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Diverse functional materials as drug delivery systems

Dr Venkata Ravi Kumar Darbha & Dr Prabhakar K Ingle
Wednesday, March 28, 2018, 08:00 Hrs  [IST]

Safe and efficient route to deliver drug is one of the major challenges of pharmaceutical sciences. Although there are several methods such as oral, intravenous, subcutaneous etc. being commonly practiced, most of the time drug loses its therapeutic activity before reaching the target. Hence, heavier load of drug is used to achieve required therapeutic action. This may cause the accumulation of drug in the body that causes unwanted toxic side effects. Hence, novel and efficient methods for drug delivery are required and these methods should mainly aim (i) decreasing the drug load and still carrying the same therapeutic action (ii) avoiding the drug degradation before reaching the target (iii) more drug availability on site of action (iv) controlled release of the drug (v) minimizing the toxic side effects.

In this regard, targeted drug delivery using functional materials has attracted attention from various scientific communities. In broader context, the drug delivery studies mainly focused on targeted delivery of cancer drugs. However, these functional materials, especially at nano level may cause wanted/unwanted cellular reactivity.  Hence, before opting a material as drug carrier the particular materials has to be critically evaluated to understand its efficiency and limitations. It is also responsibility of the scientific community to validate the materials and potentiality time to time, irrespective of the scientific novelty of the material.  Several functional materials were used as drug carriers and this particular wing of pharmaceutical science was emerged vastly in last few decades. Most often, the material size is either nano level or micron level. These materials mainly can be classified (however the classification is broad and not exclusive) as soft materials such as polymers, micelles, lipids; inorganic nanoparticles; porous materials such mesoporous silica. In this context, this article aimed to overview the recent progress in the emerging area of functional materials in drug delivery in Indian scenario.

In the above classification of the materials, under the inorganic nanomaterials gold nanoparticles and mesoporous silica were extensively studied. The interesting feature of the above materials is their biocompatibility. When compared to the other competitors such as polymers for drug delivery applications, unique features like narrow size distribution, high surface to volume ratio can be achieved in inorganic nanoparticles. The material like gold easily conjugated with several biomolecules, without altering their biological activity. Here we summarize the work on functional materials in drug delivery carried out by various research groups at CSIR-National Chemical Laboratory (CSIR-NCL), Pune.

In the well cited work of Prasad and co-workers, gold nanoparticle were fabricated with gellan gum which is a biocompatible and non-toxic material and acts as reducing and capping agent in the fabrication of gold nanoparticles.  Zeta potential studies of the above nanoparticles revel that the nanoparticles are well stabilized system with negatively charged gellan gum on the surface of the nanoparticles that gives stability by means of electrostatic repulsions. Hence these negatively charged, biocompatible gellan gum capped gold nanoparticles can be strategically used to load positively changed doxorubicin hydrochloride, a well-known cancer drug. Here it is important to note that toxicity of the carrier particles has to be critically evaluated, in this line the toxicity studies were also carried on the above mentioned functionalized nanoparticles. In continuation to this, chitosan (another biocompatible polymer) reduced gold nanoparticles were also prepared and subjected to toxicity studies to explore as carrier particles for therapeutic reagents.

Metal nanoparticles and their composites
Another anti-cancer drug methotrexate was also studied by same group for drug delivery applications using Bovine Serum Albumin (BSA) capped gold nanoparticles. Although methotrexate is potential drug for various cancers, its clinical usage is limited because of the poor solubility of the drug, this limitation can be overcome by forming nanoparticle drug conjugate. Earlier reports also focused on the nanoparticle-drug conjugates but the lack on monodispersity, difficulty in surface functionalization and tendency of the particle towards aggregation limit the application of nanoparticle-drug conjugate. The above limitations were successfully overcome by choosing the Bovine Serum Albumin as capping agent on nanoparticles which can affectively conjugate with the cancer drug. Anti-cancer activity studies on human breast cancer cell were performed using free drug and gold nanoparticle-BSA-drug conjugate. Under the similar concentrations of the drug, Au-BSA-drug conjugate has shown 20 per cent enhancement in killing the cell as compared to free drug. Enhanced activity of the conjugate is because of more cellular update by cancer cell and synergetic affect between Bovine Serum Albumin and drug.

Metal nanoparticles such as silver nanoparticles prepared using thermoassociating polymer namely, carboxymethyl guar-g-poly(ethyleneoxide-copropylene oxide) [CMG-g-PEPO] as reducing agent are used for drug delivery applications. This polymer can act as reducing and capping agent for the synthesis of silver (Ag) nanoparticles and produces excellent composite. The polymer can become hydrophilic or hydrophobic with small variation in temperature and this behavior of the polymer can successfully be used for drug delivery applications. A well-known anti-cancer drug i.e., doxorubicin hydrochloride was used as model drug to study the drug delivery applications. Effective loading of drug was studied by measuring the surface on nanoparticles by zeta potential measurements. The drug release to the buffer solution was studied by analyzing the buffer samples time to time.

