In the past two decades, several nanoparticles have reached clinic owing to their enhanced ability to transport active substances through our circulatory systems and increase the therapeutic index of the drugs. Nanoparticles selectively accumulate the tumor tissue following enhanced retention and permeation (EPR) effect that represents passive tumor targeting strategy. Incorporation of a targeting moiety to these nanoparticles further enhances the therapeutic efficiency by targeting the drug cargo to specific cells, by hijacking the specific receptors overexpressed on tumor surfaces. However, their physiochemical property, stability in blood, and interaction with blood components significantly alter their fate and therapeutic efficiency. After an intravenous (i.v.) injection, colloidal drug carriers are generally recognized as foreign bodies and quickly sequestered by opsonin proteins, and cleared from the systemic circulation by the mononuclear phagocyte system (MPS), mainly the Kupffer cells of the liver and macrophages of the spleen. Engineering nanocarriers using biopolymers or coating liposomes and micelles with these polymers would enhance its stability, induce stealth properties, increase biological half-life and thereby provide a significant improvement in therapeutic efficacy. Among different biopolymers, the natural polymers derived from our extracellular matrix are promising owing to their unique bioactivity. We have tailored several nanocarriers using the glycosaminoglycansthat were able to suppress drug mediated immune activation (ACS Appl. Mater. Interface, 2016, 8, 20614-24) and also mitigated multi-drug resistance developed by the cancer cells (Chem. Comm. 2016, 52, 966-69). We have also demonstrated efficient gene transfection by covalent coating of DNA/PEI binary complex with cancer targeting chondroitin sulfate polymer (Adv. Funct. Materials, 2015, 25, 3907-15). We are currently developing polymer coated lipid and micelle nanoparticles based dual-drug delivery systems for delivering small molecule drugs and nucleic acids.
Regenerative medicine that aims to restore the function of the damaged or diseased tissue/organ is of one of the fastest growing sciences with potential of new advancements in medicine. This technology involves novel materials that can be loaded with bioactive molecules that can trigger the natural tissues regenerative processes. A cornerstone of this technology relies on material design and methods to deliver bioactive molecule to specific sites in the human body. We aim to address this challenge by developing novel synthetic chemistry that can be performed under physiological conditions without any undesired toxic effects. Using glycosaminoglycans, we design new chemistries for tailoring extracellular matrix mimetic hydrogels for regenerative medicine and for 3D cell culture.
We have developed a hydrazone based stable click type chemistry using carbodihydrazide as a stable crosslinker, which does not undergo dissociation under physiological conditions. The hydrogel developed by this chemistry demonstrated excellent stability and in vivo bone formation (Adv. Funct. Mater. 2013, 23, 1273-1280). We are currently developing hydrogels mimicking brain tissue for encapsulating glioma cells and macrophages to study cancer cell-macrophage crosstalk, which is believed to be responsible for the progression of brain tumors.
Microencapsulation of islets cells, within stable ultra-thin membranes of maleimide-conjugated PEG-lipid (Biomaterials 2013, 34, 2683-2693)
Cell based therapies are becoming increasingly popular due to their enormous potential in treating diverse diseases, which cannot be achieved by traditional drugs. Among them insulin producing islet cells and mesenchymal stromal cells (MSCs) are most popular owing to their enormous therapeutic potential in treating diabetes and various inflammatory diseases respectively. We have recently demonstrated microencapsulation of islet cells using a PEG-phospholipid strategy (Biomaterials, 2013, 34 (11), 2683-2693). Over 5000 clinical trials involving the use of progenitor cell therapy have been performed or are ongoing showing the intense interest in stem cell-based therapies. However, significant hurdles must be overcome before unlocking the full potential of this strategy for clinical applications. As stem cell transplantation is well established for various medical conditions, such as for treating stroke, organ regeneration, myocardial infarction, graft-vs-host diseases (GVHDs) etc. enormous efforts are made to improve its efficacy. MSCs produce extracellular vesicles, including exosomes, and a multitude of cytokines and growth factors that suppress immune responses by inhibiting B- and T-cell proliferation and monocyte maturation and by promoting generation of regulatory T cells and M2 macrophages (Stem Cells, 2013, 31, 2042). Although MSCs are immunosuppressive, they are unfortunately not immunoprivileged (Nature Biotech, 2014, 32, 252). Infusion of these therapeutic cells into blood, results in triggering activation of innate immunity, causing rapid clearance of these cells from circulation (ActaBiomaterialia, 2016, 35, 194). Most of the cells undergo apoptosis and only 1-2 % of the infused allograft survives for over 24h, the fate of which is relatively unknown. Therefore, it is becoming clear that just the mere placement of cells in vivo is not enough to get the maximal therapeutic potential of stem cell therapy. We aim to improve the survival of MSCs and insulin producing cells upon transplantation in an invivo environment by encapsulating these therapeutic cells in a polyelectrolyte coat. Such encapsulation will allow permeation of nutrients and excretion of secretomes and anti-inflammatory factors, while protecting them against innate immunity.
Schematic representation of coating of material surfaces with bioactive peptides or polymers to mitigate adverse innate immune reaction
Innate immunity is fundamental to our defense against microorganisms and foreign substances and controls the discrimination between self and non-self-structures in the human body. As a consequence of its properties and actions, it is responsible for many of the incompatibility reactions that occur when nanoparticles, materials, cells, and organs are introduced into the body. These reactions pose a major problem when modern biotechnological treatment modalities are used, including biomaterial devices, drug delivery systems, various bioengineered implants, cell therapies, and transplantation. We have recently demonstrated that when Doxorubicin (a clinically used antineoplastic agent) was delivered via pH responsive gold nanoparticles coated with chondroitin sulfate, it completely mitigated Dox mediated thromboinflammation and platelet aggregation in human whole blood (Chem. Comm. 2016, 52, 966-69). We are currently developing strategies to coat material surfaces with specific intravascular innate immune regulator molecules and polymers that will silence the adverse reactions of innate immunity without compromising the function or compatibility of the treated surfaces.
With our core competence in organic chemistry and polymer chemistry, we strive to develop novel bioconjugation strategies, which could be performed under physiological conditions. We have recently discovered the role of acetates in catalyzing Oxime-coupling reaction under neutral condition which could not be achieved without aniline as catalyst (Chemistry-A European Journal 2015, 21, 5980-5985).We explore these novel reaction conditions for engineering new materials with tailored biophysical properties.