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 Methods NPs 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 Nanoparticles NPs 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. Size Shape Surface Charge Surface Modification Photon Correlation Spectroscopy Laser Diffractometry Surface Electron Microscopy Transmission Electron Microscopy Figure1: Nanoparticles physiochemical characteristics and pharmacokinetics Pharmacokinetics 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. Estimation of Protein-nanomaterial Interaction Techniques Various techniques can be utilized for the determination of affinities between NPs and proteins: ITC (isothermal titration calorimetry), SPR (surface plasmon resonance), DCS (differential centrifugal sedimentation), QCM (quartz crystal microbalance), FCS (?uorescence correlation spectroscopy), and Atomic Force Microscopy (AFM). However, AFM is a state-of-art technique utilized to study bio-physical interactions in a molecular level both qualitative and quantitative manner. This technique measures the interaction forces between NP-NP and NP-protein molecules. Nanotoxicity The correlation between physiochemical properties of nanomaterials (size, shape, surface chemistry and ingredients) and biological molecules (cell and cell components) is a potential concern because of nanotoxicity. For instance, repeated injections, nanomaterials (bio degradable and non-biodegradable) may be accumulated in vital organs (Kidney, Liver, Lungs and Spleen) cause toxicity. Biodegradable polymers have specific degradation pathway and intermediates may induce unpredictable cell toxicity, whereas non-biodegradable polymers will deposited and show toxicity. In addition, nanomaterials may cause carcinogenic effects, which are initiated by the release of macrophages that make to demolish the foreign material in the inflammation site and in terms of DNA damage as well as carcinogenesis. So, nanoparticles, cell toxicity and cellular level changes evaluation is primary importance. Usually, nanotoxicity is associated NPs with the smaller particle size, which have an ability to penetrate into cellular constituents and causes permanent damage to DNA, chromosomal breaks and point mutation. Currently, nanoparticle physiochemical characteristics and related toxicity is a field of research. Establishing bio-nano interface as a model to evaluate cellular toxicity related with nanoparticle surface characteristics. This valuable information provides successful development of nanoparticles and drug delivery into specific site as well as eliminating toxicity. To achieve this collaboration between scientists from various fields' biology, chemistry and pharmacy will produce profound knowledge on nanotoxicity. Conclusion Poor solubility and systemic toxicity of carcinogenic drugs leads to development of nanocarriers to improve the solubility, specificity and reduction of toxicity. However, profound knowledge about five physiochemical characteristics i.e. surface chemistry, size, shape, composition and surface charge of nanoparticles and their relation to ADMET not yet well established. Consequently, bio-nano interactions data will enable successful delivery nanoparticles to the targeted site as well as eliminating adverse drug reactions. AFM is a cutting edge technology able to estimate forces of interaction between nanomaterials and biological fluids as well as NP-NP interactions. Commercialization of NPs and achieving batch to batch consistency, prolong circulation, site specific targeting, eliminating of cell toxicity, improving the stability during storage of nanoparticlesis challenging and subtle changes in formulation variables may lead erroneous problems and thus affects pharmacokinetics. In this context, regulatory agencies may discontinue these products due to safety concerns leads to shortage of novel drug delivery systems.