Current Drug Delivery - Volume 16, Issue 3, 2019

Dry powder inhalers are medical devices used to deliver powder formulations of active pharmaceutical ingredients via oral inhalation to the lungs. Drug particles, from a biological perspective, should reach the targeted site, dissolve and permeate through the epithelial cell layer in order to deliver a therapeutic effect. However, drug particle attributes that lead to a biological activity are not always consistent with the technical requirements necessary for formulation design. For example, small cohesive drug particles may interact with neighbouring particles, resulting in large aggregates or even agglomerates that show poor flowability, solubility and permeability. To circumvent these hurdles, most dry powder inhalers currently on the market are carrier-based formulations. These formulations comprise drug particles, which are blended with larger carrier particles that need to detach again from the carrier during inhalation. Apart from blending process parameters, inhaler type used and patient's inspiratory force, drug detachment strongly depends on the drug and carrier particle characteristics such as size, shape, solid-state and morphology as well as their interdependency. This review discusses critical particle characteristics. We consider size of the drug (1-5 μm in order to reach the lung), solid-state (crystalline to guarantee stability versus amorphous to improve dissolution), shape (spherical drug particles to avoid macrophage clearance) and surface morphology of the carrier (regular shaped smooth or nano-rough carrier surfaces for improved drug detachment.) that need to be considered in dry powder inhaler development taking into account the lung as biological barrier.

Graphene in nano form has proven to be one of the most remarkable materials. It has a single atom thick molecular structure and it possesses exceptional physical strength, electrical and electronic properties. Applications of the Graphene Family of Nanomaterials (GFNs) in different fields of therapy have emerged, including for targeted drug delivery in cancer, gene delivery, antimicrobial therapy, tissue engineering and more recently in more diseases including HIV. This review seeks to analyze current advances of potential applications of graphene and its family of nano-materials for drug delivery and other major biomedical purposes. Moreover, safety and toxicity are the major roadblocks preventing the use of GFNs in therapeutics. This review intends to analyze the safety and biocompatibility of GFNs along with the discussion on the latest techniques developed for toxicity reduction and biocompatibility enhancement of GFNs. This review seeks to evaluate how GFNs in future will serve as biocompatible and useful biomaterials in therapeutics.

Background: Genistein (Gen) is a naturally occurring soy isoflavonoid, possessing anticancer, antiproliferation & antioxidant-like properties. The disadvantage of poor solubility and less oral bioavailability restrict its use as a potential anticancer agent. Objectives: The current work was focused on the formulation and characterization of the genistein loaded nanostructured lipid carriers that can entrap enough quantity of the drug which will provide sustained release of the drug for the treatment of ovarian cancer. Methods: The nanostructure lipid carriers of genistein were developed with the aid of solvent emulsification and evaporation technique by employing TPGS as a surfactant. The resultant formulation was characterized by various physicochemical properties. Pharmacokinetics and biodistribution studies were carried out to estimate the mean plasma concentrations of the drug. Percentage cytotoxicity was evaluated by using PA-1 ovarian cancer cell lines. Results: The resultant formulation exhibited a particle size of 130.23 nm, and entrapment efficiency of 94.27 %, & zeta potential of -20.21 mV with unimodal size distribution. Pharmacokinetics and biodistribution studies revealed that the formulation was able to provide sufficient plasma drug concentration for the longer period of time and the drug was more distributed in ovarian cancer tissues. Results of MTT assay concluded that GenNLC were more effective in comparison to pristine Gen. Conclusion: In a nutshell, GenNLC seems to be a superior alternative carrier system for the formulation industry to obtain the higher entrapment with excellent stability of the formulation.

Background: Humanin is a novel neuronal peptide that has displayed potential in the treatment of Alzheimer's Disease through the suppression of inflammatory IL-6 cytokine receptors. Such receptors are found throughout the body, including the eye, suggesting its other potential applications. Age-related Macular Degeneration (AMD) is the leading cause of blindness in the developing world. There is no cure for this disease, and current treatments have several negative side effects associated with them, making finding other treatment options desirable. Objective: In this study, the potential applications in treating AMD for a more potent humanin derivative, AGA-HNG, were studied. Methods: AGA-HNG was synthesized and encapsulated in chitosan Nanoparticles (NPs), which were then characterized for their size, Encapsulation Efficiency (EE), and drug release. Their ability to suppress VEGF secretion and protect against oxidative apoptosis was studied in vitro using ARPE-19 cells. The chitosan NPs exhibited similar anti-VEGF properties and oxidative protection as the free protein while exhibiting superior pharmaceutical characteristics including biocompatibility and drug release. Results: Drug-loaded NPs exhibited a radius of 346nm with desirable pharmacokinetic properties including a stable surface charge (19.5 ± 3.7 mV) and steady drug release capacity. AGA-HNG showed great promise in mediating apoptosis in hypoxic cells. They were also able to significantly reduce VEGF expression in vitro with reduced cellular toxicity compared to the free drug. Conclusion: The ability of this drug delivery system to reduce retinal apoptosis with desirable pharmacokinetic and biocompatible properties makes this a promising therapeutic option for AMD.

