Nanoparticle Drug Delivery System for Tumor Immunotherapy

Tumor immunotherapy uses immunological principles and methods to activate and enhance the ability of the body's immune system to recognize, attack and clear tumor cells and inhibit tumor growth. At present, tumor immunotherapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cells (CAR-T) have shown strong anti-tumor activity in the treatment of tumors such as melanoma and non-small cell lung cancer. Various tumor immunotherapy drugs such as PD-1 antibodies have successfully entered the clinical application stage. However, the in vivo delivery of tumor immunotherapy drugs still faces challenges, such as poor tumor permeability and low tumor cell uptake rates, which affect the effectiveness of tumor treatment. Nanodrug delivery systems can improve the retention, accumulation, penetration and uptake by target cells of drugs in tumor sites, and achieve controllable release of drugs in tumor extracellular matrix or tumor cells, improve the efficiency of regulating immune responses, and enhance the effect of tumor immunotherapy. This article reviews the achievements of nanodrug delivery systems in the field of tumor immunotherapy research in recent years, and also looks forward to the main challenges and development directions in this field.

What is a nanoparticle drug delivery system?

Nanoparticulate drug delivery systems refer to particles with a particle size of <100 nm or materials with a particle size of 100 nm to 1000 nm but exhibiting nanoparticle properties. According to the material composition, nano-drug carriers can be divided into organic drug carriers, inorganic drug carriers, biomaterial drug carriers and composite drug carriers. The enhanced permeability and retention effect (EPR effect) unique to tumor tissue enhances the accumulation of nanopharmaceutical delivery systems at tumor sites, thereby improving the bioavailability of antitumor drugs and reducing their side effects. With the continuous development of nanotechnology, nanoparticles are more widely used in basic research and clinical applications in tumor treatment.

Structure of lipid nanoparticle-nucleic acid carrier. (Zhou, Q.Q., 2021)

Advantages of nanoparticle drug delivery systems

Compared with traditional drugs, nanoparticle drug delivery systems have the following advantages for tumor treatment:

Delivery of drugs with different physical and chemical properties. For example, it can improve the solubility of hydrophobic drugs, enhance the blood circulation half-life of drugs, or effectively deliver nucleic acid drugs with high charge density. Most anticancer drugs are hydrophobic, such as paclitaxel, doxorubicin, methotrexate, etc., and are difficult to pass through the water environment around cells and pass through the cell membrane to reach the target of action in cells. Therefore, effective doses of such drugs in clinical use often lead to serious toxic side effects and drug resistance. A nanocapsular capsule developed by Zhao et al. can efficiently load paclitaxel (loading rate is about 76%), effectively inhibit tumor growth and vascular proliferation in paclitaxel-resistant tumor models, and has no obvious systemic toxicity.

Deliver multiple types of drugs at the same time to improve drug targeting and achieve efficient collaborative treatment of tumors. Jia et al. have built a nanodrug delivery system loaded with both CD47 siRNA and CCL25 chemokine protein, which can release CCL25 protein in tumor extracellular matrix and release CD47 siRNA in tumor cells, achieving the control of CCR9+CD8+ T cells While actively infiltrating into tumor tissue, it blocks the CD47 signaling pathway at the tumor cell immune checkpoint, effectively enhances the T-cell-mediated anti-tumor immune response and inhibits the growth and metastasis of triple negative breast cancer tumors.

Achieve controlled release of drugs. Using the sensitive characteristics of different nano-drug carriers to pH, light, temperature, etc., different types of stimulus-responsive nano-drug delivery systems are designed to achieve precise delivery and controlled release of drugs, thereby improving drug utilization and reducing toxic side effects. Neshat et al. have developed a DNA-based pH-responsive drug delivery system for collaborative cancer treatment. The system is based on a three-strand DNA nanoswitch that responds precisely to pH changes in the range of 5.0 to 7.0. Under the physiological pH conditions outside the cell, the DNA nanoswitch maintained a linear conformation and statically carried antisense DNA of three different types of drugs, adriamycin, cisplatin and survivin gene. Upon endocytotic uptake by tumor cells, the acidic environment of the lysosome causes the nanoswitch to undergo a conformational change from linear to three-strand, enabling intelligent drug release, efficient target gene silencing, and significant tumor growth inhibition.

Achieve diagnosis and treatment of tumors simultaneously. Liang et al. have developed a Fe3+ complex nanoparticle. On the one hand, this system can be used as a contrast agent for magnetic resonance imaging, and on the other hand, it can synergistically show good optical absorption in the infrared and near-infrared regions, thereby achieving photothermal treatment of tumors.

