A team of researchers at the Frederick National Laboratory for Cancer Research (FNL) has developed a nanotechnology platform which targets the lymphatic system, an approach that could provide more effective treatment and therapies against infectious diseases and cancer.
The platform is based on poly(L-lysine succinylated) (PLS) polymer, a biodegradable polymer of the amino acid lysine where all the lysine side chains have been functionalized with succinyl groups. This modification gives the platform broad versatility, enabling derivatization with therapeutic and imaging agents through conjugation chemistry.
In addition to developing a site for genetic material exchange, the Nanotechnology Characterization Laboratory (NCL) discovered that these succinyl groups target scavenger receptor A1 (SR-A1), a cell surface receptor highly expressed on the cells lining the vasculature and myeloid cells within lymph nodes.
The PLS prodrug platform’s targeting highlights the unique potential of tissue selective, nanotechnology-based drug delivery to fight disease.
Platform’s ability to target enhances drug treatment
By targeting the scavenger receptors, the platform is able to target the lymphatic system, the body’s primary defense system for mounting immune responses against diseases and foreign pathogens. The system is also a major conduit by which immune and cancer cells travel throughout the body, so a drug delivery system capable of targeting the lymphatics can have broad applicability in fighting a host of diseases.
Cancer, for instance, uses the lymphatic system to metastasize, spreading from its original site to other parts of the body. This spread is the leading cause of cancer deaths. The immune system is also central to body’s fight against cancer, and immunotherapy is a primary focus of new cancer medicines.
The PLS platform technology’s targeting effect can improve therapy by increasing the target tissue drug concentrations and reducing systemic drug toxicities, increasing a drug’s therapeutic index.
Most diseases have an inflammatory component, including conditions such as atherosclerosis and autoimmune disorders, like rheumatoid arthritis. These could all potentially leverage a drug delivery system that directly targets the lymphatics and immune cells, further expanding the possibilities for this nanotechnology.
Nanotechnology has long held the promise of improving therapeutic outcomes of cancer and other diseases by actively altering drug distribution. However, there are few examples of nanotechnology-based targeting platforms that have moved beyond preclinical evaluation, and none have yet been approved for clinical use. Current nanomedicines and conventional drug formulations on the market today do not actively target lymphatics, and this leads to suboptimal lymphatic-drug concentrations and ultimately less effective treatment.
This PLS technology affords several potential advantages over current nanomedicine therapies. In addition to the active targeting capabilities, the chemistry is simple and highly adaptive. A broad spectrum of small molecules, nucleic acids, peptides, and other therapeutic and imaging agents can be attached with high drug loading efficiency. Most of the current nanomedicines available today suffer from poor release kinetics, either being too stable, which results in poor efficacy, or too unstable, which results in off-target toxicities. The controlled drug release properties of the PLS prodrug concept afford ideal drug release profiles, with release half-lives of 10-40 hours, allowing for delivery and release of active drug within the lymphatic tissue.
Collaboration furthered prodrug platform potential
The technology was originally discovered by NCL Director of Research and Development, Stephan Stern, Ph.D., and formulation scientist David Stevens, Ph.D., but development quickly evolved into a collaborative effort.
NCL’s initial in vivo studies in mice demonstrated lymph node accumulation of the PLS platform within four hours using ex vivo fluorescence imaging and immunohistochemistry. With lymph nodes being the primary reservoir for latent HIV infection, Stern sought out partners with expertise in this area for further exploration and development.
Partners included Jacob Estes, Ph.D., chief of the Division of Pathobiology & Immunology in the Oregon National Primate Research Center (formerly of FNL’s AIDS and Cancer Virus Program) and Angela Kashuba, Ph.D., director of the Clinical Pharmacology and Analytical Chemistry Core in the UNC Center for AIDS Research. Through this collaboration, the three groups explored a proof-of-concept formulation for treatment of HIV.
The researchers first conjugated emtricitabine, a reverse transcriptase inhibitor used for treatment of HIV, to the PLS platform. They then explored properties of the new drug both in vitro and in vivo.
In vitro studies showed controlled drug release and conversion to the active metabolite, necessary for lymphatic delivery and therapeutic activity, respectively. Pharmacokinetic studies in rats further demonstrated increased drug concentration within lymphatic tissue, an order of magnitude greater than the free emtricitabine comparator. Full details of these studies were recently published in Molecular Pharmaceutics.
While the group continues to explore the full potential of the emtricitabine PLS prodrug in HIV treatment, Stern and the team are excited for the prospects of this technology, and are seeking collaborations to further develop it.
“The PLS prodrug platform has tremendous potential for not only treating infectious diseases such as HIV, but also applications including cancer therapy, vaccine delivery, immunomodulation and lymphatic imaging.” Stern said.Tagged: