Team:iBowu-China/Implementation
Proposed Implementation
Goal: To provide a targeted magneto-thermic therapy for multiple cancers.
Considering the side effects and poor efficacy of chemotherapy, we thought of a novel treatment. We aim to develop a liposomal delivery system expressing magnetic protein crystals (MPCs) as a novel magneto-hyperthermia tool. In addition, this system can be adapted to different targets for specific therapeutic purposes through various modifications. We have also designed a triple security mechanism to strengthen the targeting. Overall, this novel treatment can not only reduce the risk of off-targeting but can also be easily transformed into a widely applicable tool.Proposed Users
To put our scientific design into clinical application, we choose non-small cell lung cancer (NSCLC) patients as our proposed end-users, especially lung cancer patients with mutation site EGFR. NSCLC is the leading cause of cancer-related deaths worldwide. The survival rate of lung cancer patients is much lower than other prevalent cancers. Lung cancer can be divided into two major pathological types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), among which NSCLC accounts for more than 80% of all kinds – squamous cell carcinoma, large cell carcinoma, adenocarcinoma, and other histological types.
Figure 1: Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two main types of lung cancer. Among these, 85-90% are non-small cell lung cancer.
Drug Development: Pre-Clinical Study
Our team developed a therapy based on magneto-hyperthermia to solve the existing problems surrounding magneto-hyperthermia therapy – targeting, thermogenesis efficiency, and clinical application. We designed a vector that codes for magnetic protein crystals (MPCs) through the use of a tumor-specific promoter. Liposomes with surface PEG and GE11 modifications carrying MPC vectors will target NSCLC cells. After transfection, targeted tumor cells will express MPCs, which enable the binding of iron. Iron-loaded MPCs will then respond to localized alternating magnetic fields and induce cell death. The active targeting ligand, tumor-specific promoter, and localized alternating magnetic fields provide triple targeting security. The advantage of magneto-hyperthermia is the capability to place the heat source directly at the target region. Localized hyperthermia addresses a small area, such as the tumor per se. Therefore, the utilization of magnetic materials right at the tumor site is expected to improve the therapeutic effectiveness. Ferrite magnetic nanoparticles are also considered ideal candidates for magnetic hyperthermia therapy because of their good biocompatibility and stability. Currently, we completed the in vitro isolation and purification of the MPCs with successful confirmation of their magnetism. The successive steps are to control the MPCs’ size, add the internal targeting ligand, and experiment the targeting capabilities in vivo. However, the current heat generation efficiency of magnetic nanoparticles in the radio frequency range is still relatively low. In addition, the targeting efficiency of drugs through a delivery system still needs to be improved. In addition to confirming the effectiveness, safety is another essential factor in moving from cell experiments to animal experiments. The hepatotoxicity of liposomes and the possible risk of off-targeting may cause the project to fail. Furthermore, optimization of the delivery system is another aspect we need to address. Modifying the PEG successfully, improving the loading efficiency of liposomes, and reducing the empty packet rate are all aspects we need to consider. We need to continually optimize our therapy to get safe and useful data to apply to CFDA/FDA for IND(Investigational New Drug).Drug Development: Clinical Trials
Assuming that we can obtain the expected data before the clinical trial, we will prioritize the initiation of unregistered clinical trials(Non-IND) before registering for the formal clinical trial to reduce the research and development cost. In the non-IND phase, we will focus more on the efficacy of the treatment itself and the safety aspect. The subsequent clinical registration phase will be similar to that of other drugs: Stage I – pharmacology and human safety evaluation experiment, observation of human tolerance to drugs and pharmacokinetics, formulation of drug administration protocol; Stage II – Evaluation of drug efficacy and preliminary assessment of the efficacy and safety of the drug in patients; Stage III – Investigation with a larger group with longer follow-up time to evaluate the relationship between efficacy and risk, confirm the efficacy and safety of the treatment and assess its suitability for commercialization. Because our therapy is a form of targeted gene therapy, we need to consider the target population and the unknown risks that gene therapy may bring. During the clinical trial, we can use pharmacodynamic, genomic, and proteomic studies to evaluate the treatment efficacy to better select patients who can benefit from this treatment. Finally, if all criteria have been met, we will commercialize our product and retail it as a novel treatment for cancer patients.Safety Considerations
One safety consideration is the process of liposome encapsulation and modification, which may undesirably change the structure and property of the MPCs’ DNA. The regulation of the external alternating magnetic field's magnetic forces is also a safety issue we are seeking to address. Moreover, although this treatment doesn't have as many side effects as chemotherapy, we are still uncertain regarding the effects of it growing inside mammalian cells. Off-targeting may also occur, leading to therapeutical failure.This year, several cases of death caused by high-dose AAV gene therapy have been reported, stressing the importance of safety regarding gene therapy. Our project's liposome delivery system can also be hepatotoxic, so the dose safety assessment is critical in the following experiments.
Challenges
One challenge is that it will take a long period to research and develop MPCs products, which will invest a lot of manpower and resources. Then, the production technologies – liposome creation and PEG modification – need to be improved. Quality control during production is also essential.Another challenge that society and patients will have to face and deal with is the rapidly increasing costs of this new treatment. Also, in the process of mass production, the same challenges will arise. Hence, it is necessary to make an adequate clinical judgment to balance efficacy with costs.
Finally, competition in this field is fierce, forcing us to accelerate our research and development process.
Applications
Firstly, we hope our product can be used in the clinical treatment of patients with NSCLC. Our strategy provides a feasible method for enhanced targeted therapy with minimal side effects and a triple targeted mechanism in our design.Secondly, with this availability of different targeted therapies, tailored treatments must be administered according to the patient’s comorbidities and characteristics. In our design, the same magnetic protein sequence can be matched with different tumor-specific promoters, surface modifications, and the localized alternating magnetic field's location to target other types of cancers. Our product can be created based on tumor genetic profiles, making treatment selection for patients much more personal and practical.
In addition, many conventional therapies can be combined with magneto-hyperthermia schedules, and the combination can bring more therapeutic effectiveness into clinical practice.