This project aims at developing pulmonary system for selective and targeted treatment of Lung cancer
This project aims at developing system for the selective and targeted delivery of chemotherapy to lung tumors. The chemotherapeutic agents are loaded into suitable nano particles for optimized drug release profile and passive and active targeting of the tumors. These nanoparticles are in turn loaded into stimuli responsive particles whose role is to deliver its cargo to the deep lung bypassing the pulmonary clearance mechanisms. This project would be the first trial to employ the Enhanced Permeability and Retention Effect for passive targeting of the tumors through the pulmonary route. It would allow the use of low cost potent chemotherapeutic agents as Doxorubicin and 5-Fluoro Uracil while avoiding their side effects that currently limit their use.
Abstract: Pulmonary nanodrug delivery is an emerging concept, especially for targeted lung cancer therapy. Once inhaled, the nanoparticles (NPs) acting as drug carriers need to efficiently cross the pulmonary surfactant monolayer (PSM) of lung alveoli, which act as the first barrier for external particles entering the lung. Herein, by performing molecular dynamics simulations, we study how inhaled NPs interact with the PSM, particularly focusing on the transport of NPs with different properties across the PSM. While hydrophilic NPs translocate directly across the PSM, transport of hydrophobic NPs is achieved as the PSM wraps them. Intriguingly, when hydrophilic NPs are decorated with lipid molecules (LCNPs), they are wrapped by the PSM efficiently with mild PSM perturbation. Moreover, the structure formed is like a vesicle, which will likely fuse with cell membranes to accomplish the transport of hydrophilic NPs into secondary organs. This behavior makes the LCNP a prospective candidate for pulmonary nanodrug delivery. Herein, the effects of the physical properties of LCNPs on their transport are investigated. Increasing the LCNP size promotes its wrapping by reducing the PSM bending energy. The binding energy that drives transport can be strengthened by increasing the lipid coating density and the lipid tail length, both of which also reduce the risk of PSM rupture during transport. These results should help researchers understand how to better use surface decorations to achieve efficient pulmonary entry, which may provide useful guidance for the design of nano-based platforms for inhaled drug delivery.
Pub.: 18 Jun '17, Pinned: 08 Nov '17
Abstract: Respiratory tract being a non-invasive route of drug administration is gaining massive attention in the present time to achieve both local and the systemic effects. In order to achieve effective therapeutic effects of a drug in the pulmonary region, it requires challenging barriers like mucociliary clearance and uptake by macrophages. An effective drug delivery system delivers the therapeutically active moieties at the right time, rate and in a reproducible manner to target sites for the effectively the human illnesses. A major limitation associated with most of the currently available conventional and controlled release drug delivery devices is that not all the drug candidates are well absorbed uniformly locally or systemically.We searched for the chitosan and its derivatives based nanocarrier systems for the pulmonary drug delivery. We focused on the applications of chitosan in the development of nanoparticles for the pulmonary drug delivery.Chitosan, a natural linear bio poly amino saccharide is playing a crucial role in the development of novel drug delivery systems (NDDS) such as nanoparticles in order to treat various respiratory diseases effectively by managing these difficulties due to its unique characteristic properties of biodegradability, biocompatibility, mucoadhesivity and its ability to enhance macromolecule permeation. It also aids in providing sustained and targeted effects, which are the primary requirements of an ideal pulmonary drug delivery system. This review highlights the applications and importance of chitosan with special emphasis on nanotechnology, particularly employed in various respiratory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD), lung cancer and pulmonary fibrosis.This review will be of interest to both the biological and formulation scientists to have a quick snapshot on the utility of chitosan in pulmonary drug delivery systems. At present, there are no patented chitosan based controlled release products available with pulmonary drug delivery and therefore this area needs attention to explore the potential of this polymer in the area of respiratory research.
Pub.: 09 Aug '17, Pinned: 08 Nov '17
Abstract: Inhalational route for drug delivery and desired effects has been known since centuries. This lung-targeted therapy has benefited asthmatics and those with chronic respiratory problems. The technique has evolved greatly from crude pots and pipes to modern sophisticated drug-dispensing devices. This mode is effective, rapid and safe. Its outcome, however, is majorly determined by drug formulation, device structure and patient's coordinating skill. In spite of great advances in this field, more efforts are required to meet the unmet needs. This noninvasive mode is being increasingly studied for transfer of drugs for systemic action with promising results. The present article is an attempt to capture the recent development and progress in this field and review relevant newer patents.
