Research

Although many 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 drugs, siRNA, or miRNA, the Ingenious BioPharma-engineered Drugs and Biologics Delivery Laboratory (iBD² lab) is working on the development of multifunctional bio-responsive 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 their physiochemical properties and efficacy under in vitro cell culture and animal models.

Our multidisciplinary approach utilizes 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 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 treating cancer, asthma, COVID-19, 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 patient compliance. The preclinical studies of developed NCs under in vitro cell culture and animal models will help to evaluate the efficacy of developed NCs. Our multifunctional bio-responsive drug and gene delivery systems would represent the next generation of cancer and pulmonary disorder therapies. Our multifunctional bio-responsive drug and gene-based approaches and preclinical studies would form the framework for future clinical studies.

Various bio-engineered multifunctional delivery systems we developed include:

Polymer and lipid-based drug and/or gene delivery systems

In collaboration with bioengineers, we have engineered several polymeric materials to build multifunctional drug and gene delivery systems. Introducing the positively charged chemical functional groups turned the neutral polymer into the cationic polymer, which could carry negatively charged siRNA/miRNA. The inclusion of disulfide bonds has made these polymers able to target glutathione-rich cytoplasm. The arginine-rich polymers have shown improved cell penetration.

We developed liposomes utilizing endogenous lipids, and NCs based on natural polymers such as albumin, gelatin, and chitosan and bioengineered polymeric drug and gene delivery systems.

Fig. Scheme for formulation of matrix-based polymeric layer-by-layer nanocarriers

By utilizing these materials, we developed delivery systems that could deliver hydrophobic and hydrophilic therapeutic agents at the same time. Co-delivery of siRNA with small molecules has shown improved efficacy.

Fig. Formulation of siRNA loaded matrix-based polymeric nanocarriers.

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 focuses on developing inhalable formulations as alternative non-invasive delivery systems. We have engineered natural polymer or phospholipid-based nanoparticles for targeting delivery drugs or siRNA to treat pulmonary disorders. We have also developed nanoliposomes, which could deliver drugs 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 the industry in their marketed products. 

Combination therapies

Combination therapy has shown advantages in its efficacy against various diseases. We have developed a unique synergistically acting multi-pathway targeting combination of siRNA with small molecule drug.

We utilized a 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 effects, etc., in the chemo and gene therapy.

Fig. Design of dual therapeutic agent loaded multifunctional receptor targeted nanocarriers. 

We have studied the therapeutic effect of drug and gene delivery systems for various diseases:

Lung cancer

Lung cancer is the USA’s top cancer killer and has barely reached 18% of the five-year survival rate. The research targets non-small cell lung cancers, 80% of total lung cancer cases [1]. We have been focusing on a few strategies utilizing multifunctional bioresponsive NCs coalescing with newer targets, combination therapy, gene therapy, and chemo-gene therapy. The designed NCs have utilized both microenvironments of tumor tissue and overexpressed receptors of cancer cells to enhance the efficacy against lung cancer.

Asthma

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 asthma symptoms, 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 newer target-specific drugs or genes to improve the outcome of asthma therapy and reduce the physical and economic burden of this disease on the patients.

Mesothelioma

Malignant mesothelioma is a very aggressive tumor linked to occupational and environmental exposure to asbestos, causing over 3,000 deaths per year in the USA [4]. 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 agent delivery to tumor tissues and overcome the limitations associated with conventional delivery.

Neuroblastoma

Neuroblastoma is the most common extracranial solid cancer in childhood and infancy with patients having an average age of 17 months [5]. Most are diagnosed with advanced stage Neuroblastoma when aggressive tumor progression makes treatment even more difficult [6]. 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, which will help improve skin disorder outcomes. Additionally, the Magnesium cream formulation investigated in my laboratory has been marketed by the 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.

References

1. Siegel, R., D. Naishadham, and A. Jemal, Cancer statistics, 2013. CA: a cancer journal for clinicians, 2013. 63(1): p. 11-30.
2. Barnes, P.J., New Drugs for Asthma. Seminars in Respiratory and Critical Care Medicine, 2012. 33(6): p. 685-694.
3. Mullane, K., The increasing challenge of discovering asthma drugs. Biochemical Pharmacology, 2011. 82(6): p. 586-599.
4. Robinson, B.M., Malignant pleural mesothelioma: an epidemiological perspective. Ann Cardiothorac Surg, 2012. 1(4): p. 491-6.
5. Maris, J.M., Recent advances in neuroblastoma. N Engl J Med, 2010. 362(23): p. 2202-11.
6. Modak, S. and N.K. Cheung, Neuroblastoma: Therapeutic strategies for a clinical enigma. Cancer Treat Rev, 2010. 36(4): p. 307-17.