Research activities: an overview
Advanced nanomaterials, which stand to revolutionize biomedical science, depend on chemical innovation for optimization of their overall structure and properties. Kakkar Group focuses on simplifying synthetic schemes to uniform and well-defined nanostructures that can perform pre-determined multiple tasks cooperatively and efficiently. For example, a synergistic combination of select functions including solubility, controlled release, delivery, targeting, imaging etc., is essential in addressing complex biological problems. Using a synthetic toolbox that has building blocks with orthogonal functionalities on which high yield chemical reactions can be performed with great efficiency, we can now assemble a variety of multifunctional nanocarriers. We use two platforms based on macromolecules and metal nanoparticles, and apply them in a convergent manner to address key issues in drug delivery and diagnostics. Our choice of miktoarm stars and dendrimers relates to mediating multiple functions by molecular encapsulation or covalent linking, or combinations thereof (telodendrimers). The synthetic routes carved in our laboratory have laid the foundation in simplifying the synthesis of such complex architectures. Our research projects combine organic synthesis with materials chemistry and biology. We have on-going collaborations with researchers at McGill (Professor Dusica Maysinger, Department of Pharmacology; Professor Theo van de Ven, Chemistry), Ecole Polytechnique (Professor Frederic Lesage), Montreal Heart Institute (Dr. Eric Rheaume), and Massachusetts Institute of Technology (Professor Robert Langer).
Read some of our review articles that highlight the role chemistry is playing in designing smart nanomaterials for a variety of applications:
- Nat. Rev. Chem. 2017, 1, 0063
- Environmental Science: Water Research & Technology, 2016, 2, 71
- Molecules 2015, 20, 16987
- Chem. Comm. 2011, 9572
- Chem. Soc. Rev. 2010, 39, 1536
- Polym. Chem. 2010, 1, 1171-1185
Macromolecules for Drug Delivery
Miktoarm polymers constitute a relatively new entry to the macromolecular field. However, with the recent advances in the synthesis of miktoarm stars, the scope of their applications in biology is fast expanding. We have recently developed a “plug and play” coupling method for the rapid synthesis of ABC and ABn type miktoarm polymers. It is based on chemically stitching, one arm at a time, on the core building blocks containing orthogonal functional groups. The compositions of the arms are pre-defined based on the desired function, and this versatile methodology provides complete control on the overall composition of the star polymer. These branched polymers self-assemble into spherical micelles, and we have demonstrated their potential in building nanocarriers for a diverse range of small molecules. For example, the effectiveness of drugs such as nimodipine (NIM), commonly prescribed for neuroinflammation, is quite limited, due to several factors including very poor aqueous solubility.
We demonstrated that our star-polymer-based micelles i) provide highly efficient loading of NIM; ii) substantially enhance its aqueous solubility, and iii) the release and targeting of NIM to the inflamed tissue in the brain can be easily controlled. In a recent study, we have demonstrated that micelles obtained from asymmetric AB3 miktoarm stars are highly efficient in encapsulating curcurmin, retaining its biological activity, and in their ability to effectively kill glioblastoma cells in three-dimensional spheroids. Miktoarm-star-based nanocarriers now offer opportunities to test them in vivo in animal models of inflammation.
Read more on the scope of Miktoarm polymers in drug delivery described in select articles below:
Dendrimers constitute a topical area of research in macromolecular chemistry for a wide variety of applications. Much of the emphasis has been on developing methodologies to higher generation dendrimers, and subsequently functionalizing their surfaces with appropriate task performing units. To evaluate structure property relationships, and to simplify the process of introducing multiple functionalities into well defined dendrimer based nanostructures, we have introduced a methodology based on our core with orthogonal functionalities, and highly efficient “click” chemistry. It offers a powerful tool to introduce solubilizing, targeting, imaging and therapeutic agents, in any desired combination and composition. We have demonstrated that such nanocarriers can selectively target and label specific cytoplasmic organelles. Following the path and determining the ultimate fate of a nanocarrier are essential parameters for developing highly efficient therapeutic interventions. Macromolecules with built-in imaging capability enable tracking their passage for a better understanding of their circulation and efficient delivery of desired relief agents. Using our synthetic toolbox, we have contributed a strategy to traceable dendrimers. We have also developed a synthetic methodology which combines alkyne-azide and Diels-Alder “click” reactions in designing thermoresponsive dendrimers. This approach is particularly interesting in developing programmed formulations which can deliver the covalently linked drugs via retro-Diels-Alder disassembly at physiologically relevant temperatures.
Block-copolymers, miktoarm stars and dendrimers have been extensively studied for drug delivery, and they have offered distinct advantages through physical encapsulation and covalent linking of active pharmaceutical agents. By designing a hybrid nanocarrier, one could integrate important characteristics of these individual macromolecules in a single framework. We have developed a simple and easily adaptable methodology to architectural polymers (telodendrimers). It merges modularly functionalized dendrons with linear polymers (linear-dendritic block co-polymers) and miktoarm polymers. These telodendrimers offer considerable potential in combination therapy, and we could load two drugs that work via different mechanisms through covalent linking and encapsulation. A recent paper on telodendrimers describes this combination therapy approach: Mol. Pharm. 2017, 14, 2607
Naked Nanocarriers: Macromolecules as therapeutics
During our investigations of drug delivery using miktoarm polymers and dendrimers, we were intrigued to find that these macromolecules without any encapsulated or covalently linked drug molecules could act as anti-inflammatory agents. Through a detailed study that combined biological evaluation with molecular modeling studies, we have demonstrated that their size, build-up, and surface properties play a key role in their therapeutic efficacy. This new platform stands to simplify drug discovery. Read more on naked nanocarriers: Mol. Pharm. 2013, 10, 2502
Metal Nanoparticles For Diagnostics
For any effective therapeutic intervention in high morbidity rate diseases, parallel developments in diagnostic tools that can help us evaluate the disease sites, monitor drug efficacy, and help detect these diseases at an early stage, are required. Multiple imaging modalities are playing a key role in this regard. With the goal of developing a high resolution multimodal imaging probe, we have taken the cue from our studies on miktoarm polymers and dendrimers, and we are using these methodologies to develop two unique platforms: gold nanoshells for photoacoustic, and iron oxide nanoparticles for magnetic resonance imaging. Our goal is to mediate multiple functions on these nanostructures by surface modification. We have developed a simple methodology to decorate gold nanoshels and iron oxide nanoparticles with designed multifunctional miktoarm or dendron based ligands which incorporate therapeutic, fluorescence imaging and stealth agents on their surfaces. Multimodal molecular imaging has the potential to improve the accuracy of imaging protocols by enabling the visualization of distinct surrogates simultaneously.
We are now developing novel methodologies to link two gold nanoshells at an optimal distance using our miktoarm and dendrimer based ligands. The contrast mechanism based on plasmon resonance energy transfer between pairs of gold nanoshells is expected to yield increased photoacoustic specificity in blood rich environments.
Read more on these metal nanoparticles and their interesting dual imaging properties: