Periodic Reporting for period 4 - SCoTMOF (Combined Chemo- and Radiotherapies by Controlling the Surface Chemistry of Truncated Metal Organic Framework Nanoparticles)
Période du rapport: 2021-03-01 au 2022-08-31
The project intends to address current deficiencies in cancer therapy by preparing new types of drug delivery vehicles; tiny particles capable of delivering chemotherapeutic agents directly to tumour sites. As most anticancer drugs are unselective in their toxicity – they kill healthy cells as well as cancerous ones – side effects of treatment can be very harmful, including hair loss, kidney damage, long term sickness, etc. If the active compound can be encapsulated in a targeted carrier, then it will not interact with healthy cells as it travels to the site of disease, where it can release the drug and destroy the cancer. This concept of drug delivery promises to reduce the dose of drugs required, mitigate harmful side effects, and also widen the range of drugs that can be used, in particular allowing unstable or poorly soluble drugs to access disease. The project is developing a class of materials known as metal-organic frameworks (MOFs) for drug delivery. MOFs are network solids composed of metal nodes and organic linkers, which, on the molecular scale, resemble grids or meshes. The structures have significant empty space in their interiors, and so can absorb remarkable quantities of molecules such as drugs, and can be thought of as “nanosponges”. MOFs are ideal for drug delivery, as they have high loading capacities for drugs, and can dissociate in the body into their respective components which can be completely non-toxic. Our project seeks to develop methods to control particle size, as drug delivery agents need to be <150 nm (i.e. nanoparticles) in size to avoid blocking veins and capillaries in the body, and to control their surface chemistry, which will allow tuning of stability, incorporation of targeting functionality to direct the MOFs to specific tumours and machinery to allow release of the drug upon response to stimuli found only in cancerous cells. Our objectives are development of new methodology to control synthesis of MOFs and their size and surface chemistry, interfacing of MOFs with biomolecules such as peptides and DNA to provide targeting properties and “stealth” protection towards enzymatic degradation, incorporation of molecular machines to control drug loading and release, and using the inherent properties of the metals that link the MOFs for imaging (e.g. MRI) to allow simultaneous monitoring and treatment of cancers. The project is clearly important for society, as >1/3 of the world’s population will receive treatment for cancer in their lifetime. Any improvement in treatment efficiency or reduction in side effects will have great impact on the health of the world’s population. Additionally, the fundamental information gained from the project could influence other proposed applications of MOFs in carbon dioxide capture and green energy, to name only two, which are pressing societal problems.
We have developed a new methodology for the surface functionalisation of MOFs linked by zirconium, wherein a monotopic linker (a modulator) containing a pendant functional group is added to syntheses to cap particle growth. These modulators allow fine control of particle size and are incorporated on the surfaces of the particles, presenting a functional group which can be used to attach a variety of molecules to the surface of MOF. The process, which we have termed “click modulation”, has allowed surface modification with a variety of polymers to enhance stability of the MOFs and control release of cargo by pH. We are now in the process of extending this protocol to MOFs linked by iron and scandium, which is leading to the elucidation of fundamental information on how these MOFs grow and self-assemble. We have focussed mostly on exploiting Zr MOFs for drug delivery, showing that surface chemistry has a dramatic impact on delivery of cytotoxic cargo and thus therapeutic efficiency in in vitro assays. By tuning the functionality on the outer surfaces of Zr MOFs, we have found it possible to modify the primary endocytic mechanisms, and so by changing how cells take up nanoparticles, we can direct the nanoparticles to different locations within the cell. For example, incorporating poly(ethylene glycol) chains biases uptake towards caveolae-mediated uptake, avoiding degradation in the lysosome, and allowing efficient delivery of drug cargos in to the cytosol rather than rapid excretion after clathrin-mediated uptake and allowing for selective anticancer cytotoxicity. We have also shown that targeting functionality can be included through surface modification which has allowed us to directly target the mitochondria to enhance the activity of specific drugs which act upon these organelles. This kind of fundamental mechanistic information is key as we seek to develop candidates that may be used in in vivo experiments. We have also shown that it is possible to deliver multiple drugs in a single device, which enhances efficacy towards certain cancers, and begun to examine Zr MOFs which are linked by endogenous ligands. In particular, Zr fumarate MOFs have shown to induce no negative immune system response in lymphocytes and in cytokine secretion suggesting they will be better tolerated by humans. We have also developed new methods to monitor in vitro cytotoxicity in real time, and in doing so uncovered particular release properties depending on whether drug cargos are stored on the surfaces or pores of the MOF nanoparticles.
Overall we have made significant nanotechnological advances in the complexity of MOF nanoparticles, incorporating functionality which has bestowed them with specific cell targeting properties, we have modified their uptake mechanisms, and also targeted specific intracellular organelles. We have also made advances in the drug delivery aspect, including developing simple methodologies to deliver cocktails of anticancer drugs from one nanoparticle. New methodologies have been developed to allow us to understand compositional parameters that control MOF biocompatibility, and also applied state-of-the-art protocols to monitor interactions with cells in real time. Future work will look towards in vivo translation.
Overall we have made significant nanotechnological advances in the complexity of MOF nanoparticles, incorporating functionality which has bestowed them with specific cell targeting properties, we have modified their uptake mechanisms, and also targeted specific intracellular organelles. We have also made advances in the drug delivery aspect, including developing simple methodologies to deliver cocktails of anticancer drugs from one nanoparticle. New methodologies have been developed to allow us to understand compositional parameters that control MOF biocompatibility, and also applied state-of-the-art protocols to monitor interactions with cells in real time. Future work will look towards in vivo translation.
Significant progress has been made, with a number of publications showing that we are making inroads well beyond the state-of-the-art. We have developed a new surface functionalisation technique – click modulation – and used it to prepare Zr MOFs with unprecedented levels of control and surface functionality. In doing so, we have uncovered key fundamental concepts that govern the interaction of MOFs with cells, and so can begin to tune cytotoxicity based on chemistry of the MOF rather than the drug. We have developed defect-loading of drugs into Zr MOFs, allowing high drug loading values and secure trapping of cargo. We are also elucidating new data on self-assembly of a variety of MOFs, which has broad implications well beyond the scope of the project. Publications detailing fundamentals of Fe and Sc MOFs show that we are leading the field in probing self-assembly mechanisms and preparing new materials – we expect a significant body of work to come from these new results. As the project matures, we expect to continue to develop this fundamental understanding while applying it to the assembly of ever more complex materials targeted towards specific cancers, with fine control over reproducible, green synthesis of materials as we aim to take the MOFs towards in vivo experiments.