Targeted Dual Drug Delivery System for Non-Small Cell Lung Cancer and other diseases of the Lungs

Web Published:
12/1/2011
Description:

Princeton Docket # 10-2608

Researchers in the Department of Chemical and Biological Engineering, Princeton University and in the Department of Pharmaceutics, Rutgers University have developed a targeted lung-specific delivery system which employs both passive and active targeting to intravenously deliver anti-cancer drugs to tumor cells as well as to reduce the occurrence of metastasis. The first layer of the delivery system is a gel microparticle (GMP) designed to take advantage of the venous lung filtration pathway and passively accumulate in the lungs after intravenous injection into the body. The second layer of the delivery system consists of two types of nanoparticles (NP) embedded in the GMP. The NP surfaces are decorated with ligands to actively target cancer cells. The first type of NP will be loaded with an anti-cancer drug, while the other type of NP will be designed to irreversibly bind to cancer cell surface receptors to inhibit metastasis. The release rate of the NPs from the GMPs into the tumor and the release rate of the anti-cancer drug from the NPs can be tuned to achieve the maximum desired effect. This dual-delivery system affords the ability to sustain a high concentration of anti-cancer drugs in the lungs while minimizing the systemic exposure and accordingly reducing the side effects. Additionally, it may actively prevent the spread of the cancer to other parts of the body.

 

Figure 1. Embedded with drug loaded nanoparticles (yellow) and metastasis inhibiting nanoparticles (green), the gel microparticle (blue) is trapped in a lung capillary (red). The nanoparticles are released overtime in the lung to kill cancer cells and prevent metastasis.

 Advantages

·          Unique targeting options to the lungs

·         Control of metastasis

·         Use of alternative delivery via the venous blood stream

·         Achievement of effective lung concentrations, while minimizing systemic exposure and toxicity

·         Adaptable to incorporate novel anti-cancer, TB, and COPD drugs

Commercial Applications

This dual GMP-NP delivery system has potential commercial application for treatment of Non-Small Cell Lung Cancer (NSCLC). The delivery system is versatile and can be easily adapted to incorporate novel, anti-cancer drugs as they are developed. This allows for the system to evolve with the molecular advances in medicine and remain a relevant treatment option for years to come. The biocompatibility and safety of the gel used have been tested and approved by the FDA, which minimizes the regulatory delay in implementing this new technology. The drug we propose to deliver, Camptothecin is a current standard of care and is FDA approved.

This technology could also be developed to treat other diseases of the lung such as asthma, tuberculosis and chronic obstructive pulmonary disease (COPD).

Stage of Development

Following a recent award from the NIH, a three year timeline to develop and test the effectiveness of the dual drug delivery system is proposed. The first step in creating the drug delivery system is to synthesize NP loaded GMPs that accumulate in the lung with minimal toxicity. To this end, the Sinko group at Rutgers has bounded the required size of GMPs to passively accumulate in rat lungs between 6 and 30 μm depending on the deformability of the particles. Current work is focused on using microfluidics to controllably create GMPs of the appropriate size and NP loading. Degradation of GMPs and subsequent release of NP is also being investigated. Once a suitable delivery system has been engineered, mouse studies will be undertaken to assess the toxicity and effects of GMPS on lung function.

The second step is to create the cancer targeting NPs and test the dual drug delivery system. The Prud¿homme group at Princeton has expertise in creating nearly mono-dispersed NPs loaded with hydrophobic drugs using Flash Nanoprecipitation (FNP). Additionally, the Prud¿homme group has previously created NPs via FNP with cancer targeting ligands on the surface. To create the drug loaded NPs, Camptothecin (CPT) will be incorporated into the NPs. CPT was chosen based on previous group experience with the drug. Two active targeting approaches that can be incorporated into NPs have been identified as possible routes to inhibit cancer metastasis. The first is to functionalize the NP surface with a ligand that will bind to specific cell receptors and prevent the pro-metastatic signaling pathway. The other is to load the NPs with chemical agents known to inhibit pro-metastatic signaling. Both cell and mice studies will be conducted to assess the efficacy of the drug delivery system to kill cancer cells and disrupt the pro-metastatic signaling pathway.


