Rinti Banerjee

Intravesical drug delivery: Challenges, current status, opportunities and novel strategies.

The urinary bladder has certain unique anatomical features which enable it to form an effective barrier to toxic substances diffusing from the urine into the blood. The barrier function is due to the epithelial surface of the urinary bladder, the urothelium, which has characteristic umbrella cells, joined by tight junctions and covered by impenetrable plaques, as well as an anti-adherent mucin layer. Diseases of the urinary bladder, such as bladder carcinomas and interstitial cystitis, cause acute damage to the bladder wall and cannot be effectively treated by systemic administration of drugs. Such conditions may benefit from intravesical drug delivery (IDD), which involves direct instillation of drug into the bladder via a catheter, to attain high local concentrations of the drug with minimal systemic effects. IDD however has its limitations, since the permeability of the urothelial layer is very low and instilled drug solutions become diluted with urine and get washed out of the bladder during voiding, necessitating repeated infusions of the drug. Permeation enhancers serve to overcome these problems to some extent by using electromotive force to enhance diffusion of the drug into the bladder wall or chemical molecules, such as chitosan, dimethylsulphoxide, to temporarily disrupt the tight packing of the urothelium. Nanotechnology can be integrated with IDD to devise drug-encapsulated nanoparticles that can greatly improve chemical interactions with the urothelium and enhance penetration of drugs into the bladder wall. Nanocarriers such as liposomes, gelatin nanoparticles, polymeric nanoparticles and magnetic particles, have been found to enhance local drug concentrations in the bladder as well as target diseased cells. Intravesical drug carriers can be further improved by using mucoadhesive biomaterials which are strongly adhered to the urothelial cell lining, thus preventing the carrier from being washed away during urine voiding. This increases the residence time of the drug at the target site and enables sustained delivery of the drug over a prolonged time span. Polymeric hydrogels, such as the temperature sensitive PEG-PLGA-PEG polymer, have been used to develop in situ gelling systems to deliver drugs into the bladder cavity. Recent advances and future prospects of biodegradable nanocarriers and in situ gels as drug delivery agents for intravesical drug delivery are reviewed in this paper.

Targeted Magnetic Liposomes Loaded with Doxorubicin.

Targeted delivery systems for anticancer drugs are urgently needed to achieve maximum therapeutic efficacy by site-specific accumulation and thereby minimizing adverse effects resulting from systemic distribution of many potent anticancer drugs. We have prepared folate receptor targeted magnetic liposomes loaded with doxorubicin, which are designed for tumor targeting through a combination of magnetic and biological targeting. Furthermore, these liposomes are designed for hyperthermia-induced drug release to be mediated by an alternating magnetic field and to be traceable by magnetic resonance imaging (MRI). Here, detailed preparation and relevant characterization techniques of targeted magnetic liposomes encapsulating doxorubicin are described.

Biocompatible calcium phosphate based tubes

Porous anodic alumina template has been employed, in the presence of a precipitation reaction involving Ca(OH)2 and H3PO4, to form calcium phosphate based tubular structures. These structures are amorphous in nature and can be recovered by etching the sacrificial alumina membrane. Full characterization of these structures has been done using X-ray diffraction, electron microscopy and FTIR. In addition, their biocompatibility has been tested on L929 mouse fibroblast cells using MTT assay and the cellular internalization of these nanotubes has also been evaluated using rhodamine 6G dye tagged nanotubes in the presence of fibroblast cells. The studies also suggest that the nanotubes are non-toxic to fibroblasts and can be taken up easily by mammalian cells. Such tubes may serve as vehicles for drugs and growth factors, and for tissue repair including bone regeneration.

Proapoptotic lipid nanovesicles: synergism with paclitaxel in human lung adenocarcinoma A549 cells.

The present study focuses on the development and evaluation of phosphatidylserine based proapoptotic lipid nanovesicles (PSN-PTX) as aerosols for synergistic activity with paclitaxel against lung cancer. PSN-PTX showed a unimodal size distribution of the particles (100-200 nm), negative surface charge of -29 mV and high encapsulation efficiency of paclitaxel (82%) with 19% of it releasing in 48 h. PSN-PTX was found to be highly surface active as compared to Taxol®, marketed formulation of paclitaxel, whose surface activity was found to be detrimental for pulmonary mechanics. PSN-PTX also showed high airway patency in capillary surfactometer unlike Taxol®, suggesting its ability to mimic pulmonary surfactant functions. High deposition of PSN-PTX in lower impingement chamber of twin impinger upon nebulization suggested it to be capable of reaching the terminal regions of the lungs. Nanovesicles showed facilitated and ATP dependent active uptake by A549 cells. The combination of phosphatidylserine nanovesicles and paclitaxel as PSN-PTX enhanced cytotoxicity in A549 cell line showing an IC(50) of 18 nM which is10-50 folds less than the IC(50) values observed for blank phosphtidylserine nanovesicles and paclitaxel alone. Further, the combination index was found to be less than one which indicates a synergism of the two components. DNA fragmentation study showed that blank phosphatidylserine nanovesicles induce apoptosis in A549 cells and hence behave as proapoptotic nanovesicles in the combination therapy. Overall, these studies suggest the therapeutic potential and advantages of combination chemotherapy of proapoptotic lipid nanovesicles with encapsulated paclitaxel and their feasibility for aerosol administration in the treatment of lung cancer.

