A Review on Biomedical Applications of Polymeric Nanoparticles

Nanotechnology has achieved breakthrough in therapeutics, bioengineering, diagnostics, imaging, and optics in recent vintage [1]. The development of nanosystems by tailoring the macromolecules is the recent topic of interest. As nanoparticles possess extraordinary, often tunable properties dramatically different from the bulk materials, such as high surface to volume ratio, particle size and so forth there is an enormous demand for the tailor-made functional nanoparticle systems. Inorganic, organic or hybrid nanoparticular materials are used in various applications fields as medicine, pharmaceuticals, analytics, catalysis, coating, and several others. Nanoparticles are efficient and versatile devices for drug delivery as they can improve crucial properties of a drug entity such as solubility, pharmacokinetic, biodistribution and in vivo stability [2]. Due to their tailoring properties they can overcome physiological barriers and can help to guide their payload to specific cells or intercellular compartments. By which side effects can be minimized and therapeutic benefits of a drug can be increased. By virtue of their small size and by functionalizing their surface with polymers and appropriate ligands, polymeric nanoparticles can also be targeted to specific cells and locations in the body. Depending on the polymer characteristics, polymeric nanocarriers can also be engineered in such a way that they can be activated by changes in the environmental pH, chemical stimuli, or temperature. Macrophages are well recognized phagocytic cells of the reticuloendothelial system (RES) and one of the main cells responsible for the uptake and clearance of administered drug loaded nanoparticles. In general, once nanoparticles are opsonised, endocytosis/phagocytosis occurs, and the nanoparticles are incorporated in an endolysosome/phagolysosome and degrade [3]. However, the ability of various nanoparticles to escape the endolysomal compartment allows incorporated drugs to be delivered to the cytoplasm and finally to the nucleus. Thus, this property of the nanoparticles to be easily taken up by phagocytic cells makes them feasible to carry proteins, genes and other biological macromolecules as well [4]. Other applications include cytoplasmic release of plasmid vectors and therapeutic agents (e.g. for cytoplasmic infections and for slow cytoplasmic release of drugs that act on nuclear receptors) [5]. Depending on the preparation methods used, two different types of nanoparticles can be obtained, namely nanospheres and nanocapsules [6,7]. Nanoparticles are drug loaded particles with diameter ranging from 1 to 1000nm. Abstract Splendid achievements have been made in management of disease through invention of drugs over past decade. The present conventional drug delivery systems often have side-effects and complications due to their wide distribution throughout the body fluids. The localization of drug action in injured tissue is a promising way to solve this problem. The objective of drug targeting is to achieve a desired pharmacological response at a selected site without undesirable interaction at other sites. This is especially important in cancer chemotherapy and rheumatoid arthritis treatment. Recently invention of drugs has been generated by various drug delivery systems like microspheres, liposomes, noisomes, nanocapsules and nanoparticles. Among all colloidal drug carriers’ nanoparticles are gaining more popularity because of their stability, easy preparation, for achieving reduced toxicity, for increased drug efficacy & site targeted action. Nanoparticulation is a very useful strategy towards targeted drug delivery and also for enhancement of bioavailability of low soluble drugs. In this article nanoparticles preparation methods and their biomedical applications were discussed in detail.


Necessity of Nanoparticulate Drug Delivery Systems [8-10]
Controlled drug delivery systems are those type of devices in which therapeutic agents may be released at controlled rates for long periods of time, ranging from days to months. The control exercised over the nature of drug delivery may be in temporal nature (rate controlled) or of a spatial nature (site controlled) or both.
Currently there are a limited number of formulations approaches available for the compounds that are soluble in water, that includes, solubilisation, cosolvency, complexation with beta-cyclodextrines and solid dispersions that can enhance the dissolution of the drugs.
Another classical formulation approach for poorly soluble drugs is micronisation, that means the transfer of coarse drug powder into ultrafine powder. It's a technology for BCS classified class II drugs that are having a good permeability but a low bioavailability due to their poor solubility. But for the colonic drug delivery, micronisation often results in a low and variable bioavailability. Hence, the next step taken to improve the saturation solubility, dissolution velocity and bioavailability of drugs is by reducing the particle size from microns to nano size levels that can be termed as Nanonisation.
Hence, it was thought that nanoparticle could be used as an ideal drug delivery.
The major goals in designing nanoparticles as a delivery system are to control particle size, surface properties and release of pharmacologically active agents in order to achieve the sitespecific action of the drug at the therapeutically optimal rate and dose regimen. Though liposomes have been used as potential carriers with unique advantages including protecting drugs from degradation, targeting to site of action and reduction toxicity or side effects, their applications are limited due to inherent problems such as low encapsulation efficiency, rapid leakage of water-soluble drug in the presence of blood components and poor storage stability.
On the other hand, polymeric nanoparticles offer some specific advantages over liposomes. For instance, they help to increase the stability of drugs/proteins and possess useful controlled release properties. Nanoparticles have a relatively large surface which promotes its ability to bind, adsorb and carry other compounds such as drugs and proteins. Although the definition identifies nanoparticles as having dimensions below 0.1 micro meter and 100nm, especially in the area of the drug delivery relatively large sized nanoparticles (greater than 100nm) may be needed for loading sufficient amount of drug onto the particles.

