Anti-cancer nanomedicine has been researched for decades. Traditional nanomedicine mostly uses nanoparticles as a carrier to deliver chemotherapy and gene therapy drugs. Although some nanomedicines have entered the clinical treatment of cancer, they still face many challenges. The main two obstacles are that nanoparticles may be taken up by normal tissues and cells, and nanoparticles have limited ability to penetrate solid tumors. Cancer immunotherapy, which activates the patient's own immune system for treatment, has made many breakthroughs in recent years. In particular, the advent of immune checkpoint inhibitor drugs has benefited many patients, but they still face challenges such as individual differences in efficacy and side effects. Considering that nanomedicine has the characteristics of protecting the drug from being degraded, extending the circulation time of the drug, and having a strong ability to be taken up by phagocytic immune cells, can nanomedicine enhance cancer immunotherapy? How does it help immunotherapy?
Overview Of Anti-Cancer Nanomedicine
Nanomedicine And Mononuclear Phagocyte System
The mononuclear phagocyte system (MPS) consists of a series of phagocytes residing in the liver, spleen, lymph nodes and bone marrow, which can swallow nanoparticles. After the nanoparticles enter the blood, their surface will quickly bind various proteins to form a protein crown, which contains many opsonins. Opsonin mediates the phagocytosis of nanoparticles by the MPS system. Previously, a large number of studies have been studying how to reduce the phagocytosis of nanoparticles by the MPS system, so as to extend the blood circulation time and enrichment of nanomedicine. Corresponding strategies include surface modification of nanoparticles, the most common of which is polyethylene glycol (PEG) modification. Many studies have shown that PEG modification (PEGylation) can extend the half-life of nanomedicine by preventing protein adsorption and phagocytes ingestion. In addition, another effective strategy developed in recent years is biomimetic, which wrap or modify nanoparticles through a series of cell membranes (white blood cells, tumor cell red blood cells) or self-recognizing peptides to extend the circulation time and enhance the accumulation of drugs in tumor tissues.
Renal Clearance of Nanomedicine
Another clearance mechanism of nanomedicine is renal clearance. Studies have shown that the size and charge of nanoparticles are decisive factors for renal clearance. Under normal circumstances, nanoparticles smaller than 6 nm are easier to clear through the kidney, and may be different due to changes in the structure of the kidney under pathological conditions.
Passive/Active Delivery of Nanomedicine
In the context of solid tumors, the enhanced permeability and retention (EPR) effect has become an important driver of cancer nanomedicine design and it has served as a key cornerstone of tumor-targeted drug delivery. Excessive pro-angiogenic signals at the tumor site result in highly irregular, highly heterogeneous, and porous tumor vessel walls (some pores up to several microns), which leads to the tendency of nanomedicine to leak from the tumor site blood vessel into the tumor tissue. In addition, due to the dense extracellular matrix of the tumor, the lymphatic system is damaged and the lymphatic drainage function is weakened, making it more difficult for nanoparticles to be cleared through lymphatic drainage. Although the passive targeting strategy based on the EPR effect has significant efficacy in preclinical models, it still faces many problems, including the heterogeneity of tumor blood vessels, the difference in EPR effect, and the uptake of drugs by tumor tissues and lung tumor cells. The active targeting strategy of modifying molecules targeting specific tumor surface markers on the surface of nanoparticles can solve these problems to a certain extent.
Enhance Delivery Of Nanomedicine To Tumor Sites
Based on advances in tumor biology, researchers have developed some methods to enhance the delivery of nanomedicine to tumor sites. For example, modifying special antibodies, targeting peptides and targeting molecules to promote the adhesion of nanoparticles to cancer cells to enhance tumor enrichment and uptake; targeting tumor stromal cells; targeting tumor blood vessels to prevent oxygen nutrient delivery; modifying tumor homing peptides; normalizing tumor blood vessel and stimulating and responsing to multi-level transport (using local tumor stimulation to change the size of nanoparticles or change the surface properties), etc.
Nanomedicine And Tumor Immunotherapy
Controllable Multiple Immune Response
Unlike chemotherapy, immunotherapy can stimulate a small number of immune cells in the body to rapidly proliferate for tumor detection and killing. The immune system is divided into the innate immune system and the adaptive immune system. Tumor immunotherapy involves the interaction of these two systems. On the one hand, innate immune cells (such as macrophages, dendritic cells, natural killer cells) can directly recognize and kill tumor cells through surface receptors. On the other hand, adaptive immune cells (T, B cells) generate cytotoxic T cells and antibodies that specifically recognize tumor cells through antigen presentation by professional antigen presenting cells (APC, macrophages, dendritic cells) to kill tumor cells. At the same time, in order to escape immune killing, tumor cells have also evolved a series of immune escape mechanisms: such as producing signal peptides (such as CD47) expressing "don't eat me" to avoid recognition by macrophages and dendritic cells; down-regulating immune activation signals ( such as MHC); recruiting immunosuppressive cells (such as regulatory T cells, bone marrow-derived suppressor cells); creating immunosuppressive tumor microenvironment through immunosuppressive cytokines, etc. Therefore, the simultaneous regulation of multiple signal pathways of tumor immunity helps to enhance the efficacy of immunotherapy. Nanoparticles have the advantages of simultaneously delivering multiple drugs, protecting drugs from degradation and interference, and tending to be taken up by innate immune cells, so they play an increasingly important role in tumor immunotherapy.
How Does Nanomedicine Mediate Tumor Immunotherapy?
At present, many studies have focused on nanomedicine-mediated tumor immunotherapy. Currently, the commonly used strategies are as follows: 1) Use viral proteins or antigens delivered by nanoparticles as tumor vaccines. Although it has curative effects in animal models, the shortcomings are obvious, that is, it cannot target tumors that do not express the antigen or antigenic variants, and there is a risk of autoimmune response; 2) Delivery of mRNA, siRNA and gene editing systems to interfere with gene expression of immunity cells, regulate the immune system, and promote anti-cancer immunity; 3) Use the properties of nanoparticles to stimulate the immune system, such as artificial APC based on nanoparticles; 4) Use bio-nanoparticles; 5) Use nano-drugs to suppress immunosuppressive signals.
At present, the main problems of tumor immunotherapy are: 1) It takes a certain period of time to produce a sufficiently strong anti-cancer immune response. For example, patients with a survival period of more than 6 months are more likely to benefit from immune checkpoint inhibitor therapy; 2) There are relatively large individualized differences in treatment effects. The patient's immune status, genetic information, living environment, tumor size, blood vessel and infiltrating T cell status all affect the efficacy; 3) There are certain toxic and side effects, mainly based on inflammatory reactions.
As a multifunctional drug delivery platform, nanomedicine can not only deliver immune system regulation drugs, but also deliver genes and gene editing systems for immune cell gene intervention to regulate immune system functions. Therefore, tumor immunotherapy nanomedicine can activate the innate immune system and the adaptive immune system at the same time, and activate the anti-cancer immune response by enhancing APC's recognition of cancer cells, enhancing T cell activation, weakening immune suppression signals, and allowing tumors to express tumor-specific antigens. From a research perspective, nanomedicine researchers may need to change the design strategy of nanomedicine, because traditional nanomedicine needs to avoid uptake by the immune system, while immunotherapy nanomedicine needs to selectively target specific immune organs or immune cells. In addition, the choice of model is also very important. Previous studies mostly used immunodeficient mice, but in the research of immunotherapeutic nanomedicine, immune animal models or patient-derived heterotopic tumor models are required. Of course, the cell population to be manipulated also needs to be carefully selected.
Nanomedicine may revolutionize cancer immunotherapy, and the continuous development and optimization of nanomedicine by researchers will inevitably accelerate the application of nanomedicine in cancer immunotherapy.
 Designing nanomedicine for immuno-oncology, Nature Biomedical Engineering volume 1, Article number: 0029 (2017)
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