Background

The American Cancer Society estimated that in 2009, 1,479,350 new cancer cases would be diagnosed in the United States of which 219,440 would be lung and bronchus related. Although only the second most prevalent type of cancer, behind prostate and breast cancer for men and women respectively, lung cancer is the most lethal accounting for a projected 159,390 deaths in the United States. Non-small cell lung cancer (NSCLC), a subset of lung cancer, encompasses a set of diseases with similar prognosis and treatments. The standard treatments for NSCLC include surgery, chemotherapy, radiation, laser and photodynamic therapy, all with various success rates depending on the stage of the cancer. National Cancer Institute assesses, however, that results of standard treatment are generally poor with only a 15 percent 5-year survival rate for combined cancer stages. Challenges facing the current chemotherapy drugs include excessive toxicity to healthy tissues and limited ability to prevent metastases. The dual drug delivery system described herein aims to overcome these two challenges by selectively targeting the lung to deliver anti-cancer drugs and inhibit the formation of metastases.

The design of the human lung affords unique targeting options. Delivery via inhalation of anti-cancer drugs has been explored; however, low absorption and poor lung distribution of drugs has limited this avenue. A more promising approach involves passive targeting of the lung via the venous blood stream. The lung receives the entire venous blood supply from the heart and passes it through the intricate capillary beds on the alveoli. Large particles in the venous blood are thus trapped in these capillary beds. This filtering phenomenon can be used to selectively deliver particles to the lung. Such delivery methods have been safely employed in pulmonary perfusion diagnostic agents; however the use of this novel delivery route for chemotherapeutic drugs has not been appreciated or utilized by the drug delivery community. Initial IP for this mode of delivery has been filed by our collaborator, Dr. Patrick Sinko of Rutgers University, and additional IP on the production of nanoparticles and combination of the gel particles and specific drug formulations have been filed.

Principal Inventors

Robert K Prud¿homme

Professor Prud¿homme is Professor of Chemical and Biological Engineering, Department of Chemical and Biological Engineering and the Director, Program in Engineering Biology, at Princeton University. His research focuses on how weak forces at the molecular level determine macroscopic properties at larger length scales. Equal time is spent on understanding the details of molecular-level interactions using NMR, neutron scattering, x-ray scattering, or electron microscopy and making measurements of bulk properties such as rheology, diffusion of proteins in gels, drop sizes of sprays, or pressure drop measurements in porous media. The work is highly interdisciplinary; many of the projects involve joint advisors and collaborations with researchers at NIH, Argonne National Labs, CNRS in France, or major corporate research.

Professor Patrick Sinko

Professor Sinko is Associate Vice President for Research and Professor II (Pharmaceutics), and holds the Parke-Davis Endowed Chair in Pharmaceutics and Drug Delivery at Rutgers University. Dr. Sinko's research is focused on the mechanisms and applications of biopharmaceutics and polymers to drug delivery and targeting. Professor Sinko¿s research efforts focus on the design, fabrication and evaluation of molecular-scale drug and diagnostic delivery technologies applied broadly to asthma, AIDS, cancer, and chemical counterterrorism.

Professor Howard Stone

Professor Stone is the Donald R. Dixon and Elizabeth W. Dixon Professor of Mechanical and Aerospace Engineering at Princeton University. His research interests lie in the broad space of the dynamics of complex fluids, which encompass multiphase flows, colloid science, physical chemistry, biophysics, and physicochemical hydrodynamics. Using experiments, simulations, and modeling the objective is to quantitatively characterize problems and to explore new research directions. Whenever possible, we actively collaborate with industry and scientists and engineers from many disciplines. For example, these collaborations involve home and personal care products, oil-field services, fiber coating, float-glass manufacturing, and medical/clinical applications.

Intellectual Property and status:

Patent pending

Contact

Laurie Tzodikov

Princeton University Office of Technology Licensing ¿ (609) 258-7256¿ tzodikov@princeton.edu

PU #10-2620

Patent Information:
For Information, Contact:
Tony Williams
Princeton University
anthonyw@Princeton.edu
Inventors:
Robert Prud'homme
Patrick Sinko
Howard Stone
Nathalie Pinkerton
Lei Shi
Jiandi Wan
Sherif Ibrahim
Dayuan Gao
Keywords: