A Comprehensive Review on PLGA - based Nanoparticles used for Rheumatoid Arthritis

 

Sangeeta Mohanty ^*, Sthitapragnya Panda, Debashis Purohit, Sudam Chandra Si.

School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar, India.

 

ABSTRACT:

Worldwide, Nanotechnology is frequently used for various applications in fields of medical science and therapeutics. However, biodegradable nanoparticles can improve the therapeutic value of various H₂O soluble / insoluble drugs by improving solubility, bioavailability, retention time and protection of premature degradation of drugs in biological environment. In comparison to general Nanoparticles (NPs), encapsulation process with polymeric NPs are considered to be more fruitful and advanced as it provides better patient compliance. Since three decades through extensive research, polymers were first introduced as biodegradable or naturally dissolved surgical device. Current scenario utilizes polymeric based nanoparticles for the treatment of various ailments. Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease related to joints which hampers the normal life by exhibiting extra-articular manifestations. In-spite of major advances in drug therapies, still limitations are pervading with severe side effects in case of conventional drug delivery systems. Although different polymers are used for the preparation of Nanoparticles, utilization of USFDA and EMA approved Poly (lactic-co-glycolic acid) (PLGA) has gained much more popularity due to its unique features like low cytotoxicity, biocompatibility, biodegradability, targeted drug delivery, possibility of sustained release formulation and long biomedical applications. Nevertheless, researchers reveled that for targeted drug delivery, key factor involved is the persistance of NPs in systemic circulation of body. However, conventional NPs are rapidly opsonized and cleared through macrophages (fixed MPS) which is considered as foremost challenge in preparing these type of formulations. Hence, in order to overcome these problems, surface modification of conventional NPs with different molecules are needed so as to increase the circulation time and persistance of NPs in the blood. Furthermore, this review explores various key design parameters of RA targeted PLGA- based nanotechnology strategies in improving the treatment of rheumatoid arthritis. It comprehensively addresses various issues related to PLGA-based nanoparticles along with its method of preparation, surface modification and characterization techniques. Unlike usual drugs, nanoparticle drug delivery system aims at providing better patient compliance by delivering the drug to inflamed synovium by reducing systemic side effects.

 

 

 

 

 

 

 

 

 

 

 

INTRODUCTION:

Inflammation is a general term used for physiopathological process which is generally characterized by fever, pain, redness and swelling. It is a part of immune response to destructive injuries or infections which results in increased blood flow, decreased cellular metabolism, dilation of blood vessels and release of soluble mediators.¹ It also plays important role in the physiology of arthritis, heart diseases, irritable bowel syndrome, diabetes, parkinsonism and rheumatoid arthritis. ² Rheumatoid arthritis(RA) due to its severity and vast epidemiology needs no description. It is characterized by chronic joint inflammation, progressive cartilage and destruction of bone, tendon, ligaments.³ About 1% of world population affected by RA and the occurrence of RA in women is more than that of men. In India the occurrence of RA, ranges from 0.28 to 0.7% which is similar to the prevalence of all developed countries.⁴ Peoples of all the age groups are affected but it is more common in case of middle age populations ranging from 30-50 years of age⁵.

 

 

Nanoparticles are solid, spherical structures which are ranging around 100 nanometers in size and are synthesized from different natural or synthetic polymers. Variety of drugs can be delivered through nanoparticles. For example, hydrophilic drugs, hydrophobic drugs, vaccines macromolecules and so on⁶. These nanoparticles are having wide applications as it makes a very good platform for targeted drug delivery.

 

Since three decades ago, Polymers were first introduced as bioresourcable surgical devices and are used in various fields. Nanocarriers which are prepared with biodegradable and biocompatible polymers are authenticated by EMA, USFDA and are utilized in controlled drug delivery systems. Poly lactic-co-glycolic acid (PLGA) is most successfully used environment-friendly polymer due to its unique properties like sustained release, less toxicity, long term biomedical applications, bio affinity with tissues and prolonged residence time with targeted drug delivery.⁷ Moreover, its hydrolysis leads to metabolite monomers, glycolic acid and lactic acid. Since these monomers are endogenic and metabolism occurs easily through Krebs cycle⁸ hence produces minimal systemic toxicity. The present review explains the symptomatic features of PLGA and its related potentials by structure-property relations in terms of targeted drug delivery, as well as exploring their efficacy in-vitro and in-vivo.

 

RHEUMATOID ARTHRITIS

 

Fig.1 Pathogenic condition of affected fingers having RA

It is a common autoimmune disorder identified by increase in bone and cartilage destruction that results in serious functional limitations, decreased life spans. RA causes inflammation at different organs, as well as in different joints or tissues of the body which leads to long term joint destruction. Most commonly affected joints are fingers, wrists, arms, spins and legs. [Fig.1]

 

PATHOPHYSIOLOGY:

Primarily affected site of RA is synovial membrane, where infiltration by immune cells occurs due to swelling. Generally, Pathophysiology of RA occurs in three different phases. Initiation Phase occurs due to imparticular inflammation, Amplification Phase occurs due to activation of T cells and Chronic Inflammatory Phase which is associated with injuries in different tissues due to IL-1, TNF-alpha and various cytokines. ⁹The primary stage of disease starts in peripheral lymphoid organs. In spite the mechanisms which contribute to pathogenesis of RA, a genetic predisposition is being identified in different ethnic groups. This genetic predisposition, as well as the affinity and activation of matured auto reactive B-cells and T-cells present in the joints, indicates a role towards adaptable immunity in the pathogenesis of RA.

 

Symptoms, Causes and Risk factors affecting Rheumatoid arthritis:

Fig.2, Fig.3 and Fig.4 summarizes the various Symptoms, different causes and Risk factors associated with Rheumatoid arthritis.

 

 

Fig 2. Predicators of RA

 

 

Fig3.Pathogenesis of RA

Fig 4. Factors involved in pathogenesis of RA

 

CONVENTIONAL AND CURRENT NOVEL STRATEGICS USED FOR RHEUMATOID ARTHRITIS:

Conventional and current novel strategies used for rheumatoid arthritis were demonstrated in Table 1and 2.

 

Table 1. Conventional drugs used for Rheumatoid arthritis

Biologics	NSAIDs	Disease-modifying antirheumatic drugs (DMARDS)	Glucocorticoids
cytokine antagonists, Rituximab, T-cell costimulationmodulator, Anakinra	Aspirin, ibuprofen, Naproxen	Methotrexate, sulfasalazine, hydroxychloroquine, leflunomide	Prednisolone, dexamethasone

 

Table 2. Current novel strategics for Rheumatoid arthritis

Nano DDS	Type of therapy	DRUGS	REFERENCE
Liposomes	NSAID	Piroxicam	(10)
Polymeric nanoparticles	NSAID	Nimesulide	(11)
Nanoparticles	Gold salts	Gold salts	(12)
PEGylated liposomes	Corticosteroid	Prednisolone	(13)
PEGylated Liposomes	Corticosteroid	Dexamethasone	(14)
PEGylated Nanomolecule	TNF-α inhibitor (immunosuppressant)	Fragment TNF-α inhibitor	(14)
Polymeric nanoparticles (hyaluronic acid)	γ-secretase inhibitor	DAPT	(11)
Liposomes	Gene therapy	siRNA (TNF-α silencing)	(12)
Lipid Nanoparticles	Angiogenesis Inhibitor	Fumagillin	(15)
PEGylated lipid Micelles	Topoisomerase inhibitor (cytotoxic)	Camptothecin	(16)
Nanoemulsions	Immunomodulatory Agent	Curcumin	(17)
tgAAC94 (TNF-α silencing)	Gene therapy	Adenoassociated virus (AAV)	(18)
Lipid Nanoemulsions	Folic acid antagonist (immunosuppressant)	Methotrexate	(19)
Polymeric micelles (polysialic acid)	Immunosuppressant	Cyclosporine	(20)

 

 

Fig:5 Different novel drug delivery system for RA

IMPORTANCE OF NANO THERAPEUTICS IN RHEUMATOID ARTHRITIS:

Nowadays, a variety of nanoformulations were used for targeted drug delivery and are having vast applications in pharmacy and biomedical fields. Fig.5 shows various types of nano formulations beneficial in RA treatment. Nano therapeutics limits the distribution of drugs by controlling the amount of the drug particles and reduction in adverse effects. These can be used for extended use of NSAIDs in high-risk patients. Recently, developed polymeric nanoparticles have furnished a new proposal to overcome from several difficulties associated with conventional therapeutics. The main objective behind development of nano technology is to reduce cost for the treatment of the therapy and to develop a new novel drug delivery for in vivo studies²¹.

 

POLY (LACTIC-CO-GLYCOLIC ACID) NANO PARTICLES:

Poly (lactic-co-glycolic acid) i.e PLGA is regarded as a fruitful biodegradable polymer and is approved by USFDA and European Medicines Agency. As, they get metabolized easily inside body through Krebs cycle that leads to decrease in the toxicity, associated with the delivering of drugs by PLGA Nano particles. Currently, PLGA is available with different molecular weights and their co-compositions in the market. The degradation time of the PLGA nano particles may change according to copolymer ratio and their molecular weight. ²²Furthermore, it can increase drug stability by preventing the drugs from degradation. It also allows the specific delivery of drugs into their proper site of action by penetrating different tissues through receptors in the BBB (blood brain barrier). The effectiveness of the treatment may increase which can lead to development in their pharmacokinetic and pharmacodynamic profile for sustained release of drugs from the stable nano particles.

 

METHODS OF PREPARATION OF PLGA NANOPARTICLES:

Emulsification (solvent evaporation technique):

a. Single emulsion technique:

It is most commonly used method which involves o/w emulsification but not suitable for water soluble drugs due to its encapsulation incapability. ²³Here, at first, a proper ratio of polymer is dissolved in water insoluble volatile solvent to prepare single phase solution. The size of drug particles generally ranges from 20 - 30 µm. By continuous stirring, the polymer gets dissolved and dispersed solution is further proceeded for emulsification by using large amount of water in presence of emulsifying agents (PVA) at required temperature. The organic solvent present in the solution is further extracted for hardening the oil droplets either by magnetic stirrer or by reducing pressure.

 

b. Double emulsion technique:

This technique is otherwise known as w/o/w emulsion method and is widely used for water-soluble drugs like peptides, proteins etc. An aqueous solution of drug is mixed with the organic phase containing polymers and large volume of water containing the emulsifying agent (PVA) in order to form w/o/w emulsion. Furthermore, by solvent evaporation method the solvent is removed from the emulsion²⁴.

 

c. Emulsification-solvent diffusion technique:

It involves the emulsification of solvent and water which is saturated at room temperature. Here, both drug and polymer is emulsified in an aqueous surfactant along with vigorous addition of water and continuous stirring, so as to form the emulsion system. By nano precipitation transformation methods, nano particles are formulated with outward diffusion of the solvent. This technique has many advantages like improved encapsulation, higher rate of production, simplicity etc. It has also some limitations i.e. dismissal of higher amount of water from suspension and exposure of water-soluble drugs²⁵.

 

d. Reverse Emulsification Salting out technique:

It is an alternative method for the fabrication of PLGA nano particles. Here, the oil phase undergoes emulsification in aqueous phase by mechanical stirring. Magnesium acetate tetra hydrate / Magnesium chloride are the most commonly used salts. Therefore, the hydrophilic solvents transfer from oil phase to aqueous phase, which leads to formation of Nanoparticles. Merits of using this technique is the encapsulation of temperature sensitive materials like DNA and RNA²⁶.

1.5- Nano precipitation method or Solvent displacement method

 

This technique comes with a demerit of poor incorporation of water-soluble drugs during preparation of nano particles. The polymer and drug after properly weighed gets dissolved in polar solvents like acetone and acetonitrile. Furthermore, both the organic phase and aqueous phase were added in drop wise manner with continuous stirring at room temperature unless complete removal of organic solvents occurs which leads to formation of nanoparticles²⁷.

 

e. Dialysis:

It is a versatile, easy and simple technique to prepare nanoparticles with lower range of distribution. Dialysis membrane is used for the incorporation of both drug and polymer. The organic phase diffuses into aqueous phase through the dialysis membrane which leads to decrease in interfacial tension. Therefore, homogeneous suspension of nanoparticles is formed through displacement of solvent inside the membrane²⁸.

 

f. Spray drying technique:

In this technique, the drug is mixed with polymeric solution by addition of required cross linking agents. Finally, the solution is atomized in a stream of hot air which causes formation of nano particles²⁹.

 

g. Super critical fluid technology:

Super-critical fluid technology is an eco-friendly approach for production of Polymeric Nano-Particles (PNPS). This technology has the capability of formation of highly purified polymeric nano particles (PNPS)³⁰.

 

Phase separation method or Coacervation:

It is a well-established method which includes three steps mainly i.e. phase separation of coating polymer solution, adsorption of the coacervate around drug particles and microspheres quenching. It focused on preparation of micrometer sized biodegradable polymer encapsulation techniques using liquid-liquid phase separation³¹.

 

CHARACTERIZATION OF PLGA NANO PARTICLES:

Characterization of PLGA nano particles were carried out using Cryogenic-transmission Electron Microscopy (Cryo-TEM), Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM). Cryo-TEM is used for observation of miscellaneous formation of PLGA. ³²whereas TEM is used to identify aggregation and internal structure of NPs. Similarly, SEM is utilized for characterization of shape, surface distribution of nano particles. Dynamic light scattering (DLS) is mostly used for determination of size by Photon Correlation Spectroscopy within suspension medium at room temperature. ³³Moreover, Laser Doppler anemometry is considered important to access stabilization of nano particles in measuring Zeta potential. ³⁴During in vitro studies, more repulsion occurs within the particles resulting in reduced aggregation of particles. In order to estimate the characterization of chemicals, FTIR is preferred. Entrapment of drug into nanoparticles can be determined by calculating ratio of amount of drug incorporated in nano particles to the nano particles. The bio distribution of nano particles depends upon hydrophobic nature of the particles. Many researchers have revealed that degradation time of hydrophobic substances is less than that of hydrophilic substances.

 

SURFACE MODIFICATION OF PLGA NANO PARTICLES:

The main aim of NPs is to reach the target site for better patient compliance which is possible through prolonged circulation time. On contrary, they gets removed from the blood stream by reticuloendothelial system (RES) which is considered as the most challenging factor in formulating Nanoparticle based drug delivery system. Moreover, when opsonin protein binds with NPs administered through I.V. route, it gets attached to the macrophages incorporated with phagocytes and these particles gets removed from the body through renal system. Although PLGA is having unique properties of biocompatibility and biodegradation, but still it gets rapidly cleared from the blood stream after their I.V. administration³⁵.

 

Therefore, in order to solve these problems the uncovered bared nano particles are subjected for surface modification process. Furthermore, to give a hydrophilic core around PLGA nano particles, these nano particles are coated with surface modifiers. Some examples of valuable surface modifiers are summarized below.

 

PEG (PEGylation method):

PEG is regarded as a hydrophilic polymeric compound with good biocompatibility whereas PEGylation is considered as the most common technique used in surface modifications of nano particles in which aqueous solubility and stability of the PLGA nano particles gets increased.

 

Direct conjugation method:

Encapsulation of required agents with the nano particles will provide direct conjugation of PLGA nano particles with PEG. It is having limitations like low yielding capacity. So, the nano particles should be placed into the aqueous environment to achieve maximal effectiveness throughout the conjugation process.

 

Activated conjugation method:

In this method, unwanted formation of PEG-PEG is ignored and hydrolysis of the active intermediate is decreased. It is a two step process where activation is followed by conjugation³⁶.

 

Ring-opening polymerization method:

Most common and widely used technique for preparation of PEGylated PLGA nano particles. Here, the reaction is initialized by the protic agents with hydroxyl end groups which are further utilized in formation of PLGA nano particles. It shows the ring opening of PEG to PLGA NPs.

 

Polysorbate:

Due to surface coating of polymer with polysorbates, the potential to cross blood-brain barrier (BBB) is strengthened. Most commonly used surfactant and emulsifying agents in food and different cosmetic industries include polysorbate 20, 40, 80. The drug delivery to the brain is achieved by the binding of NPs into the brain stratum and an increase in the passive diffusion which occurs by accompanying a significant change in the concentration gradient.

 

Vitamin ETPGS:

It is an aqueous synthetic form of vitamin E, mostly used as an emulsifying agent for encapsulation, loading of drugs and as a release modifier of hydrophobic drugs like 5-flurouracil and paclitaxel. ³⁷Further, it improves the hemodynamic properties of NPs.

