INTRODUCTION:

Targeted drug delivery systems (TDDS) also known as smart drug delivery as this method comprises of raising the concentration of drug in a specific target organ in comparison to other organs or part of the body. There are two types of targeting methods that are used very frequently to enhance the concentration of drug in the specific organ are active targeting and passive targeting.

Carrier systems either transport the drug in the targeted organ or sometimes in the surrounding space of specific organ. A prominent carrier system is should be able to penetrate across the most prominent barriers like Blood Brain Barrier (BBB). Presently, nano medicines emerging as a medical application of nanotechnology process. Since these nanoparticles are of nano size hence they allow the delivery of hydrophobic drugs and also helpful in preventing the metabolic degradation of drug in the liver. Nanotechnological application of drug delivery helps the drugs to stay in blood and therefore have minimal fluctuations in the dose levels in plasma, hence produces minimal adverse effects. For delivery of drugs to targeted site, nanotechnological carrier systems like transferosomes, liposomes, dendrimers, etc and drug-polymer conjugates were used. There are various other approaches used for this purpose like binding of drug molecules targeting ligands that helps to recognize the antigens associated with specific disease. Pharmacological characteristics of the active drug moiety have vital role in deciding the biological activity of the drug in the patient’s body. This biological activity takes place when drug-receptor interaction took place at specific site of delivery. Whereas, this drug-target interaction is useful only when drug produces maximum therapeutic effect and lesser adverse effects¹. This is the aim that targeted drug delivery is focused for achieving. This offers an enhanced treatment efficacy and reduced adverse effects²and the multifunctional nature of nanomaterials can be seen in Figure 1⁵.

Newer delivery systems mostly consist of lipid moiety, surfactants, polymeric and proteic technology to deliver the sustained delivery of the drug through proper distribution in the body and protecting the drug candidate from the harsh body environment and also prevents the drug from the metabolic processess like first pass metabolism to avoid maximum drug loss. There are various nanotechnological systems used in this process are transferosomes, liposomes, dendrimers, quantum dots, nanocapsules, hydrogels, aquasomes, phytosomes, resealed erythrocytes, etc in different disease states for targeted drug delivery. These TDDS were used in such diseases where it is so critical for active drug candidate to reach to its target site through the internal complicated network in the body of patient. These systems are very helpful to raise the amount of active drug moiety in the specific organ as compared to other organs³. The advantages of these TDDS can be seen in Figure 2⁴ along with various other nanovesicular systems for delivery of drugs that are under research to minimizes the limitations of these systems and also to enhance the efficacy and therapeutic response of the drugs molecules and secondly the focus is on cells microenvironment and how it interacts with these under process new drug delivery systems⁴.

The drug candidates get decomposed before reaching to its specific site because it does not able to bear conditions of body’s internal harsh microenvironment and decompose the drug. This emerges the need to develop the site specific drug delivery systems that helps to reach drug to its specific site and act on the specified organ. Therefore, these nano systems are very significant in guiding the nano system to its desired site of action by changing the physiochemical nature of delivery system against microenvironment of the body and deliver the drug at predetermined rate. The process of encapsulation, response to various stimuli and fabrication are very helpful to great extent and thus these systems are then able to surpass any barrier and deliver maximum therapeutic response.

Figure 1: Multifunctional Nanomaterials and Their Application in Drug Delivery⁵

Figure 2: Advantages of Targeted Drug Delivery Systems⁴

DISCUSSION:

Strategies of drug targeting:

Drug targeting is the area of focus because of emerging need to deliver drug at its specific site and hence maximizing the therapeutic efficacy in the target organ and therefore minimizing the adverse effects that may rise up otherwise. There are two most common strategies that are taken into considerations to delivery drug to desired organ⁶.

Passive targeting:

Passive targeting process mainly focus on accumulating the drug in the vicinity of target organ/tissue like in case of cancer tissues. This effect of accumulating the drug in target organ vicinity is known as Enhanced Permeability Retention (EPR) effect. This type targeting process mostly occur with all types of nanovesicular systems. The term passive targeting is not appropriate as it does not clearly define as a part of selective framework. However, the EPR effect is for administration of nanoparticles and 95% of the total drug accumulates in the other organs than those of targeted organs like lungs, liver and spleen and thus drug is distributed to target organs through blood circulation. For example, Leishmaniasis, candidiasis and brucellosis are being treated for microbial contamination by some of antimalarial drugs^6,7.