Method of Synthesis
Nanomaterials exhibit unique properties at nanoscale of 1 to 100 nanometer (nm). However, achieving sizes <100nm is more feasible with hard materials (like Silica, Metal oxides and diamonds) compared to drug and polymer molecules, which are soft materials.
Production of nanoparticles for drugs that are usually soft materials with melting point below 300⁰C is much more challenging than that of hard materials because of high stickiness of the former. For this reason, it is a reasonable goal to aim at <300nm for drug and polymer materials. Hence two basic approaches are employed for the synthesis of nanostructures in the 50-300nm range for drug delivery, irrespective of the field or discipline. The two approaches are 'Bottom-Up' approach and 'Top-Down' approach [2].

'Bottom-Up' Approach
The building of nanostructures is achieved by growing or assembling of atoms or molecules which are the building blocks.
The building blocks may be manipulated through controlled chemical reactions to self-assemble and make nanostructures such as nanotubes and quantum dots. Atoms or molecules may also be physically manipulated to form nanostructures using minute probes. Self-assembling of atoms or molecules can be achieved by templating and non-templating. Templating involves the interaction of bio macromolecules under the influence of a specific sequence, pattern, structure, external force or spatial constraint.
Non-templating is the formation of nanostructures from atoms or molecules with external influence. nanoparticles which were administered once a day orally for a five consecutive days. A clinical activity score and myeloperoixidase activity were determined to assess the inflammation.

Nanoparticles for Per Oral Administration of Proteins and Peptides
Proteins and peptides are seen as therapeutic drugs. They are susceptible to proteolytic degradation. Therefore, lead to problems Nanoparticles for Brain Delivery: The blood brain barrier represents one of the hurdles for drugs including antibiotics, antineoplasic agents. One of the possibilities to overcome this barrier is drug delivery to brain using nanoparticles. Drugs used for brain targeting include hex peptide dalargin, the dipeptide kyotropin, loperamide, tubocurarine and doxorubicin. Kreuter and co-workers in a series of studies advocated nanoparticles for brain delivery. They reported transport of the hex peptide dalargin across the blood brain barrier using poly(butyl cyanoacrylate) nanoparticles which were coated with polysorbate 80. Some neuropeptides are also delivered across blood-brain barrier using nanoparticle technology.

Work Done on The Nanoparticle Drug Delivery System
Hasaan A et al. [14] aimed to prepare anti-glaucomatous Dorzolamide hydrochloride-(Dorzo) loaded nanoparticles as a controlled release system. Eudragit RS 100 (RS) and/or RL 100 (RL) were used in formulations by an opportunely adapted Quasiemulsion solvent diffusion technique. The formulations were evaluated in terms of particle size, zeta potential, drug entrapment, and release profile. All formulations showed tiny particle size varying from 114 to 395 nm for RS and 65 to 277 nm for RL.
Positive zeta potential was +19 to +32 mV for RS and +23 to +42 mV for RL formulations. It was demonstrated that increasing polymer concentration lead to increase the percentage of drug entrapped in all batches, to a certain extent (drug: polymer 1:4). Nanoparticles S Tamizharsi et al. [16] aimed to prepare and evaluate polymethacrylic acid nanoparticles containing Lamivudine in different drug to polymer ratio by nanoprecipitation method. SEM indicated that nanoparticles have a discrete spherical structure without aggregation. The average particle size was found to be 121nm. The particle size of the nanoparticles was gradually The results for the best formulation showed a mean particle size of 267nm, entrapment efficiency 65.07 % and in-vitro release 96.97 %. In-vitro release pattern of methotrexate from nanoparticles in pH 7.4 phosphate buffer showed a biphasic pattern with an initial burst effect and prolonged release over 24hrs.Stability studies showed that similar drug content and closest in vitro release profile to initial data when the sample stored at 25⁰C.
Poovi et al. [20,21] formulated and optimized Repaglinide (RG) loaded chitosan (CN) nanoparticles were prepared by solvent evaporation method in three different ratios. The prepared nanoparticles were characterised for particle size, FTIR, percentage yield, drug entrapment and for invitro release kinetics. The surface morphology of these RG-CN preparations was found to be smooth.
At high polymer concentration RG-CN preparations showed high drug loading and encapsulation efficiency with nano size. Invitro release kinetics studies shown that RG loaded CN nanoparticles were capable of releasing the drug in a slow sustained manner for 15 days following first order release with fickian diffusion. From their investigation it was concluded that the repaglinide loaded chitosan nanoparticles is an effective carrier for the design of a controlled drug delivery system (Table 1).