Polymeric nanoformulations for drug delivery to treat cancer

 

In 1989 we pioneered use of polymeric micelles for targeted drug delivery. We further discovered sensitization of multidrug resistant cancer and cancer stem cells by Pluronic block copolymers and established mechanisms responsible for these effects. This research led to first-in-man polymeric micelle drug candidate to treat cancer (SP1049C) that has shown high efficacy against advanced esophageal cancer in phase II clinical trial. Our recent work in this field discovered polymeric micelles based on amphiphilic poly(2-oxazoline) block copolymers with unprecedented high capacity for poorly soluble uncharged drugs (e.g. taxanes) and drug combinations. Such polymeric micelles allow 1) increasing therapeutic index compared to existing drug formulations and 2) “rescuing” highly potent but insoluble drug candidates that failed due to formulation and drug delivery. We have also used ionic block copolymers to develop cross-linked polymeric micelles and nanogels to deliver otherwise “impossible” combinations of hydrophobic and ionic molecules for combination therapy of cancer. Our current projects focus on understanding the structure-functional relationships that govern 1) the micelle loading with the drugs, 2) the targeted delivery of the drug-loaded micelles to the tumors and 3) the drug release to efficiently kill drug resistant and cancer stem cells and disrupt the tumor microenvironment. This work provides basis for developing highly efficient combination therapeutics to treat cancer, which we then translate to clinical evaluation in collaboration with scientists at the Lineberger Comprehensive Cancer Center.

Protein, drug and gene delivery to central nervous system (CNS)

 

The challenge of the delivery of therapeutic molecules (low molecular drugs, proteins and nucleic acids) to the brain is well recognized. Low permeability across the blood-brain barrier (BBB), and low serum bioavailability and stability of these molecules (especially of therapeutic proteins, siRNA and DNA) tremendously limit their effective amounts that can enter the brain. Our current work focuses on cutting edge polymer therapeutics and nanomedicines that address this problem by enabling efficient delivery of various therapeutic molecules to CNS after systemic and intranasal administration. We invented and develop novel technologies such as 1) modification of proteins with amphiphilic block copolymers that help proteins crossing BBB, 2) incorporation of small drugs, proteins and siRNA in polyion complexes and exosomes that increase delivery of these molecues to various brain regions; and 3) use of macrophages loaded with nanoparticles and genes that migrate to sites of inflammation in the brain and release their payloads in the disease affected areas. We focus our research on obesity, stroke, neurodegenerative and neurodevelopmental diseases. Examples of the current projects include 1) modified forms of gut-brain-hormones to control appetite in overweight and obese populations; 2) delivery of neurotrophins to treat RETT syndrome and stoke; and 3) gene delivery of antioxidants and neurotrophins to the brain neurons to treat Parkinson’s disease. We strive to bring our innovative technologies to human clinical trails to develop therapeutics for devastating human diseases that currently do not have treatment option.

Remotely controlled nanomedicines

 

From the standpoint of the drug delivery science the nanomedicine tasks include 1) efficient loading of the drugs or biomacromolecules into a nanoparticulate carrier, 2) safe delivery of the loaded carrier to the target organ and/or cell in the body, and 3) timely release of the payload. Selected nanomaterials are being themselves sought as therapeutic, diagnostic or theranostic modalities that in some cases need to be actuated at the site of the action. The first task – loading has been addressed very well, for what purpose scientists initially adopted nanoscale structures already discovered by polymer and material sciences and then followed up by invention of the whole range of new nanomaterials specifically tailored for the drug delivery purposes. The second task remains a field of active research and discovery, where we have lately seen some successes and can reliably deliver the therapeutically effective doses of some major anti-cancer and other medications using nanoformulations. The third task has not been addressed and is the field where the advances are very much needed. Of particular interest are remotely actuated theranostic drug delivery systems. They represent a class of multi-modal systems, which contain an agent that is responsive to external stimuli, an imaging agent and a polymer matrix. Our research focuses specifically on magnetic field responsive superparamagnetic nanoparticles. Exposure of such nanoparticles to alternating current (AC) magnetic fields results in mechanical actuation of the particles and can trigger changes in structure of the surrounding materials at the nanoscale. The motion of the particles generates forces acting upon the surrounding materials and induces drug release, as well as molecular deformation of the connected molecules, which is great interest in many therapeutic applications. Taken together the imaging capabilities and the remote actuation of nanoparticles allow creating cutting-edge multi-modal theranostic systems for treatment of cancer and other diseases.