Protein based nanoparticles as platforms for aspirin delivery for ophthalmologic applications.

Most conventional ophthalmic dosage forms, though simplistic are limited by poor bioavailability in the posterior chamber of the eye. Application of nanotechnology has the potential to overcome this problem. By varying aspirin albumin ratios from 0.06 to 1.0, we obtained electrokinetically stable, pharmacologically active albumin based aspirin nanoparticles of <200 nm diameter with low polydispersity. In vitro release study showed nanoparticle formulation can release aspirin at a sustained rate for prolonged duration (90% at 72 h) and 11% drug release in the posterior chamber over a period of 72 h under simulated condition. Stability of the formulation was well maintained on storage for six months and after reconstitution for 24 h. The formulation showed no hemolysis in contrast to the high hemolysis due to the free drug. This study shows that aspirin loaded albumin nanoparticles prepared by coacervation holds promise as a formulation for topical delivery in diabetic retinopathy.

Trigger-responsive nanoparticles: control switches for cancer therapy

Conventional chemotherapy in cancers suffers from drawbacks of toxicity and nonspecificity. Nanotechnology has the potential to develop diagnostic and therapeutic platforms for the efficient diagnosis and treatment of cancers. One of the crucial aspects of the success of nanoparticle-based technologies is its ability to specifically attack the cancer cells due to several strategies like passive targeting by the enhanced permeation and retention effect, active biological targeting as well as triggered responses at the desired sites.

Nanovesicle aerosols as surfactant therapy in lung injury

UNLABELLED Acute lung injury causes inactivation of pulmonary surfactant due to leakage of albumin and other markers. Current surfactants are ineffective in this condition and are instilled intratracheally. Nanovesicles of 300 ± 50 nm composed of nonlamellar phospholipids were developed as pulmonary surfactant aerosols for therapy in acid-induced lung injury. A combination of dipalmitoyl phosphatidylcholine and dioleoyl phosphatidylethanolamine was used. The size and composition of the nanovesicles were optimized for an improved airway patency in the presence of albumin and serum. In an acid-induced lung injury model in mice, on treatment with nanovesicle aerosols at a dose of 200 mg/kg, the alveolar protein leakage decreased from 8.62 ± 0.97 μg/mL to 1.94 ± 0.74 μg/mL, whereas the airway patency of the bronchoalveolar lavage fluid increased from 0.6 ± 0.0% to 91.7 ± 1.05%. Nanovesicle aerosols of nonlamellar lipids improved the resistance of pulmonary surfactants to inhibition and were promising as a noninvasive aerosol therapy in acute lung injury. FROM THE CLINICAL EDITOR In acute lung injury, intrinsic surfactants are inactivated via albumin leakage and other mechanisms. Currently existing intratracheal surfactants are ineffective in this condition. The authors demonstrate that novel nanovesicle aerosols of nonlamellar lipids improved the resistance of pulmonary surfactants to inhibition and are promising as a noninvasive aerosol therapy in acute lung injury.

Overcoming the stratum corneum barrier: a nano approach

The skin represents a large surface area which is easily accessible and can potentially serve as a very attractive non-invasive route of delivery of drugs. However, there have been very few technologies exploiting this route of drug delivery commercially. One of the main reasons for the limited success is the presence of the “brick and mortar” barrier of the stratum corneum which acts as a defensive wall that needs to be overcome in order to improve the efficiency of transdermal drug delivery. Understanding the organisation of the stratum corneum can help in designing more efficient drug carriers which are based on their biophysical effects on the stratum corneum barrier.

Thermosensitive gold-liposome hybrid nanostructures for photothermal therapy of cancer

Thermosensitive liposomes with self assembled gold nanostructures have been developed for photo-thermal therapy. These liposomes (DSPC: CH: POPG, w/w ratio 7:2:1) have been prepared by thin film hydration and incorporated with gold nanostructures in two different ways. In one of the types, the liposomes were synthesized to encapsulate near infrared (NIR) absorbing gold nanocages within them. In another type, gold nanoclusters were self assembled on to the surface of these preformed liposomes. Among the two systems, the gold cluster coated liposome was chosen for further analysis owing to its better degradability criteria. It was found that the presence of a liposome template helps in tuning the absorbance of gold nanoclusters to NIR wavelength. NIR laser mediated temperature rise experiments were performed and the photothermal efficiency of these gold-coated liposomes was compared with gold nanoshells. It was found that gold - cluster self assembled liposomes were equally efficient as gold nanoshells in photo-thermal conversion. In addition, they have the capacity to act as carriers for drugs for targeted drug delivery. Gold nanocluster self-assembled thermosensitive liposomes are biocompatible and have tremendous potential in killing cancer cells by dual modes of photo-thermal effect and temperature triggered drug delivery.

Nanoparticle aerosols: boon or bane for breathing?

Nanoparticle aerosols represent an emerging area of nanobiotechnology and nanotoxicology. The dispersion of nanosized particles within aerosol droplets have different effects on biological systems depending on the nature of the nanoparticle aerosol. Degradable, drug-loaded nanoparticle aerosols can directly deliver actives in the lungs in a noninvasive and safe manner for treatment of respiratory diseases. However, many environmental nanoparticle aerosols of fine suspended matter act as pollutants and increase the risks of respiratory problems.