#homopolymer

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Qatar Polymer Industrial Company

VeeChem Global is a Qatar polymer industrial company specialized in marketing and distributing a variety of high-quality commodities as well as specialized plastics. The bring packaging to life.

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Excited Triplet States of Organic Molecules and Reactive Free Radicals in Polymers

Abstract

The mini-review is devoted to the recent investigation the role of cage effect during photopolymerization. Benzophenone was selected as a photoinitiator of polymerization.

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Introduction

Free-radical photopolymerization (UV-cure) of organic coatings is a very important process that has been used for more than half a century. Academic and industrial researchers study the basics of this complex process [1-4] In this mini review we will briefly consider the important role of low MW free radicals of photoinitiators (PIs) and the excited triplet states of PIs in photopolymerization. On the contrary, residual PIs in the cured coatings and other low MW photoreactive species in the cured coatings/polymers lead to a negative effect: photodecomposition of polymers outdoors, poor weatherability. We will comment on that as well.

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Discussion

A primary chemical act of free radical photopolymerization is the generation of radical pairs (RP) in the triplet spin state. PI absorbs UV- or visible light; populates the excited singlet state of PI which in turn undergoes intersystem crossing into the triplet state. PIs often contain a carbonyl group in their structure. Reactive triplet state either undergoes dissociation into two radicals (Norrish 1 process) or H-abstraction from co-initiator or even from the coatings material or a polymer, both possessing C-H bonds. The first PIs are dubbed as Type 1 PIs, and the latter PIs as Type 2 PIs [4-6]. We will use a commercial PI benzophenone (BP) as an exemplar. Photochemistry of BP and reactions of corresponding free radicals BPH• have been extensively studied. Thus, the action of BP as a PI or as a residual PI in the cured coatings can be presented by eq. (1):

Here RH is a hydrogen donor. The RP formed in reaction (1) either decays in the polymer cage or radicals escape into the polymer bulk, as per (Scheme 1) shown below. The formation of an RP in the triplet state is a hurdle for a cage reaction. RP can react only in the singlet state with few exceptions. We include in our discussion low MW radicals which are formed at a high degree of photopolymerization (conversion of vinyl groups), say at . At high the media can be regarded as a polymer. A fraction of photogenerated radicals which decay inside a cage is called cage effect. Obviously, chemists are interested in the lowest possible in the case of photoinitiation of polymerization and in the highest possible in the polymers outdoors. (For fairness sake, we will mention that an aromatic radical BPH• does not initiate polymerization, but a counter radical R• does.) 3BP and R• are damaging species in the cured coatings or polymers that facilitate photodegradation. Photopolymerization usually does not lead to complete consumption of PI. On average 20% of the dissolved PI stays in the cured coatings. Being outdoors, the cured coating is subjected to destruction initiated in particular by the residual PI and possibly by carbonyl compounds formed during autoxidation. (Here we talk about processes which last years.) Thus, cage effect value and its dependence upon the degree of photopolymerization and properties of a polymer are very important for practice [7,8] It was demonstrated that the value of depends in particular upon the free volume of a polymer Vf and the glass transition temperature of a polymer Tg [3,9]. Cage effect dynamics (Scheme 1) since the inception of RP at t 0 till relatively long time upon completion (milliseconds) of cage reactions has been studied by ns flash photolysis with optical or ESR detection. This research was done mainly with PI=BP. 10 ns resolution of such instruments is okay. Cage reactions in the viscous media (polymers) lasts microseconds [1-3,9,10]. Application of moderate external magnetic field affects [1-3,7] and should find a practical application in the cure of coatings. An interesting type of coatings are coatings which can be photopolymerized without a PI [10,11].

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Conclusion

It is not surprising, that commercial PIs [4-6] are molecules that have a high quantum yield of an excited triplet state and which dissociate from a triplet state with a formation of a triplet RP [10]. Triplet RP has a high probability of dissociation and initiation of polymerization even in a viscous media.