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Nanoparticle uses in tumor immunotherapy

Nanoparticles eliminate immune escape from tumor cells

Tumor cell death events that promote anti-tumor immune responses are called immunogenic cell death (ICD). ICDs are mainly mediated by damage-associated molecular patterns (DAMP) released by apoptotic cells, such as adenosine-triphosphate (ATP) and high mobility group protein (HMGB1), calreticulin and heat shock protein (HSP90). Tumor cells that undergo immunogenic death promote the activation of antigen-presenting cells through the released DAMP, thereby increasing the activation of antigen-specific T cells, thereby enhancing the tumor effect. Nanopharmaceutical delivery systems are used to deliver traditional chemotherapeutic drugs and can improve specific delivery to tissues or cells. The FOLFOX regimen includes folinic acid (FnA), 5-fluorouracil (5-Fu), and oxaliplatin (OxP) and is the standard chemotherapy regimen for advanced colorectal cancer (CRC) and hepatocellular carcinoma (HCC). GUO et al. designed a Nano-Folox nanopharmaceutical by encapsulating FnA and OxP in a lipid nanopharmaceutical carrier, modifying the nanopharmaceutical carrier with polyethylene glycol (PEG) and attaching aminoethylbenzamide (AEAA) to the PEG end, a ligand of the sigma-1 receptor that is overexpressed in most solid tumors. Combination treatment with low-dose Nano-Folox and free 5-FU significantly promoted the regression of CRC tumors compared with high-dose free FOLFOX. This enhanced antitumor effect was mainly due to OxP-mediated immunogenic cell death. The nano-delivery system is easy to be modified by PEG to improve the stability and half-life of the drug. In addition, it can achieve tumor cell targeting by connecting ligands. At the same time, it can be combined with multiple types of drugs to play a synergistic effect, achieving high-efficiency, low-toxicity anti-tumor immunotherapy.

The development of gene editing technology has made it possible to accurately regulate the expression of target genes in cells. Therefore, combining gene editing technology with immunotherapy is expected to develop new, safer and effective therapies. For example, using small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeat-associated nucleotide 9 (CRISPR-Cas9) gene editing technology to block the expression of immune checkpoint genes can effectively activate the anti-tumor immune response. Because nucleic acid drug molecules themselves have poor ability to penetrate cell membranes, do not have targeting ability, and are extremely unstable in physiological environments, the bottleneck of nucleic acid drugs used for gene editing in vivo lies in the construction of drug delivery systems in vivo. KIM et al. developed Nanosac, a non-cationic soft polyphenol nanocapsular capsule, which serves as a carrier for PD-L1 siRNA, enhances the penetration and targeting of siRNA to tumor tissue and induces mouse colorectal cancer CT26 tumor growth through immune checkpoint blocking. Significantly reduced.

Nanoparticles improve tumor immunosuppressive microenvironment

The efficacy of immunotherapy will be affected by the tumor immunosuppressive microenvironment. The immunosuppressive cells in the tumor microenvironment mainly include tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). A variety of nanodrug delivery systems have been designed to target MDSCs and TAMs to deliver drugs, thereby reducing the immunosuppressive effects of the tumor microenvironment by inducing apoptosis, inhibiting cell infiltration and activation, or regulating cell differentiation. TANG et al. designed protein nanogels (NGs) and coupled them to the surface of T cells. This nanogel responds to the increase in reducing capacity on the surface of T cells, so it can release drugs to antigen contact sites. Compared to systemic injection of free cytokines, NGs delivery selectively expanded T cells in the tumor microenvironment by a factor of 16 and had no significant toxic side effects at cytokine injection doses up to 8 times the free drug.

Nanoparticles enhance anti-tumor function of peripheral immune system

Tumor-draining lymph nodes contain high levels of dendritic cells, and tumors release cytokines and other factors to inhibit the draining lymph nodes and maintain them in an immature, non-functional state. Strategies such as intra-nodal injection of immunostimulants have been shown to directly activate dendritic cells residing in lymph nodes and promote cytotoxic T cell responses. Local injection (intramuscular or intradermal, etc.) of nano-drug carriers with a size in the range of 5 to 50 nm can infiltrate into the lymph vessels and target enrichment into the downstream lymph nodes. Nanoparticles can also be used to target antigen-presenting cells in lymph nodes or spleen of the peripheral immune system to deliver tumor antigens, enhancing the activation of tumor antigen-specific T cells.