Objective: The label free ultrasmall fluorescent ferrite clusters have been engineered in a controlled fashion which was stabilized by serum protein and functionalized by folic acid for the application of targeted multimodal optical and Magnetic Resonance (MR) cancer imaging. Methods: The ultra-small manganese ferrite nanoclusters (PMNCs) with a diameter of 4 nm have a commendable effect on the longitudinal (T1) and transverse (T2) relaxation in MR imaging that was evident from the phantom and animal MRI. Results: The calculated longitudinal molar relaxivity of nanoclusters was found to be 6.9 ± 0.10 mM-1 S-1 which was exactly 2.22 times better than the conventional Gd-DOTA and their 4.01 ratio of the transverse (r2) and longitudinal (r1) relaxivities made them a potential candidate for both T1 and T2 contrast agents in MRI. In addition, the fluorescence-based small animal imaging showed folic acid driven accumulated fluorescent signal at the tumour site to conclude the capacity of PMNCs for targeted fluorescence imaging of cancer diagnosis. Conclusion: The cytotoxicity assay and histopathology studies were the evidence for their safe biodistribution in animal systems. Furthermore, the protein encapsulated clusters have the ability to deliver the anticancer drug Methotrexate (MTX) to the cancer tissues with a sustained manner. Therefore, one can conclude the remarkable efficacy of architect nanoclusters for theragnosis.

Objective: The study describes the development of chitosan-based (AMPS-co-AA) semi-IPN hydrogels using free radical polymerization technique. Methods: The resulting hydrogels were characterized using Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC), X-Ray diffraction (XRD), and Scanning Electron Microscopy (SEM). The successful crosslinking of chitosan, 2- Acrylamido-2-Methylpropane Sulfonic Acid (AMPS), and Acrylic Acid (AA) was confirmed by FT IR. Unloaded and drug-loaded hydrogels exhibited higher thermal stability after crosslinking compared to the individual components. XRD confirmed the decrease in crystallinity after hydrogel formation and molecular dispersion of Oxaliplatin (OXP) in the polymeric network. SEM showed rough, vague and nebulous surface resulting from crosslinking and loading of OXP. Results: The experimental results revealed that swelling and drug release were influenced by the pH of the medium being low at acidic pH and higher at basic pH. Increasing the concentration of chitosan and AA enhanced the swelling, drug loading and drug release while AMPS was found to act inversely. Conclusion: It was confirmed that the hydrogels were degraded more by specific enzyme lysozyme as compared to the non-specific enzyme collagenase. In-vitro cytotoxicity suggested that the unloaded hydrogels were non-cytotoxic while crude drug and drug-loaded hydrogel exhibited dose-dependent cytotoxicity against HCT-116 and MCF-7. Results of acute oral toxicity on rabbits demonstrated that the hydrogels are non-toxic up to 3900 mg/kg after oral administration, as no toxicity or histopathological changes were observed in comparison to control rabbits. These pH-sensitive hydrogels appear to provide an ideal basis as a safe carrier for oral drug delivery.

Background: The use of Misonidazole (MISO), the first and a potential hypoxic tumor cell radiosensitizer, has been limited by peripheral neurotoxicity, thus discouraging phase III clinical trials. Objective: To develop a targeted drug delivery and tracing System with pH-sensitive liposomes (SpHLs) and Superparamagnetic Iron Oxide Nanoparticles (SPIONs) to counter MISO-related adverse effects and to enable tracing under magnetic resonance. Methods: SPION-MISO-SpHLs were prepared by a reverse evaporation and freeze-thawing method. HPLC and phenanthroline spectrophotometry were established for MISO and Fe determination. The characterization and in vitro pH-sensitivity of SPION-MISO-SpHLs were evaluated. Results: The maximal entrapment efficiencies of MISO and SPIONs in SPION-MISO-SpHLs were 30.2% and 23.7%, respectively. The cumulative release rates of MISO and SPIONs were respectively 2.49 and 2.47 times higher in pH 5.5 than in pH 7.4 buffer. The mean particle size of SPION-MISOSpHLs was 950 nm. The zeta potential was -58.9 mV in pH 7.4 buffer and 36.3 mV in pH 5.5 buffer. SEM imaging showed that SPION-MISO-SpHLs had similar spherical morphologies. SPIONs were packed in the center of liposomes and were well dispersed in a TEM graph. Magnetization curve showed that SPION-MISO-SpHLs retained superparamagnetic properties. SPION-MISO-SpHLs were compared with MISO+SPION+blank liposome in hypoxia and control groups of A549 cells. MISO and SPION concentrations in culture medium showed significant differences between the same concentration groups (P < 0.0001) and at different times (P < 0.0001). Conclusion: SPION-MISO-SpHLs possess pH-dependent release ability and superparamagnetism, and thus provides a system for targeted delivery and tracing under magnetic resonance.

The advances and the impact of nanostructured systems on therapeutics constitute a constantly evolving reality. New strategies have been developed for drug delivery control and for directing these systems to the targeted site improving the therapy. In this commentary, the lectins are briefly reviewed; their fundamentals and the proposed applications as ligands in nanostructured drug delivery systems are discussed.