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Co- Excipient: Future of Formulation Industry

Abstract

This article will give complete overview on recent development in co-process excipient technology and approaches involved in its development. The co-processed excipients help to overcome deficiencies occurring with use of single general grade excipients. Formulation scientist recognized that the single component excipient cannot always provide the essential performance in manufacturing or formulation to certain active pharmaceutical ingredient (API). Hence attention on the production of multifunctional excipient with improve performance was seen to meet the need of formulation. In order to justify rise in new drug development and also high industrial output demand new combinations of existing excipient were tested for improving excipient functionality. Now days the particle engineering of individual excipient and their combinations by using co-processing technique has provided an attribute tool for developing high functionality excipients to modern drug delivery system. The co-processing is a process with interaction of two or more excipients at sub particle level which turn to provide a synergy of functionality improvement as well as masking the undesirable properties of individual excipients. It is synergistic outcome of the combination of excipients as material property into consideration .The specific excipients are best suited for particular dosage form as a selection criterion for excipients and various excipient interaction. The excipient as like of API need to be stabilized and to be standardized along with safety evaluation parameters. These co-excipients have high functionalities as compared to the individual excipients like better flow property, reduced lubricant sensitivity and compressibility.

Keywords: Excipients; Co-Processing; Particle Engineering; Novel Drug Delivery System

Introduction

In recent year scientists have found that a single excipient cannot always provide the requisite performance to allow the certain API to be manufactured or formulated. The co-processed excipients are combination of two or more compendial or non-compendial excipients which are designed to physically modify their properties in manner that are not achievable by simple physical mixing and without a significant chemical change. Development of the co-processed excipients starts with selection of excipients to be combined, preparation method, their targeted proportion to get optimized product with desired physico-chemical parameters and minimizing avoidance with batch to batch variations. Excipient of a reasonable price has to be combined with optimal amount of functional material in order to obtain the integrated product, with a superior functionality than simple mixture of components. The co-processing is interesting because products are physically modified in special way without altering chemical structure. The fixed and homogenous distribution of components is achieved by embedding then within mini granules. Segregation is diminished by the adhesion of actives on the porous particles making process validation and in process reliable and easy control. Co-processed excipient enhances performance of established excipient that possess performance and improvements: in flow, increased surface area, compaction etc [1-3].

Types of Excipients [2,4-6]

Generally, types of excipients are classified into four types enlisted below:

i. Single chemical entity

ii. Physical mixture or blends of excipients

iii. New chemical entities

iv. Co-processed excipients

i. Single chemical entity

The single entity excipient is nothing, but the primary component used as excipient. It may contain other components like:

a. Concomitant component: is a balance between excipient composition and its functionality. These components should be considered as part of composition profile and hence not be construed as being a undesirable, nor confused with presence of added substance [2].

b. Processing Aids: are chemical substances which are used for specific processing need and benefit in excipient manufacturing process, like to improve chemical and physical process ability, to enhance a chemical synthesis reaction, to provide stabilization during the manufacturing process etc. The processing aids can be removed during the excipient manufacturing process or, depending on process clearance capability; it may remain as low level residual in final excipient. [4,5].

c. Additives: It is defined as any substance not normally consumed as a food by itself and one which is intentionally added to food, or for technical purpose in manufacture, processing, preparation or storage of such food to improve their physico-chemical properties. Normally additives are added by simple mixing process and they are incorporated in amount required to produce intended effect. Additives added not be of official grade, it should be of appropriate quality with safety been evaluated for their proposed use. Hence, the additive does not detrimental impact on excipient function and the final drug product safety/efficacy [5].

ii. Physical mixture or blends of excipients

It is a simple physical mixture or blends of two or more excipients to maintain shear processes where, individual components are mixed together without significant change. For solid mixture the individual excipients remain physically separate at particulate level. Excipient blends can be either solid or liquid after simple mixing typically for short duration [3,4].

iii. Novel excipients or new chemical entities

An excipient used for first time in formulation or by a new route of administration is classified as novel or new according to the ICH Guideline. On the other hand, this guideline defines known excipients that are commonly used and well-established usually included in pharmacopoeias and used in registered drug products. When an excipient has not previously been used in a pharmaceutical formulation then there are a number of conditions set out by the US and European regulatory authorities to allow for its use. They are not fully qualified by existing safety data with respect to currently proposed level of exposure, route of administration or duration of exposure [4,5].

iv. Co processed excipients

It is a combination of two or more compendial or noncompendial excipients that are designed to physically modify properties in such manner not achievable by simple physical mixing without significant chemical change. Various methods are available for co-processing like milling, granulation, melt extrusion, spray drying etc. The choice for the specific method/ technique will depend on the material used and desired physical properties to be achieved. Likewise, ratios of the components may vary depending on target performance to attain [2,5].