Pub.: 19 Aug '17, Pinned: 08 Nov '17
Abstract: This brief communication evaluates the cytotoxicity and targeting capability of a dry powder chemotherapeutic. Nano-in-microparticles (NIMs) are a dry powder drug delivery vehicle containing superparamagnetic iron oxide nanoparticles (SPIONs) and either doxorubicin (w/w solids) or fluorescent nanospheres (w/v during formulation; as a drug surrogate) in a lactose matrix. In vitro cytotoxicity was evaluated in A549 adenocarcinoma cells using MTS and LDH assays to assess viability and toxicity after 48 hours of NIMs exposure. In vivo magnetic-field-dependent targeting of inhaled NIMs was evaluated in a healthy mouse model. Mice were endotracheally administered fluorescently-labeled NIMs either as a dry powder or a liquid aerosol in the presence of an external magnet placed over the left lung. Quantification of fluorescence and iron showed a significant increase in both fluorescence intensity and iron content to the left magnetized lung. In comparison, we observed decreased targeting of fluorescent nanospheres to the left lung from an aerosolized liquid suspension, due to the dissociation of SPIONs and nanoparticles during pulmonary administration. We conclude that dry powder NIMs maintain the therapeutic cytotoxicity of doxorubicin and can be better targeted to specific regions of the lung, in the presence of a magnetic field, compared to a liquid suspension.
Pub.: 27 Oct '17, Pinned: 08 Nov '17
Abstract: Functional nanoparticles, such as liposomes and polymeric micelles, are attractive drug delivery systems for solubilization, stabilization, sustained release, prolonged tissue retention, and tissue targeting of various encapsulated drugs. For their clinical application in therapy for pulmonary diseases, the development of dry powder inhalation (DPI) formulations is considered practical due to such advantages as: (1) it is noninvasive and can be directly delivered into the lungs; (2) there are few biocomponents in the lungs that interact with nanoparticles; and (3) it shows high storage stability in the solid state against aggregation or precipitation of nanoparticles in water. However, in order to produce effective nanoparticle-loaded dry powders for inhalation, it is essential to pursue an innovative and comprehensive formulation strategy in relation to composition and powderization which can achieve (1) the particle design of dry powders with physical properties suitable for pulmonary delivery through inhalation, and (2) the effective reconstitution of nanoparticles that will maintain their original physical properties and functions after dissolution of the powders. Spray-freeze drying (SFD) is a relatively new powderization technique combining atomization and lyophilization, which can easily produce highly porous dry powders from an aqueous sample solution. Previously, we advanced the optimization of components and process conditions for the production of SFD powders suitable to DPI application. This review describes our recent results in the development of novel DPI formulations effectively loaded with various nanoparticles (electrostatic nanocomplexes for gene therapy, liposomes, and self-assembled lipid nanoparticles), based on SFD.
Pub.: 03 Nov '17, Pinned: 08 Nov '17
Abstract: Direct pulmonary delivery of anti-cancer agents is viewed as an effective way of treating lung cancer. Here, we fabricated inhalable nanoparticles made of human serum albumin (HSA) conjugated with doxorubicin and octyl aldehyde and adsorbed with apoptotic TRAIL protein (TRAIL/Dox HSA-NP). The octyl aldehyde and doxorubicin endowed HSA with significant hydrophobicity that facilitated self-assembly. TRAIL/Dox HSA-NP was found to have excellent particle size (~340nm), morphology, dispersability, and aerosolization properties. TRAIL/Dox HSA-NP displayed synergistic cytotoxicity and apoptotic activity in H226 lung cancer cells vs. HSA-NP containing TRAIL or Dox alone. TRAIL/Dox HSA-NP was well deposited in the mouse lungs using an aerosolizer, and TRAIL and Dox-HSA were found to be gradually released over 3days. The anti-tumor efficacy of pulmonary administered TRAIL/Dox HSA-NP was evaluated in BALB/c nu/nu mice bearing H226 cell-induced metastatic tumors. It was found that the tumors of H226-implanted mice treated with TRAIL/Dox HSA-NP were remarkably smaller and lighter than those of mice treated with TRAIL or Dox HSA-NP alone (337.5±7.5; 678.2±51.5; and 598.9±24.8mg, respectively). Importantly, this improved anti-tumor efficacy was found to be due to the synergistic apoptotic effects of Dox and TRAIL. In the authors' opinion, TRAIL/Dox HSA-NP offers a potential inhalable anti-lung cancer drug delivery system. Furthermore, the synergism displayed by combined use of Dox and TRAIL could be used to markedly reduce doxorubicin doses and minimize its side effects.
Pub.: 03 Dec '14, Pinned: 08 Nov '17
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