Plant Extract Loaded Nanoparticles

Plant extract, a natural source containing complex mixture of compounds, offers many properties such as antiparasitic, antibiotic, antioxidant, anti-hypertensive, antiviral, insecticide, anticancer, antifungal, hypoglycemic properties. Recent research has been focused on developing formulation the plant extracts not only to deliver them safely but also to enhance its therapeutic efficacy. Nanotechnology-based strategies have been proposed as a system that can be used to formulate plant extracts. Plant extract loaded nanoparticles (NPs) is aimed to facilitate in crossing the biological barriers, to increase bioavailability of poorly water-soluble phytochemicals, to encapsulate mixture compounds of different phytochemicals, to provide targeted delivery of phytochemicals to specific organs resulting in low toxicity, to get effective purification process, to mask unpleasant taste and odor, to protect sensitive phytochemicals from biological (e.g. enzyme, pH) and environmental (e.g. light, temperature, humidity) degradation, to control release of encapsulated phytochemicals, and to provide a more flexible control over the size and shape of the NPs. This review is focused on plant extract loaded NPs including its advantages, stages for developing formulation of plant extract loaded NPs, and nanosystem used to loading plant extract. In addition, this review also depicts studies which have been conducted by many researchers in developing plant extract loaded NPs. The data were collected from published journals with 21 and 39 journals as primary and supporting literatures, respectively. Plant extracts loaded NPs could be a promising delivery system for active phytochemical contained in the plant extract which is not only to deliver them safely but also to enhance its therapeutic efficacy.


Introduction
Plants have been used for treatment various diseases since long time. Biological active compounds are obtained by extracting mainly the leaves, the fruits, the stems, or roots of medicinal plants (1). The biological active compounds can have antiparasitic, antibiotic, antioxidant, anti-hypertensive, antiviral, insecticide, anticancer, antifungal, hypoglycemic properties (1). To increase the application of plant extracts, a technology must be performed in formulation development of plant extracts (2).
Recently, many studies use nanotechnology to formulate plant extract. By using nanotechnology-based systems, biopharmaceutical and technological properties of plant extracts can be improved (2). The nanosystems used commonly are nanoparticles (NPs) (either polymer or lipid-based NPs), liposomes, and nanoemulsions (2). Formulation development of plant extract loaded NPs has been focused by researchers to combine the benefits offered by nanotechnology and the diversity of biological activities of plant extracts (2).
Plant extract loaded NPs offers numerous advantages because of their size and unique physicochemical characteristics. Moreover, plant extract loaded NPs can be used to decrease plant extracts toxicity, to provide targeted drug delivery and to solve stability related problems (1). There are several stages involved in developing preparation of plant extract loaded NPs (1).
The aim of this review is to describe about plant extract loaded NPs including its advantages, stages for developing formulation of plant extract loaded NPs, and nanosystem used to encapsulate plant extract. In addition, this review also shows many studies which have been investigated by researchers to develop plant extract loaded NPs.

Methodology
This review was obtained by using specific keywords "plant extract and nanoparticles," by following an inclusions criteria (related to specific keywords) and exclusions criteria (opinions and unrelated topics). We collected about 21 journals published in 2010-2021 as a primary literatures and 39 journals published as supporting literature. The flowchart of methodology can be seen in Figure 1.

Nanoparticles (NPs)
The rapid development of nanotechnology has good prospect to develop formulation of active compounds loaded NPs. NPs are commonly defined to particulate substances which have diameter in the range of 1 to 100 nm although in principle NPs are described as substances with length of 1-1000 nm in at least one dimension (3)(4)(5)(6). NPs have been widely used in many applications such as medications, electronics, manufacturing and materials, environment, mechanical industries, etc. (6). Classification of NPs are polymeric NPs, lipidbased NPs, carbon-based NPs, ceramics NPs, semiconductor NPs, and metal NPs and can be synthesized either top-down or bottom-up method (6). The most common nanoparticle systems used for the delivery of natural products are nanoliposome, polymeric NPs, solid lipid nanoparticle (SLN), dendrimer, nanocrystal, nanoemulsion, micelle, hydrogel, fullerene, and zeolite (7).
The nanosystems used commonly are nanoparticles (NPs) (either polymer or lipidbased NPs), liposomes, and nanoemulsions (2). Figure 2 shows the nanosystem used for loading plant extracts. Some techniques which are very frequently used for loading plant extract into NPs are emulsion solvent evaporation, nanoprecipitation, emulsion solvent diffusion, and ionic gelation. These techniques differ by their principles and are also influenced by nature of the encapsulated phytochemicals. Correct selection of the techniques very important to obtain a formulation of plant extract loaded NPs (1).