History

The key objective for co-processing was to achieve a product with additional value associated to the ratio of its functionality and cost. The aspect that occurs during the co-processing method is not understood absolutely but appears to achieve product components in intimate association with each other as single entity. This association cannot be achieved by simple dry blending but requires appropriate co-processing technique.

Primarily, co-processing concept was implemented in food industry to improve stability, dispersibility, gelling properties of food additives. Few co-processed combinations used were Micro crystalline cellulose (MCC) and galactomanan with glucomannan, MCC with Carboxy methyl cellulose (CMC) and sodium alginate complex.

In pharmaceutical industry, the co-processing concept was established in early 1990 with the introduction of co-processed combinations like MCC and calcium carbonate. Cellactose is a co-processed combination of cellulose and lactose, ProSolv is a combination of MCC and colloidal silicon dioxide [7,8].

Excipients Selection Criteria in Co-Processing

The combination of excipient selected for co-processing should compatible and non-reactive to each other. For example, two hexitol group excipient Mannitol: Sorbitol are co-processed to achieve good compressibility as tablet excipient where first is poorly compressible and less hygroscopic and later is good compressible but highly hygroscopic to create balance between plasticity and brittleness. A few other examples of co-processed excipients studied are combination of Lactose: PVP K30: Starch as a ready to use excipient for tablet with diluents, binder and disintegrant property, MCC: Sodium starch glycolate for direct compression immediate release formulations, Dibasic Calcium Phosphate dihydrate co-processed with Pre gelatinised starch for direct compression with binder and diluents property [9-12].

Regulatory Aspects in Co-Processed Excipient

Excipients combinations through co-processing do not produce any chemical modification in the incorporated excipients. Individual properties of excipient are retaining in the combination, the only novelty is the improved functionality with same physical form. Hence, the co-processed combination does not require any toxicological study and can be considered safe if the parent excipients are declared safe by the regulatory agencies GRAS. Very few co-excipients are described in official monograph like Dispersible Cellulose in B.P., Compressible Sugar in U.S.P/NF. Their non-compendial status is the major hurdle in the success of coprocessed excipient in the market. This obstacle will be overcome in the coming future as with New Excipient Safety Evaluation Procedure (NESEP), and excipients now could be reviewed outside the FDA drug approval process. Affirmative opinion from experts of IPEC team will limit the risk of FDA dismissal of drug based on excipient and could encourage innovation in the pharmaceutical industry [13,14].

Current & Future Status of Co-process excipients

At present co-processed excipients have less applicability in the pharmaceutical industry but surely these will be utilized with enhanced functional properties at low concentration in future. Very few new chemical entities are being introduced in market due to stringent rules and regulations by considering safety, efficacy, and cost. Also, very few improvements in existing excipients will help in increased use of co-processed excipients in coming future. Uprising technologies and many more modification are implementing daily in Pharmaceutical industry to achieve high production rate. A growing popularity of high functionality excipients counterpart tablet machine increasing speed capabilities, to modulate the permeability, solubility, or stability of drug, increasing performance expectations related to disintegration, dissolution, bioavailability etc. makes a fantastic opportunity for the development of novel drug delivery system. Forthcoming novel excipient combinations and new co-processing techniques without any doubt going to attract both in research and pharmaceutical industry [15,16].

Fundamental solid-state properties of excipient

The solid-state properties are characterized by three levels as molecular, particle and bulk. These levels are closely linked with each other, reflecting change in one level with another level shown in (Figure 1). The first molecular level is crystal lattice and include phenomenon such as polymorphism, pseudo polymorphism and amorphous state. The second level consist of individual particle size, shape, porosity, and surface area. The third is bulk level comprises of a group of particles and their physical properties. The individual levels depend over each other which provides framework for the development of novel combination of existing and new grade of excipients. The essential solid-state properties of particles like morphology, size, shape, porosity, density, surface area influence excipient functions such as flowability, dilution, lubrication and disintegrating potential, compressibility and Compatability.