Active targeting:

Active targeting used to describe the drug targeting interactions by using receptor-ligand interactions. Although the interaction among ligand and receptor is possible only when these two are in closer proximity (i.e., ≤ 0.5 mm). Extravasation and blood circulation are helpful in delivery of currently available drugs to its specific site. Active targeting basically means the interaction of ligand and receptor but it happens after extravasation and systemic circulation. Active targeting can be sub-classified in 3 sub class of drug targeting⁷. The active and passive targeting processess are depicted in Figure 3^6,7.

First order targeting:

This sub class of active targeting focuses on drug distribution to capillaries of the specific organ/tissue. For e.g., lymphatic tissue is connected with cerebral ventricles, peritoneal cavity and pleural cavity, etc^6,8.

Second order targeting:

This sub class target drugs to desired sites, like to specified tumor cells in case of cancer and to “Kupffer cells” in liver⁶.

Third order targeting:

This sub class of active targeting, drug is targeted to specific site by intercellular localization via the process of receptor based ligand mediated entry and endocytosis⁸.

Figure 3: Active vs Passive Targeting^6,
7

Components of drug targeting:

Target and the drug carriers are the two main components of drug delivery system to deliver drug to specific site/organ/tissue.

Target:

An organ or tissue or cell that is being treated is termed as ‘Target’.

Drug Carrier or Marker:

The process of drug delivery can only be possible only through a carrier systems or marker that carry drug molecule to desired site of action. Carriers are designed systemically in a manner that it can hold the active drug molecule in them by the process of encapsulation^6,8.

Drug Delivery Vehicles:

Drug delivery vehicles or system that transport the drug to specified organ or into the surrounding of specific target site. A drug delivery vehicle is known ideal when it has the characteristic of crossing even the most prominent barrier like BBB. It must be rapidly recognizable by specified cells and further the drug-ligand complex formation must be stable and it should be completely biodegradable and reduced toxicity. This nature helps the carrier system to be completely cleared from the body and physiological means and thus prevents the chances of any type of further tissue toxicity^4,6.

Nanotechnology-based delivery systems:

The nanomaterials are being used for treatment of various diseases. So it is necessary to study the properties of the nanomaterials that can later be used for various treatment purposes^9-12. Though the recent trend has been shifted to the field of drug delivery. It is due to use of large molecules for drug delivery that are slightly incompatible and results in less therapeutic efficacy, poor solubility, reduced bioavailability, adverse effects and raise the need of targeted drug delivery^13-16. The delivery of nanostructures become possible because of fabrication of nanomaterials at nanoscale^17,18,19.

By the virtue of nanotechnology, the drug adheres in the blood circulation for a longer duration, thus lesser fluctuations and lesser adverse effects. These nanoparticulate materials can easily penetrate through tissue and taken up by cells. These systems have an important role in effective targeted drug delivery process. As compared to microparticles, uptake of these nanoparticles can be 15-250 time faster and better^17,20.

Nanoparticulate Drug Delivery Systems Transferosomes:

Transferosomes are just modified form of liposomes, that comprises of phosphatidylcholine and edge activators. These are tailored for delivery of active constituents at enhanced rate as these are soft malleable vesicles by nature and composition^21,22. IDEA AG a German company registered it first and were used for its proprietary technology for the purpose of drug delivery ^23-26. The term Transferosomes means ‘to carry body’ and it is extracted from a Latin word ‘Transfere’ and a Greek word ‘soma’ for ‘body’^27,28. Figure 4 depicts the structure of transferosomes comprising of phosphatidylcholine and edge activator. It is an artificially designed vesicle and or a cell engaged in exocytosis. It is very helpful and suitable for targeted drug delivery at controlled rate to specific target site with minimal metabolic degradation. These can easily adapt to certain stress levels, complex aggregates. The modified liposome is preferred because of its ultra-deformable nature and has a hydrophilic core followed by a lipoidal bilayer. It’s interdependent in composition and shape makes it self-optimizing and self-regulating^{29, 30}. This nature helps transferosomes to cross even most prominent barriers with ease and for release of therapeutic agent, it acts as a carrier system for non-invasive site specific delivery of drugs and sustained release of dosage form^31-35.

Figure 4: Structure of Transferosomes showing ultradeformable vesicles²¹

Composition and Mechanism:

Transferosomes comprises of optimized lipid aggregate and are self-adaptable. The surfactant molecules attached to it acts as “edge activators” providing it ultra-deformable nature that allows to penetrate through various barriers of the body to 1/10^th of its original diameter and after penetration it can regain its original structure. As compared to case of conventional liposomes that hardly penetrate through a pore size of 50 nm due to its large size whereas transferosomes having a diameter upto 500 nm can also penetrate across the barriers by squeezing them upto 1/10^th of their original size³⁶. It is suggested that the driving force needed to penetrate through various barriers is known as “gradient concentration”. Use of adequate ratio of surfactants contributes to its property of deformability. The amount of surfactants plays a very vital role in the formulation of transferosomes as it provides provide flexibility to vesicle membrane at sublytic concentration whereas at higher concentration it can completely rupture the vesicles³⁷.