Magnetic nanoparticles and their composites
Biocompatible superparamagnetic iron oxide nanoparticles were further explored as drug delivery systems by Joy and co-workers. Magnetic nanoparticles (Fe3O4) were prepared by reverse co-precipitation method. Citric acid and cyclodextrin complex was added to magnetic nanoparticles to prepare surface functionalized nanoparticles. Curcumin, a hydrophobic drug was loaded on these particles. The loading capacity of curcumin on functionalized nanoparticles is much higher than drug loading on simple cyclodextrin. The drug released was studied at physiological pH by dialysis bag method. The amount of drug released in buffer was studied by recording the absorbance at 425 nm which is ?max (wavelength) for curcumin. It was observed that the curcumin release profile follows zero order kinetics at the physiological pH. Hence, magnetic nanoparticles can release curcumin at a constant rate, after the initial burst release. Nuclear magnetic resonance (NMR) studies showed that the functionalized nanoparticles are suitable for contrast enhancement in MRI. Hence the water-dispersible, citrate, cyclodextrin functionalized magnetite nanoparticles can act as efficient drug delivery systems as well as MRI contrast agents.  Another interesting magnetic nanoparticles-polymer composite was reported by Singh and co-workers. A chemotherapy drug Cyclophosphamide was loaded on the polymer scaffolds. Preparation of scaffolds involves the synthesis of Co3O4-Fe3O4 nanoparticles and incorporating them to the glycolic acid-grafted chitosan. The chemotherapy drug was loaded on the above scaffolds and the scaffold immersed in the aliquots of phosphate buffer. After specific time interval aliquots were collected, the drug content was estimated my recording UV-vis spectrum of the aliquot and it was concluded that the drug release is following the first order kinetics and the release of drug is high initially and slowly it is decreased with time. The cell viability was also studied on the Co3O4-Fe3O4 bio polymer composite.  

Metal organic frameworks - novel porous materials for controlled drug delivery
Metal organic frameworks popularly known as MOFs are explored in various areas like CO2 capture, catalysis etc. But, their application in drug delivery was not well studied till recent years. Main reasons for the limited applications of metal organic frameworks as drug delivery systems could be (i) instability of MOF in physiological conditions (ii) small pore sizes to load large drug molecules (iii) expected toxicity of MOF due to metal back bone present in it. In the view of answering the above limitations and fulfilling the requirements for the ideal drug delivery system, Banerjee’s group designed a novel gadalonium (Gd III) based MOF using 1,4-bis(5-carboxy-1H-benzimidazole-2-yl) benzene (pDBI) linker. The size of Gd-pDBI size is reduced mechanical grinding to get optimum size for intravenous injection. Doxorubicin hydrochloride was loaded on the above mechanically ground Gd-pDBI MOF and it showed 12 per cent loading of doxorubicin hydrochloride which is high among drug loaded MOFs. Drug release studies were carried out at different pH (5 and 7.4) and the complete drug release to cancer cells was observed after fifteen days. The non-toxic nature of MOF was also studied using MTT assay.  

2D materials as drug delivery systems

Covalent organic frameworks (COFs) similar to metal organic frameworks are interesting class of materials. Two dimensional covalent organic nanosheets (CON) can be obtained by exfoliation of the covalent organic frameworks. Diversity of these materials in different properties such high surface accessibility, functionality, chemical stability project them as potential candidates for the biomedical applications. The CONs does not contain any metal, hence there is no possibility of the toxicity of these materials as a result of metal ion leaching. Banerjee and co-workers developed potential CONs with above mentioned qualities, quite interesting candidates for drug delivery applications.  These covalent organic nanosheets are derived from COFs by post synthetic methods. Anti-cancer drug 5-Fluorouracil was used for drug delivery studies with breast cancer cells. Drug loading on above mentioned covalent organic nanosheets is higher than the biocompatible polymers like polyethylene glycol-4000 (PEG-4000), polyvinylpyrrolidone (PVP), polylactic acid (PLLA). The drug release studies were carried out at different pH {(from potential of hydrogen) the logarithm of the reciprocal of hydrogen-ion concentration in gram atoms per litre; provides a measure on a scale from 0 to 14 of the acidity or alkalinity of a solution (where 7 is neutral and greater than 7 is more basic and less than 7 is more acidic)}  and 74 per cent of drug release was noted after 72 hours when the pH is 5. Drug loaded covalent organic nanosheets could establish controlled release of the drug and death of cancer cells by apoptosis. Moreover, it decreases the expected side effects.

Dr Venkata Ravi Kumar Darbha is working as an assistant professor, Department of Sciences, Amrita University, Coimbatore-641112). Dr. Prabhakar K. Ingle is Head, Publication and Science Communication, CSIR-NCL, Pune 411008)

 

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