The primary characteristic associated with excipient is that no chemical change occur during co-processing and also the reflected changes showed in the physical properties have to prove that coexcipient do not show any chemical change. There should not be covalent bond formation when these individual ingredients are combined to form co-excipient. Also, stereochemical environment, reorientation, bond breaking and the intermolecular forces responsible for new shapes confirms the formation of a new composition. Analytical techniques for characterization used like particle size distribution, specific surface area, SEM images and X-ray diffractogram (XRD) etc. However, the techniques NMR, HPLC, FTIR, DSC, are used in order to aid control their structural properties [17-19].

Methods Of Coprocessing [20-25]

i. Spray Drying.

ii. Solvent Evaporation.

iii. Crystallization.

iv. Melt Extrusion.

v. Granulation/Agglomeration

i. Spray Drying

This technique is applicable for transformation of feed from fluid state into dried particulate form by spraying the feed into the hot drying chamber. It involves continuous drying operation processing. The feed may be in the form of solution or suspension. The dried product can be obtain in powders, granules or agglomerates depending upon it’s physical and chemical properties, dryer design and final powder properties desired. The spray drying combination of ingredient under solid or dry form during drying, by atomizing active compound in suspension or solution form (Figure 2).

ii. Solvent Evaporation

It involves use of liquid as a vehicle to dissolve excipient in organic solvent in which it is immiscible. A core excipient material are also microencapsulated in dissolved or dispersed liquid phase to obtain appropriate size microparticles. The mixture is then heated if necessary, to evaporate the solvent. Once all the solvent gets evaporated, the mixture temperature is reduced to ambient temperature (if required) with continuous agitation. Also, the particles can be used in isolated form as powders or coated sub states. The obtained material can be either water soluble or insoluble depending on material property. After complete drying of obtained mixture is in the form of new single entity co-excipient [26,27].

iii. Crystallization

Crystallization is a solid crystals formation process of precipitating naturally or artificially from the solution and rarely deposited directly from a gas. It is a chemical solid-liquid separation technique, in which mass transfer of solute from the liquid to crystalline solid is obtained and it must be supersaturated. It means that solution has to contain more solute dissolved, unless equilibrium i.e. Supersaturation is achieved. It can be achieved by various methods such as, solution cooling, addition of second solvent to reduce solubility of the solute or by chemical reaction. Change in pH is one of the most common method used in industry for crystallization.

iv. Hot Melt Extrusion

The technique involves mixing of co-processed excipients with meltable binder on a water bath, and then cooling agglomerates to solidify the mass which is subsequently pass through sieve for size reduction. It is a solvent free technique and requires a less processing time. The concentration of selected excipient ratio is a critical variables in the process. The process is a formation of small pellets, beads from the molten mass which is an extruded through extruder. Schematic presentation shown below (Figure 3).

v. Granulation /Agglomeration

The granulation is a process of forming or crystallizing into grains. The granules typically have size range between 0.2 to 4.0mm depending on their use. The Agglomeration is synonymous to granulation process involves particle size enlargement technique to alter product properties. The Agglomeration process is widely used to enhance physical properties like flowability, bulk density, wettability, and product appearance. In pharma industry two types of granulation technologies are employed, mainly dry and wet granulation. Wet granulation is a more preferred method for co-processing (Table 1).

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Gellan Gum Immobilized Anticancer Drugs and Gold Nanoparticles in Nanomedicine-Juniper Publishers

JUNIPER PUBLISHERS- ACADEMIC JOURNAL OF POLYMER SCIENCE

Abstract

This review is devoted to recent progress in the design of anticancer drug delivery systems with participation of unique polysaccharide gellan gum. At first a brief literature survey on conformational and phase behavior of gellan gum as a function of external stimuli, such as temperature, pH, salt addition etc. is presented. Then the immobilization protocol of anticancer drugs and gold nanoparticles within gellan-based hydrogel matrix is discussed. Release of anticancer drugs from gellan gel matrix to outer solution is considered. Cytotoxicity of gellan gum-immobilized gold nanoparticles together with their anticancer activity is summarized.