The membrane present in the transferosome reduces the chance of complete vesicle to rupture due to its flexible nature and allows it to reconstitute its components composition accordingly locally or reversibly when they squeeze themselves against any barrier or pores of cells/tissue. It also prevents the cost of membrane rupturing and able to get through the pores very efficiently and effectively at a faster rate ^38-41. It is consisting of atleast one phosphatidylcholine moiety that act as aqueous solvent that self-resemblance to lipid bilayer. By addition of one component in the bilayer that contributes to its softness(surfactant), flexibility of lipid bilayer and its permeation enhance to a great extent. Therefore, by optimizing the permeability and flexibility results in adapting to a suitable shape and size frequently and rapidly⁴².

Method of Preparation:

The suitable solvent system for dissolving phospholipids, drug and surfactants is alcohol. Further, the organic solvent is evaporated by rotary evaporator under a reduced pressure of 40°C^43-45 and leftover quantity of organic solvent is removed by vacuum. Then there is formation of lipid film that is later hydrated with appropriate buffer system by rotating the rotary evaporator at 60 rpm for atleast 1 hour followed by vesicles left for swelling for 2 hours at room temperature. Therefore, the formed Multilamellar Vesicles (MLVs) are sonicated so that it can transform into smaller vesicles listed in Table 1^42,46,47 and the manufacturing process is depicted through the flowchart in Figure 5⁴⁸.

Table 1: Different additives used in the formulation of transferosomes Ingredients Examples Functions

S.No.	Ingredients	Example	Function	Reference No.
1.	Phospholipid	Soya phosphatidylcholine, Egg phosphatidylcholine, Dipalmityl phosphatidylcholine, Distearyl phosphatidylcholine	Vesicle forming component	42,46,47
2.	Surfactant	Sod. Cholate, Sod. deoxy- cholate, Tween 80 and Span 80	For providing flexibility	42,46,47
3.	Alcohol	Ethanol, Methanol	As a solvent	42,46,47
4.	Dye	Rhodamine-123,DHPE and Fluorescein-DHPE, Nile-red, 6 Carboxy fluorescence	Confocal Scanning Laser Microscopy (CSLM) study	42,46,47
5.	Buffering agent	Saline phosphate buffer at pH 6.5; 7% v/v ethanol Tris buffer at pH 6.5.	Hydrating medium	42,46,47

Figure 5: Method of Preparation of Transferosomes⁴⁸

Table 2: Methods for the characterization of transferosomes

S. No.	Parameter	Method	Reference No.
1.	Morphology of vesicle structure	TEM	49,50
2.	Entrapment Efficiency (EE)	Mini column centrifugation method	49,50
3.	Vesicle size and size distribution	Differential Laser Scanning (DLS) method	49,50
4.	Skin permeation potential	Confocal laser scanning microscopy	49,50
5.	Phospholipid surfactant Interaction	Fluorescence microscopy	49,50
6.	Degree of deformability	Transmission electron microscopy	49,50
7.	Charge density and surface charge	Thin layer chromatography	49,50
8.	Turbidity	31P NMR	49,50
9.	In vitro release study	DLS, Calorimeter, Extrusion method	49,50
10.	Effect on the skin structure	Zeta meter, Nephelometer	49,50
11.	Stability study	Diffusion through biological or synthetic membrane, diffusion through dialysis bag, Histological studies, TEM and DLS method.	49,50

Characterization of transferosomes:

· Morphology of transferosomes can be conducted using Scanning Electron Microscope (SEM) and Transmission Electron Microscope (TEM)⁴⁹.

· Dynamic Light Scattering and Photon Correlation Spectroscopy used for the purpose of particle size determination and size distribution^49,50.

· Entrapment Efficiency (EE) of transferosomes for drug candidate can be easily determined by the method of ultracentrifugation.

· Stability of vesicles can be assessed by any change in shape and size of the vesicular structure over a period of time and drug content determination can be performed using Spectrophotometric methods like High Performance Liquid Chromatography (HPLC)⁵¹.

· In vitro release studies of drug molecule can be done using dialysis bag method or a Franz diffusion cell. All characterization methods are depicted in Table 2^49,50.

