Nanomaterials application in various sectors: fluorescent biological labels, drug and gene delivery, bio detection of pathogens, detection of proteins, probing of DNA structure, tissue engineering, tumour destruction via heating (hyperthermia), separation and purification of biological molecules and cells, MRI contrast enhancement and phagokineticstudies. In the biomedical application, nanoparticles are delivered into the targeted tissues, for imaging/ treating/ simultaneously both imaging and treating.
Currently, most of the drugs are synthesized from medicinal chemistry have poor solubility and this makes challenging for pharmaceutical scientists to deliver drugs into systemic circulation through oral route. Based upon solubility and permeability of chemical moieties, Amidon et al. developed BCS with four classes.
In these Class II and IV drugs having poor solubility (eg. Paclitaxel 1µg / mL), therefore, solubility enhancement for these drugs is required. Indeed, pharmaceutical products which have <10 mg/ml will have oral bioavailability problems. There are numerous methods utilized for the enhancement of solubility: nanonization, micronisation, prodrugs, salt formation, solid dispersion and cosolvent etc. However, these methods have several limitations.
For instance, pro drugs and salt formations is not panacea for all chemical entities for the improvement of solubility. Cosolvents are employed for the improvement of poorly soluble drugs can directly inject into I.V to achieve 100% bio availability. On the other hand, by improving the solubility we can improve bioavailability, but it does not have any impact on elimination half life (Ke), this is an intrinsic property of a drug. Moreover, the drugs which have short Ke require a sustained release (SR) formulation.
SR formulations consist of dissolution rate limiting polymers. A SR formulation does not improve greater extent of bioavailability for poorly soluble as well as first pass effect drugs. In addition, systemic exposure carcinogenic drugs (oncology products) will cause normal cell toxicity. Cancer treating drugs cannot differentiate between normal cells and tumour cells. Therefore, stealth liposomes and surface modification of nanoparticles (NPs) are developed for long circulation in blood and targeted to particular affected organs to avoid systematic toxicity (normal cells).
Preparation MethodsNPs are prepared by several production techniques. Generally, top down and bottom up techniques are employed for the preparation of NPs, but, nowadays, commercialization only possible with top down approach (pearl/ball milling and high pressure homogenization). Pearl/ball milling has a disadvantage: potential erosion of material from the milling pearls leading to product contamination and long milling time to obtain desired particle size. High pressure homogenization is most widely used technology for size reduction process but numerous cycles are required for harder drugs. The NPs particle size characterization is performed by photon correlation spectroscopy and laser diffractometry. Drug release is usually determined by the dialysis membrane method and free drug estimated by centrifugation (supernatant liquid). Pharmacokinetics of NanoparticlesNPs present in systemic circulation interact with biological molecules.
These major interactions are with blood or plasma proteins and immune components. Nanoparticles bound to the protein molecules will causes changes in protein structure. This phenomenon may stimulate immune system, consequently, rapid elimination of NPs. Physicochemical characteristics (e.g.
: surface charge, nanoparticle composition, surface modification, shape, and size) of the nanoparticles will influence on protein adsorption. A study demonstrated that negative or positive charged nanoparticles shows greater protein adsorption compared to neutral charged nanoparticles. Figure1: Nanoparticles physiochemical characteristics and pharmacokineticsPharmacokinetics of nanoparticles is similar as xenobiotics. Regardless of route of administration, nanoparticles are considered as foreign materials whether it has surface coated or not.
Consequently, immune system will be triggered and elimination process will begin. For instance, uncharged PEG, not easily detected by the immune system which provides a prolonged systemic circulation, however, PEG antibodies will be stimulated and effective on repeated injections (Accelerated Blood Clearance). Clearance of nanoparticles is mainly through two processes: immune and non-immune opsonins. These opsonins interact with the nanoparticles in the blood. In the immune opsonins is straight forward process where engulfing of NPs by immunoglobulins whereas, non-immune opsonins consist of proteins are attached to nanoparticles subsequently influences distribution and elimination. In fact, nanoparticles surface and opsonins interactions are very weak and non-covalent bonding. Opsonin binding will decide the fate of nanoparticles.
The opsonized nanomaterials are recognized by reticular endothelial system (RES) and are cleared from blood tissue and are accumulated in liver and spleen. It is desired when nanoparticles are intended to target liver and spleen if it is not then it will be a question of toxicity.The fate (pharmacokinetics) of nonmaterials can be predicted from protein corona formation. NPs enter into systemic circulation the primary bio-physical interaction with proteins known as corona formation. Proteins are absorbed on NPs surface with lower or higher affinities. Proteins adsorbed on the surface of NPs with lower affinities known as soft corona, whereas proteins adsorbed on NPs with higher affinities known as hard corona. Soft corona is observed in PEG coated NPs, loosely bound proteins, and shorter desorption times vice versa for hard corona. Generally, hard corona formation may be observed with non-PEG coated and surface charged NPs.
Consequently, this phenomenon will trigger the immune system, activation of RES and rapid elimination from systemic circulation.