Keywords: Gellan gum; Coil-helix transition; Hydrogel; Anticancer drugs; Gold nanoparticles; Cytotoxicity; Anticancer activity

Abbrevations: GG: Gellan Gum; EOR: Enhanced Oil Recovery; AgNPs: Silver Nanoparticles; AuNPs: Gold Nanoparticles, AuNR: Gold Nanorods, DDS: Drug Delivery System; PCT: Paclitaxel; Ge-Pred NHs: Gellan-Prednisolone Nanohydrogel; PCT Ge-Pred NHs: Gellan-Prednisolone-Paclitaxel Nanohydrogel; GG-AuNPs: AuNPs Covered by Gellan Gum; GG-AgNPs: AgNPs Covered by Gellan Gum; DOX: Doxorubicin Hydrochloride; SL: Sophorolipid; NIR: Near-IR; PPTT: Plasmonic Photothermal Therapy; CTAB: Cetyltrimethylammonium Bromide; LBL: Layer-By-Layer; SaOS-2: Sarcoma Osteogenic; PVCL: Poly(vinylcaprolactame); TNBC: Triple Negative Breast Cancer

Introduction

Over the past few decades, microbial polysaccharides have been under intense investigation due to their advantageous physicochemical properties. Currently, one of the most widely studied and comprehensively described member of this group is gellan a linear polymer produced by Sphingomonas elodea consisting of a tetrasaccharide repeating unit of 1,3-linked β-D-glucose, 1,4-linked β-D-glucoronic acid, 1,4-linked β-D-glucose, and 1,4-linked α-L-rhamnose [1] (Figure 1). Fermentative production and manufacturing of gellan on industrial scale is described in reviews [2,3].

So far most of the studies have been focused on the application of gellan as a food ingredient. Last year’s however, the applicability of gellan gum in EOR was demonstrated [4-12]. Due to the unique structure and beneficial properties, gellan is currently described as a potent multifunctional additive for various pharmaceutical products. Specific gelling properties in different media led to the development of controlled release forms based on gellan. Various formulations have been studied including oral, ophthalmic, nasal and other [13,14]. Recent report [13] suggests that gellan-based materials can also be used in regenerative medicine, stomatology or gene transfer technology. Gellan gum-based hydrogels exhibit excellent in vivo and in vitro biocompatibility [15], tunable physical mechanical and injectable properties [16-18] for application in regeneration of cartilage [16,17], tissue engineering [19], cell encapsulation [20], nucleus pulposes regeneration [21]. Recent progress in the design of multi-functional hydrogels with participation of gellan gum in the context of biomedical engineering and regenerative medicine is discussed and summarized in recent review [22]. In spite of a wide application of gellan in medicine, pharmacy and biotechnology it is noteworthy that the gellan based anticancer formulations have not been described.

Conformational and phase behavior of gellan gum in response to external stimuli

Table 1 represents the chemical and physical properties of gellan. The native gellan is composed of high acyl and low acyl precursors [23]. The main difference between them is that the high acyl gellan contains two acyl substituents: acetyl and L-glyceril [24]. Low acyl gellan is obtained by removal of the acyl residues by alkaline hydrolysis [25]. Differences between highand low acyl gellan are summarized in Table 2 [26]. Authors [1,27] comprehensively reviewed the structure, conformation, gelation, topology, rheology, and application aspects of gellan. The coil-helix conformational and sol-gel phase transitions of gellan gums induced by temperature, salt addition, pH change etc. became the main subject of many studies [28-33]. A series of publications cover formation of interpenetrating networks with participation of gellan and natural polymers [34-42]. It is commonly accepted [43-51] that gellan gum exhibits a conformational change from the disordered state (single chain) to the ordered state (double helix) with decreasing of temperature, and the gelation is considered to be mediated by the double-helix formation and the association of such helices, which is enhanced by the presence of mono- and divalent alkaline and alkaline earth cations [52-55] (Figure 2).