Advantages and disadvantages of plant extract loaded nanoparticle
Many studies reveal that nanotechnology offers many benefits, including for formulation of plant extract loaded NPs. Plant extract loaded nanoparticle have several advantages such as facilitating in crossing the biological barriers, increasing bioavailability of poorly watersoluble phytochemicals, encapsulation of mixture compounds of different phytochemicals, providing targeted delivery of phytochemicals to specific organs resulting in reducing toxicity of phytochemicals, getting effective purification process, masking unpleasant taste and odor, increasing stability of the encapsulated phytochemicals by protection of the sensitive phytochemicals from biological (e.g. enzyme, pH) and environmental (e.g. light, temperature, humidity) degradation or inactivation, controlling the release of encapsulated phytochemicals, and providing a more flexible control over the size and shape of the NPs during synthesis of NPs using plant extract (1,(7)(8)(9)(10)(11)(12).

Figure 2. Illustration of nanosystems used for loading plant extract
On the other hand, the drawback of NPs should be a careful consideration in formulation of plant extract loaded NPs such as a tendency to high aggregation in biological system due to high surface area and energy, high immunogenicity, long and expensive cost, and chance of poor targeting (13).  (Figure 3). Phase one was focused on extract standardization. Phase two was aimed to encapsulate both extracts in SLN-Cs to obtain an optimum formulation of SLN-Cs. Phase three was concerned on the cytotoxicity evaluation (14).  Gold and Silver NPs (60) antimicrobial applications. Curcumin is the main content in the rhizome of the turmeric. This group proved that Curcumin loaded PLGA NPs (Cur-PLGA NPs) are successfully to be used for not only bioimaging but also antibacterial application ( Figure 5) (42).

Stages for developing preparation of plant extract loaded nanoparticle
The release of loaded phytochemicals can be controlled and the stability can be increased when plant extract is loaded in NPs. Sanna et al. showed the effectiveness of white tea extract loaded PCL NPs. This nutraceutical application is used to control the release of tea polyphenols and to maintain the antioxidant activity. The release study showed that the polyphenols was released from NPs about 20% at pH 1.2 (simulated gastric medium) and 80% at pH 7.4, respectively ( Figure 6). This result proved that NPs can be used to control delivery of the polyphenols In addition, the encapsulation of the white tea extract into NPs significantly increased stability, thus preventing the losses of TPC and catechins over 30 days of storage (50    PLGA as an anticancer. This group reported that the anticancer activity of the extract loaded PLGA NPs was more effective than extract per se (16). In addition to anticancer activity,

Conclusion
The use of nanotechnology-based systems has been grown rapidly. Plant extract loaded nanosystems such as nanoparticles (NPs) (either polymer or lipid-based NPs), liposomes, and nanoemulsions can bring many benefits which can be aimed to facilitate in crossing the biological barriers, to increase bioavailabilityof poorly water-soluble phytochemicals, to encapsulate mixture compounds of different phytochemicals, to provide targeted delivery of phytochemicals to specific organs resulting in low toxicity, to get effective purification process, to mask unpleasant taste and odor, to protect sensitive phytochemicals from biological (e.g. enzyme, pH) and environmental (e.g. light, temperature, humidity) degradation, to control release of encapsulated phytochemicals, and to provide a more flexible control over the size and shape of the NPs. Recent research has been focused on developing formulation the plant extracts not only to deliver them safely but also to enhance its therapeutic efficacy which involves several stages for developing formulation of plant extract loaded NPs.