The advantages and limitations of these TDDS for nanovesicular system (Transferosomes) are depicted in Table 3^52,53 for delivery of drugs that are under research to minimizes the limitations of these systems and also to enhance the efficacy and therapeutic response of the drugs molecules and secondly the focus is on cells microenvironment and how it interacts with these under process new drug delivery systems⁴.

Table 3: Advantages and Limitations of Transferosomes

S. No.	Advantages	Limitations	Reference No.
1.	High penetration due to high deformability	Expensive manufacturing process	52,53
2.	More stable	Chemically unstable due to its predisposition to oxidative degradation	52,53
3.	Incorporate wider range of molecular weight	Difficulty in loading hydrophobic drugs	52,53
4.	Biocompatible and Biodegradable	Lack of purity of natural phospholipids	52,53

LITERATURE REVIEW^54-61:

Author	Results	Reference No.
(Azimi et al., 2019) (Jiang et al., 2018)	Apart from all the mentioned studies, transferosomes have been recently formulated to deliver proteins, such us the growth hormone or oligopeptides.	[54,55]
(Wu et al., 2019; Yang et al., 2019)	In the case of microneedles, the formation of micron-scale pathways into the skin, as well drive nanomedicines directly into the skin can potentially enhance the delivery of transferosomes across the SC.	[56,57]
(Salem et al., 2019)	The transferosomal gel was formed by adding Carbopol 934 and then Poloxamer 407 to the reconstituted transferosomes. The mixture was stirred until a clear solution was obtained. Two drops of triethanolamine were finally added to adjust the pH and form the gel. Optimized transferosomes resulted in 4.5-fold more permeable than resveratrol suspension across sheep nasal mucosa.	[58]
(Omar et al., 2019)	The burst effect observed during the first hours upon administration has been also linked with a small breakage of the lipid bilayer due to the vesicle deformation taking place during the permeation, allowing a partial release of the drug located in the core.	[59]
(van Zyl et al., 2019)	In terms of zeta potential, transferosomes seem have shown the greatest colloidal stability when compared to liposomes and niosomes in liquid media.	[60]
(Hadidi et al., 2018)	Transferosomes have exhibited good colloidal stability (with no sign of aggregation) up to three months both at 4 °C and 25 °C.	[61]

Future Perspectives:

Targeted drug delivery has immense scope due to various limitation of these non-site specific drug delivery systems. By using nanomaterials for site specific delivery can provide an alternative approach for short term strategies. Rate limiting factor might be a concern for toxicity in the cells/organs. New strategies can be framed to overcome and it can be important path forward to focus and find new techniques to minimize the toxicity in the organs. There is vast potential in this area to maintain its tolerability and efficiency. Newer drug delivery systems are under development phase that surely contributes to this concept of targeting drug delivery of drugs to specific site and gain maximum therapeutic efficacy.

CONCLUSION:

This concept of targeted drug delivery results in administering injectables of low dose and hence the adverse effects were found significantly less as compared to conventional drug delivery systems. The main disadvantage of this conventional system of drug delivery emerges the need of fast developing of these TDDS for site specific delivery of drugs. Nanotechnology application in the process of drug delivery has now particularly helpful in enhanced drug delivery. There are various nanovesicular carrier systems that have already been approved for their clinical use and many more are there in the research pipeline that open the way for further research too. There are some other targeting approaches that have been developed based on the same principle. This indicated a bright future of targeted drug delivery approaches. As this review mainly focuses on the targeted drug delivery of transferosomes being an efficient carrier system. Likewise, many other carrier systems can be further modified or optimized to a certain extent so that these will be helpful in one or the other drug delivery approaches. Transferosomes has the ability of ultra deformability and squeeze itself to 1/10^th of its diameter due to presence of phosphatidylcholine and edge activators that contributes to its property of enhanced permeation and penetration across the barriers. Transferosomal formulations are approved for cosmetic and pharmaceutical use. These have the ability to increase prolong the release, transdermal flux and also improves the targeted delivery of these bioactive molecules and can hold drug candidate to a wider solubility range. This opens new opportunities and challenges for more site specific therapies.

ACKNOWLEDGEMENT:

All The authors would like to thank Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus for providing the library facilities for the review work.

CONFLICT OF INTEREST:

The authors declare no conflict of interest, financial or otherwise.

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Received on 03.10.2020 Modified on 23.05.2021

Research J. Pharm.and Tech 2022; 15(2):913-920.

DOI: 10.52711/0974-360X.2022.00153