As gellan molecules contain the carboxyl groups in the repeating unit, the gelation of gellan is remarkably enhanced by the addition of cations in aqueous solutions. It has been established that the extent of aggregation and effectiveness in promoting gel formation by addition of ions follows this order: Cs+> Rb+> K+>Na+> Li+. This sequence follows the Hofmeister series and agrees well with increasing of the ionic radius of cation species. The higher effectiveness of divalent cations in comparison with monovalent ones may be attributed to additional crosslinking of gellan chains due to cooperative binding (or “bridging”) of the divalent cations between glucuronate residues according to their ionic radii. Divalent cations seem to bind directly to gellan macromolecules to form aggregates of gellan helices with the effectiveness of Ca2+˃Mg2+ [56-60]. The main difference between the monovalent and divalent cations is that the monovalent cations shield the electrostatic repulsion between the COO- while the divalent cations, rather than by suppressing electrostatic repulsion, form interchain ionic bonds with carboxylic groups of the glucuronic acid units resulting in the aggregation of the double helices [55,56]. As for the divalent cations, they do not appear to obey the Hofmeister series and the order among the divalent cations is more difficult to rationalize. Gellan salts with the monovalent cation, such as lithium or potassium, form stiff gels and that with divalent cation, Ca2+, make a more rigid gel. The mechanism for conformational change of gellan in the presence of mono- and divalent cations can be represented as shown in Figure 2 [61]. K+ accelerates the formation of cooperative hydrogen bonds between gellan molecules by the charge-shielding effect and hydrogen bonds reinforces the double-helices and their aggregates. Ca2+ forms ionic bonds between carboxylic groups of gellan in addition to hydrogen bonds and leads to the continuous structural change depending on concentration of the divalent cations.

Immobilization of anticancer drugs within gellan hydrogel matrix

Recently authors [62,63] developed gellan-based nanohydrogel systems to deliver multiple drugs: prednisolone and paclitaxel. Prednisolone was chemically linked to the carboxylic groups of gellan while placitaxel was physically entrapped into gel marix. The synergistic anti-inflammatory and anti-cancer effect were reached with respect to malignant cells and tumor inflammatory components.

The kinetics of prednisolone release from gellan hydrogel was measured with respect to NIH/3T3 cells. Figure 3 shows the intracellular release kinetics of gellan-immobilized prednisolone from the gel matrix. It is seen that 40% of total prednisolone is delivered during 30min, 70% after 1h and 100% drug delivery after 24h. It is suggested that the release of prednisolone from gellan-based nanohydrogel is hydrolysis of ester bonds between prednisolone and gellan gum by esterase. Immobilized within gellan nanohydrogel prednisolone exhibits a core-shell structure and allows solubilizing up to 40% water-insoluble drug paclitaxel in hydrophobic environment. The main role of paclitaxel is disrupting of the dynamic equilibrium within the microtubule system and inhibiting the cell replication. The cell-killing drug formulation consisted of gellan-immobilized prednisolone with loaded paclitaxel. The latter released from gellan-prednisolone nanohydrogel kills the cancer cells with higher efficiency (56.1  0.8% cell viability) than free drug (91.6  3.5 cell viability) especially at lower concentration (3nM) (Figure 4).

The cell killing effect of gellan-prednisolone-paclitaxel nanohydrogel was also tested with respect to A2780, MDAMB- 231 and Skov-3 cells. Thus gellan-immobilized antiinflammatory and anti-cancer drugs can be effective for treatment of malignant and inflammatory cells involved into tumor microenvironment. Analgesic, antipyretic and antiflammatory drug-diclofenac sodium was immobilized into the matrix of polymethacrylamide-grafted-gellan gum and its sustained in vitro release kinetics was studied [64]. It was shown that the diclofenac sodium releases over a period of 8 h and the release profile is described by Higuchi square root kinetic model and release mechanism is governed by Fickian diffusion.

Gellan gum immobilized gold nanoparticles for treatment of cancer cells

It is well known that cancer is one of the leading causes of mortality in the modern world, with more than 10 million new cases every year. Targeting nanoparticles that selectively recognize and destroy cancer cells in the body remain key concept in nanomedicine [65-67]. According to literature survey of authors [68] only 7 out of 1000 administered nanoparticles are applicable in a mouse model limiting their clinical translation. Authors [69] concisely highlighted the current state and recent advances of stimuli-responsive polymers commonly employed in oncology applications.