 

PLGA –BASED NANO PARTICLES USED FOR RHEUMATOID ARTHRITIS:

Different researchers contributed their novel work towards Rheumatoid arthritis using PLGA nanoparticles. Few of them are being summarized below. According to Whitmore, controlled drug delivery of Betamethasone Sodium phosphate for RA treatment can be approached through encapsulation of Betamethasone sodium phosphate in PLGA nanoparticles. Increased therapeutic activity was obtained with targeting the inflamed joints and its prolonged release in situ³⁸.

 

According to Butoescu et al; for treatment of inflammatory disease like arthritis Corticosteroids Dexamethasone acetate and SPIONS are encapsulated into microspheres containing PLGA. Dexamethasone acetate that contains super paramagnetic micro particles provided drug carriers for treatment of arthropathies. However, it is regarded as a versatile system. By changing the polymer matrix, incorporation of other active substances can be possible with modified release profiles. Hence, allowing different treatment options for joint diseases³⁹.

 

Khaled et al; prepared prednisolone-loaded PLGA microspheres by using o/w emulsion solvent evaporation method. The treatment protocol using prednisolone-loaded PLGA microspheres has not only protected the cartilages and bones from destruction but also decreased the inflamed FCA injected joints. This therapy can be a successful alternative to steroid multiple dosage regimens and an essential step in treatment of RA during early stages⁴⁰.

 

Park et al; studied the potential effects of dexamethasone which was incorporated in PLGA nanoparticles complexed with specific siRNA and used for treatment of RA. COX-2 siRNA and Combined dexamethasone decreased the appearance of apoptosis and inflammation-related factors produced in C28/I2 cells that were responsible for the state of inflammation through Tumour necrosis factors-α (10 ng/ml). However dexamethasone alone had a little effect in reducing the atopsis and inflammation related factors⁴¹.

Cong et al; argued Micelles Self-assembled from PLGA-PEG-ALN copolymer were produced in delivery of Vancomycin and are used in bone targeted disorders. He revealed that conjugation of ALN neither produced acute cytotoxicity on the micelle nor it has any effect on the release properties or drug loading of the micelle. Moreover, these formulated micelles inhibits the growth of Staphylococcus aureus which was confirmed through in vitro antibacterial test, in which osteomyelitis is the main key pathogenic bacteria. The adhesion of micelle to HA was facilitated by strong affinity of ALN to HA, that is not affected by its conjugation to micelle. Therefore, for targeted treatment of osteomyelitis, ALN-conjugated micelle has a greater prospective⁴².

 

Zhang et al; revealed that Ketoprofen and miR-14 which were co-loaded in PLGA microspheres can be used in the treatment of arthritis. In-vitro release study indicated that miR-14 and Ketoprofen may be released persistently for a long period of three weeks. Further, miRNA-124 co-loaded microspheres with Ketoprofen have greater role in reducing the level of inflammatory diseases including RA as it can reduce the swelling and demolition of bone in Adjuvant Induced Arthritic (AIA) rats^43,44,45.

 

CONCLUSION:

RA is chronic inflammation leads to several destructions of joint and cartilage. Consequently the treatment of such inflammation is critical owing to poor patient compliance. However, on long term treatment the dose limiting therapies leads to severe negative side effects. Nanoparticle drug delivery system indicates localized and specific drug delivery by minimizing unwanted side-effects. PLGA based Nanoparticle improves the stability of drug by protecting it from degradation.

In PLGA based Nanoparticle drug delivery systems, despite of several advantages still limitations are present such as low drug loading efficiency as in case of clinical trials. However, these limitations can be overcome by biodistribution, pharmacokinetics and toxicity studies. More investigation is needed in future to control nanoparticle size and surface morphology. Nevertheless, in the next generation it will certainly be an exciting option to incorporate the prospects of Nanoparticle-based drug delivery systems using PLGA, in all the emerging sectors for RA therapeutics.

 

ACKNOWLEDGMENT:

The authors are thankful to School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan (Deemed to be University) for constant help, support and encouragement in carrying out this work.

 

 

CONFLICT OF INTEREST:

There are no conflicts of interest.

 

FINANCIAL SUPPORT AND SPONSORSHIP:

Nil.

 

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Received on 12.10.2018         Modified on 17.11.2018

Accepted on 18.12.2018      © RJPT All right reserved