Although a large number of therapeutic agents have been found to have a therapeutic effect, the application of these therapies has been limited due to pharmacokinetic limitations and associated adverse side effects. To achieve the targeted delivery of therapeutic agents such as drug, siRNA or miRNA, the Translational Bio-pharma Engineering Nanodelivery Research Laboratory is working on the development of multifunctional bioresponsive NCs which will be selectively delivered to the site of action i.e. disease tissue or cells while sparing healthy tissues. We have developed the NCs using biodegradable and safer natural polymers such as albumin, gelatin, and chitosan. In addition, we are developing engineered polymeric multifunctional NCs and evaluating for their physiochemical properties, efficacy under cell culture and animal models.
Our multidisciplinary approach utilizes the nanotechnology, engineering, drug discovery, and molecular biology techniques. By applying this approach, we could engineer the NCs to bypass the multiple clearance mechanisms in the human body and target to the disease site to exert a therapeutic effect. We believe the targeted delivery of therapeutic agents using NCs delivery via inhalation, parenteral and oral routes to the site of action will improve the efficacy for the treatment of cancer, asthma and skin disorders, and minimize the associated adverse side effects. In addition, the dose and frequency of dosing will also be reduced by increasing the blood circulation half-life, which will increase the patient compliance. The preclinical studies of developed NCs under cell culture and animal models will help to evaluate the efficacy of developed NCs. Our multifunctional bioresponsive drug and gene delivery systems would be a representative of the next generation of cancer and pulmonary disorder therapies. Our multifunctional bioresponsive drug and gene-based approaches and preclinical studies would form the framework for future clinical studies.
Various bio-engineered multifunctional delivery systems we developed:
Polymer and lipid based drug and/or gene delivery systems:
In collaboration with bioengineers, we have engineered several polymeric materials to build the multifunctional drug and gene delivery systems. By introducing the positive charged chemical functional groups, the neutral polymer was turned into the cationic polymer which could carry negative charged siRNA/miRNA. The inclusion of disulfide bonds has made these polymers able to target glutathione rich cytoplasm. The arginine-rich polymers have shown an improved cell penetration.
We developed liposomes, natural polymers such as albumin, gelatin and chitosan based NCs and bioengineered polymeric drug and gene delivery systems.
By utilizing these materials, we developed the delivery systems which could deliver hydrophobic and hydrophilic therapeutic agent at the same time. Co-delivery siRNA with small molecules has showed improved the efficacy
An another focus is to enhance the delivery of NCs across the tumor or diseased tissue. The receptor targeting strategy has increased the specificity of drug or siRNA loaded nanoparticulate based delivery systems.
Inhalable drug and/or gene delivery systems
The research is focused on the development of the inhalable formulations as alternative non-invasive delivery systems. We have engineered natural polymer or phospholipid based nanoparticles for targeting delivery drugs or siRNA to the treatment of pulmonary disorders. We have also developed nanoliposomes which could deliver drug and or siRNA for specific diseased cells or tissue. We have developed nanosuspension based nebulizers and dry powder inhaler products. Our group has developed dry powder inhaler products for pharmaceutical industries which were successfully transferred and adopted by industry in their marketed products.
Combination therapy has shown their advantages on their efficacy against various diseases. We have developed a unique synergistically acting multi-pathway targeting combination of siRNA with small molecule drug.
We utilized targeted nano delivery system to further enhance the performance of this combination and thus to overcome the current limits, such as poor pharmacokinetic profile, low solubility or stability, severe adverse effect, etc., in the chemo and gene therapy.
We have studied the therapeutic effect of drug and gene delivery systems for following diseases:
Lung cancer is the USA’s top cancer killer and has barely reached 18% of five years survival rate. The research is focused on targeting non-small cell lung cancers, which is 80% of total lung cancer cases . We have been focusing on a few strategies which utilize the multifunctional bioresponsive NCs coalescing with newer targets, combination therapy, gene therapy and chemo-gene therapy. The designed NCs have been able to utilize both microenvironments of tumor tissue and overexpressed receptors of cancer cells to enhance the efficacy against lung cancer.
Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness, remodeling, and mucus production. Asthma remains poorly controlled due to suboptimal treatment methods that only alleviate the symptoms of asthma, but do not act on the underlying causes of asthma, such as the immunological mechanisms that mediate allergic airway response [2, 3]. Our lab has formulated liposomes and polymeric drug and gene delivery systems. The main goal is to deliver the newer target specific drugs or gene to improve the outcome of asthma therapy and reduce the physical and economic burden of this disease.
Malignant mesothelioma is a very aggressive tumor and has been linked to occupational and environmental exposure to asbestos, causing over 3,000 deaths per year in the USA . Due to unresectable tumors, current treatments, surgery, and radiotherapy, are not viable for most patients while chemotherapy results in low response rates with adverse side effects. We have employed an innovative approach to delivering proteins or drugs via receptor targeted hybrid NCs, which could improve therapeutic agents delivery to tumor tissues and overcome the limitations associated with conventional delivery.
Neuroblastoma is the most common extracranial solid cancer in childhood and infancy with patients having an average age of 17 months . Most are diagnosed with advanced stage Neuroblastoma when tumor progression is aggressive, making treatment even more difficult . We are developing a stable, epitope or receptor-guided PEGylated NCs to co-deliver the therapeutic agents in a targeted fashion to Neuroblastoma, which will result in a significant improvement of anticancer activity at lower doses, reduced adverse side effects and prolonged biological half-lives of therapeutic agents.
Skin disorders – topical and transdermal delivery
The clinical outcome of skin diseases such as psoriasis, and atopic dermatitis is poor. We are developing NCs to deliver drugs via topical application what will help to improve the outcome of skin disorders. Additionally, Magnesium cream formulation investigated in my laboratory has been marketed by Center for Magnesium Education and Research, LLC. We are also working on the transdermal delivery of therapeutic agents using human skin based permeation and molecular studies.
- Siegel, R., D. Naishadham, and A. Jemal, Cancer statistics, 2013. CA: a cancer journal for clinicians, 2013. 63(1): p. 11-30.
- Barnes, P.J., New Drugs for Asthma. Seminars in Respiratory and Critical Care Medicine, 2012. 33(6): p. 685-694.
- Mullane, K., The increasing challenge of discovering asthma drugs. Biochemical Pharmacology, 2011. 82(6): p. 586-599.
- Robinson, B.M., Malignant pleural mesothelioma: an epidemiological perspective. Ann Cardiothorac Surg, 2012. 1(4): p. 491-6.
- Maris, J.M., Recent advances in neuroblastoma. N Engl J Med, 2010. 362(23): p. 2202-11.
- Modak, S. and N.K. Cheung, Neuroblastoma: Therapeutic strategies for a clinical enigma. Cancer Treat Rev, 2010. 36(4): p. 307-17.