Gold nanoparticles (AuNPs) with controlled geometrical, optical, and surface-chemical properties are the priority research of intensive studies and applications in cancer diagnosis, treatment and as drug delivery system (DDS) [70]. The effectiveness of many anticancer drugs is limited due to the inability to reach the target site in sufficient concentrations and efficiently exert the pharmacological effect without causing irreversible unwanted injury to healthy tissues and cells. The cellular uptake and toxicity of AuNPs stabilized by gellan gum (GG-AuNPs) was studied on mouse embryonic fibroblast cells, NIH 3T3 and human glioma cell line LN-229 [71]. It was shown that in the cancerous cells the GG-AuNPs were localized mainly in the cytoplasm and perinuclear region of the cells. Oral administration of GG-AuNPs did not cause any toxicity in rats for 28 days and was no any significant difference in hematological, biochemical and histopathology of organs demonstrating potential of GG-AuNPS as DDS.

The AuNPs stabilized by gellan gum was loaded by doxorubicin hydrochloride (DOX) one of the potential and wellknown anticancer drugs [72] was conjugated with sophorolipid (SL) [73] and their cytotoxicity were evaluated with respect to human glioma cell line LN 229 and human glioma stem cell line HNGC-2 (Figures 5 & 6).

Both SL-conjugated and DOX-loaded gellan gum containing AuNPs exhibited increased effectiveness against glioma tumors. The same authors [74] studied the antibacterial activity of the dispersions of silver nanoparticles (AgNPs) stabilized by gellan gum (GG-AgNPs), the cytotoxicity of GG-AgNPs against mouse embryonic fibroplast cells NIH 3T3 and also evaluated the in vitro diffusion of AgNPs dispersions/gels across rat skin. The results show that GG capping effectively passivates the AgNPs and does not display any cytotoxicity against NIH 3T3 and exhibits eligibility for topical treatments.

Photothermal damage of cells is currently one of the most promising research avenues in the treatment of cancer and infectious diseases. The essence of this phenomenon is as follows: AuNPs have an absorption maximum in the visible or near-IR (NIR) region and get very hot when irradiated with corresponding light. If, they are located inside or around the target cells (which can be achieved by conjugating gold nanoparticles to antibodies or other molecules), these cells die. The revolution in thermal cancer therapy is associated with 20-40nm AuNPs that convert the 20ns laser irradiation (514nm) to local heat (up to 40-45oC), and selectively kill the cancer cells (Figure 7). This method called plasmonic photothermal therapy (PPTT) [75] has extensively been researched and used for biomedical application [76]. The PPTT has much potential in diagnosis, treatment and evolution of diseases, in particular cancer [77]. In recent review [78] the advancements of plasmonic nanoparticles and films in the field of biomedicine was overviewed.

Among the numerous nanomaterials the best one is gold nanoparticles (AuNPs) because of their biocompatibility, low toxicity, ability to absorb in visible or NIR region, excellent photostability, and availability in various morphologies [79]. Among the gold nanoparticles the gold nanoshells [80] and nanorods (AuNRs) [81] are especially suitable for PPTT due to their tunable longitudinal plasmon band in the NIR region [82].

Small spherical AuNPs exhibit poor NIR absorption, therefore nanoaggregates, nanoshells, nanorods and nanomatryoshkas stabilized by functional polymers are suitable for PPTT [78]. Gellan gum coated gold nanorods (GG-AuNRs) was fabricated by authors [83] and used for intracellular drug delivery and imaging. The preparation strategy of AuNRs includes several steps: at first the fine dispersed AuNRs is synthesized by a seed-mediated growth method using cationic surfactant - cetyltrimethylammonium bromide (CTAB) as surface passivant [84], then the layer-by-layer (LBL) technique is used for coating, and finally AuNRs are coated by gellan gum (Figure 8).

The direct use of as-prepared AuNRs with biological materials is highly limited because the cytotoxicity of CTAB is high and can lead to cell death. The successive deposition of poly (acrylic acid), poly (allylamine hydrochloride) and GG allows the formation of GG shell with nanometric size around individual AuNRs. The cytotoxicity and osteogenic ability of gellan-coated AuNRs was tested with respect to SaOS-2 (Sarcoma osteogenic), a human osteoblast-like cell line commonly used as osteoblastic model [85]. It was found that AuNR-GG were not cytotoxic after 14 days of culturing and were localized inside lysosomes. The images in Figure 9 show that AuNRs-GG is aggregated within multilammelar vesicles identificed as lysosomes.

