. Although softDDS show some promising results, however premature drug leakage followed by uncontrolleddrug release remain two major problems that motivated the scientists for the development of other DDS based on hard materials. Hard materials primarily consist of inorganicnanoparticles and inorganic-organic hybrid materials including mesoporous silica nanoparticles, gold nanoparticles, silver nanoparticles, iron oxide nanoparticles, quantum dots, carbon nanotubes,metal organic frameworks etc.[2] Out of these materials, Mesoporous Silica Nanoparticles (MSN) and Metal Organic Frameworks (MOFs) have made their own space inbiomaterials science. Several pioneer works show that both MSN and MOFs can be used as promising drug delivery system. MSN are one of the inorganic porous nanomaterials which have been used in biomedical science since early 2000. Due to the easy synthesis, highlyporous structure, high surface area, high pore volume, tunable pore size, high drug loading ability,biocompatibility, easy surface modification, MSN becomes one of the favorite choice of the scientists as DDS for the last few years. [3] There are several reports in the literaturewhich shows that MSN can be used as potential DDS. Although conventional MSN have several advantagesbut MSN suffer from few problems like drug leakage and fast release of the cargo.Several strategies have been adopted to resolve these issues. Improved MSNs werealready prepared by either surface functionalisation or by conjugation with different inorganic aswell as organic molecules including iron oxide, polymers, polyelectrolytes, quantum dots, goldnanoparticles, cyclodextrin, biomolecules, enzymes etc. Several differentchemotherapeutic drugs e.g. Doxorubicin, camptothecin, paclitaxel, docetaxel, were alreadydelivered using modified MSN. [4] In this chapter, we have developed a new strategy to modify the MSN by making a composite with zeoliticimidazole frameworks (ZIFs). ZIFs are one of the subclasses of metal organic frameworks, composed of zinc as metal ions and imidazole and imidazole derivatives as organic ligands. Due to high surface area,porous structure, tunable shape and size etc. ZIFs have been used in different field of science including gas storage, gas sensing, catalysis, gas separation etc. Although, hundreds of ZIFs have been synthesized during the last few years, only few of them went into the application in DDS. Recently, ZIFs have been used as DDS forvarious types of drugs because of their biocompatibility, biodegradability, huge cargo loadingability etc. Different types of drugs including Doxorubicin, camptothecin, curcumin, etc. were already delivered through ZIFs which indicate promising future of ZIFs asDDS. Although these reports show positive results but still this area is in underdevelopment stage, therefore, more research is needed furtherso that ZIFs can be used efficiently and practically in biomedical science. [5]

Keeping all these points in mind, here in, we developed a new strategy to improve conventional MSN by combining with ZIFs to make a hybrid system. The main objective of thiswork was to control premature drug release and prevent drug leakage from the MSN which were very common phenomenon with conventional MSN. We used two ZIFs, ZIF-7 and ZIF-8, to form the composite DDS (ZIFs/MSN DDS). We chose these two ZIFs because both the ZIFs were known to be biocompatible, biodegradable and have been already used for delivery of chemotherapeutic drugs. We used a prominent anticancer drug Doxorubicin (DOX) as a model chemotherapeutics to explore this new ZIFs/MSN composite DDS as a newdelivery vehicle. At first, DOX was incorporated in MSN following a previously reported postsynthetic drug incorporation method. We used this DOX loaded MSN (MSN@DOX)for composite formation during the synthesis of ZIFs. MSN, MSN@DOX and ZIFs-MSNcomposite (ZIF-8/MSN@DOX & ZIF-7/MSN@DOX) were characterised by Powder X-ray Diffraction, IR spectroscopy, Thermogravimetric analysis, BET analysis, scanning electronmicroscopy. We have shown the drug release from MSN@DOX as well as fromZIFs/MSN@DOX under external triggering agents. We used acidic pH (pH~5.0) as external stimuli because the micro environment of the cancerous cells are acidic than normal cells. MSN@DOX shows very fast release of the drug that completed by three hours. Onthe other hand, composite DDS release the drug slowly in a controlled way over a period of 12hours which is almost 4 times slower release than normal MSN. So, the composite systems havesubstantial control on the drug release over the conventional MSN. We hypothised that the ZIF frameworks act as a shield against the external stimuli and protects the bare silica from contact with the external agent and results in slower drug release. But in case of bare silica due to theabsence of this kind of protection, drug release becomes very fast under acidic conditions. We also described that the reason behind the drug release is the rupture of the ZIFs frameworks at acidic conditions because of the detachment of the ligand from the metal center which results in destruction of the frameworks. As soon as ZIF framework collapses, bare silica starts to release the drug slowly at acidic pH. Overall the present work highlights a novel strategy for modification of MSN and prevent drug leakage and uncontrolled drug release. We hope this study will help further in the future development of drug delivery system based on composite materials.

References:

1.    Biomater. Sci. 2013, 1, 114–134 (DOI:10.1039/C2BM00085G).
2.    ACSNano.3, 16-20 (DOI:10.1021/nn900002m).
3.    J.Mater.Chem.B,3,8599-8622(DOI:10.1039/C5TB00757G).
4.    Journal of Drug Delivery Science and Technology, 45,303-314
5.    Mol. Pharmaceutics. 12, 3158−3166 (DOI:10.1021/acs.molpharmaceut.5b00043).

Chandan Adhikari

Chandan Adhikari is currently working as Assistant Professor at Lovely Professional University, India. He completed Masters from IIT Hyderabad, India and Ph.D. from IIT Indore, India with specialisation in ‘Applications of Nano-materials in Biomedical Science’ [Published 13 Research article]. He also worked at IACS Kolkata as National Post-Doctoral Fellow [2017-2018].

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