NIR lasers are selected due to higher penetration of human tissue resulting in minimal damage. In vitro experiments show that heating of tumor tissues is observed in the presence of NIR-exposed AuNRs, however laser irradiation in the absence of AuNRs causes negligible damage of healthy tissues [78]. Without coating by biocompatible polymers, AuNRs cannot infiltrate the blood vessels and therefore their concentration increases in plasma. In vivo tumor ablation requires a tissue temperature of around 48-50oC for successful operation.

Magnetic nanoparticles coated by GG exhibited low cytotoxicity with potential drug delivery applications [86]. Apart from gellan both natural and synthetic polymers can be used for stabilization and coating of AuNRs. Absorption spectra of polymer-coated AuNRs are in NIR region and equal to 770nm (Figure 10a). According to TEM measurements the average size of AuNRs covered by poly(vinylcaprolactame) (PVCL) is < 100nm (Figure 10b).

Multilayered Au nanoparticles (Au/SiO2/Au ~ 90nm) called as nano-matryoshkas (“matryoshka” is Russian nesting doll) was tested against triple negative breast cancer (TNBC) tumors [87]. In vivo injection of Au nanomatryoshkas and NIR treatment (2W.cm-2 for 5min) of TNBC tumor-bearing mice show health improvement and complete recovery for two months (Figure 11a). In contrast, NIR treatment of TNBC in saline water without Au nano-matryoshkas considerably increases the size of tumor for 18 days (Figure 11b).

The Au-based nanomaterials have failed in clinical trials as PPTT agents. The further development of PPTT and its acceptance in actual clinical practice depends on success in solving many problems, the most important ones being

a) The choice of nanoparticles with optimal optical properties,

b) The enhancement of nanoparticle accumulation in tumors and the lowering of total potential toxicity, and

c) The development of methods for the delivery of optical radiation to the targets and the search for alternative radiation sources combining high permeability with a possibility of heating AuNPs.

The selection criteria of PPTT depend on

a) The ability of gold nanoparticles to absorb in the near- IR region;

b) Size of nanoparticles (usually less than 100nm);

c) Low toxicity (in terms of excluding or replacement of toxic CTAB);

d) Good biocompatibility and easy biodegradability of polymeric coatings used for entrapment of gold nanoparticles. Moreover, the aggregated AuNPs should be disintegrated and removed from the organs and not cause tissue damage or metal toxicity.

It is expected that in near future the priority research will be focused on probing the fundamental interactions of nanoparticles with organs and tissues that accumulate, sequester or eliminate nanoparticles (such as liver, spleen and kidney), as well as the interactions between nanoparticles and tumors with respect to the physico-chemical properties of the nanoparticles.

Conclusion

The unique properties of gellan gum, in particular, biocompatibility, low toxicity, biodegradability, commercial availability and low cost argue the successful application of this class of polysaccharide in biomedicine, pharmacy and bioand nanotechnology. The ability of gellan to undergo coil-helix conformational, sol-gel phase transitions, and stimuli-sensitive character of macromolecules to response temperature, pH, salt addition, addition of organic ions and molecules open new perspectives to design drug delivery systems. Anticancer drugs and gold nanoparticles immobilized within gellan gel matrix is effective for treatment of cancer cells. It is expected that in near future the priority research will be focused on probing the fundamental interactions of nanoparticles with organs and tissues that accumulate, sequester or eliminate nanoparticles (such as liver, spleen and kidney), as well as the interactions between nanoparticles and tumors with respect to the physicochemical properties of the nanoparticles. For the successful application of nanoparticles there should be a coordinated research program to establish correlations between the particle parameters (size, shape, and functionalization with various molecular probes), the experimental parameters (model; doses; method and time schedule of administration; observation time; organs, cells and subcellular structures examined; etc.), and the observed biological effects.

Acknowledgements

This work was supported by Sichuan Science and Technology Program (No. 2018HH0024, 2018-2019) and carried out in the frame of collaborative research project entitled “Fabrication and controlled drug release of thermosensitive gradient nanocomposite hydrogels” between College of Chemistry, Sichuan University, China and Institute of Polymer Materials and Technology, Kazakhstan.

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