Progress of New Liposomes in Anti-Tumor Drug Research

Cancer stands as one of the principals worldwide diseases posing a threat to human health. Chemotherapy remains the most effective treatment for human tumors yet normal cell accumulation of chemotherapy drugs leads to side effects including bone marrow suppression and nausea along with neurotoxicity hair loss fatigue and liver kidney damage. The advancement of nanomedicine delivery systems has partly resolved two main chemotherapy issues including insufficient drug concentration at tumor locations and extensive toxic effects due to systemic drug distribution. At present, various new NDDS designed according to the characteristics of targets specifically expressed by tumor tissues and microenvironments have emerged in an endless stream, becoming a hot spot in the research of anti-tumor drugs. Liposomes (Lip) are the most successful NDDS in clinical application so far. They have the advantages of low toxicity and immunogenicity, good biocompatibility, and easy surface modification. They have been widely used in the delivery of anti-tumor drugs. New liposomes such as targeted modified liposomes, stimulus-responsive liposomes and biomimetic liposomes have emerged in an endless stream, which is a hot spot in the research of new formulations of anti-tumor drugs. Since doxorubicin liposomes became the first nanodrug to be marketed in 1995, more and more liposome preparations have been successfully marketed and become a new choice for cancer patients. This article reviews the new progress of new nanodrug delivery systems in anti-tumor drug research, and organizes liposome preparations in clinical research and on the market, in order to provide a reference for research in related fields.

Progress of Novel Nano Drug Delivery Systems in the Study of Anti-Tumor Drugs

In the past few decades, traditional NDDS such as nanostructured lipid carriers, nanoshells, microemulsions, nanoemulsions, nanogels, polymer micelles, and polymer nanoparticles have been widely used in the delivery of anti-tumor drugs and have made great progress. In recent years, new NDDS, such as carbon nanotubes (CNT), graphene oxide (GO), micro-nano robots, metal-organic frameworks (MOF), viruses and other carriers have flourished and become a very promising research field with huge potential for clinical application.

Progress of Novel Liposomes in the Study of Anti-Tumor Drugs

Previously, there have been many studies on non-functionalized liposomes such as traditional liposomes, long-circulating liposomes, and cationic liposomes. However, due to the special physiological environment of the tumor site, traditional liposomes are difficult to penetrate into the deep layer of the tumor site, resulting in a low effective concentration of drugs in the tumor tissue. Using ligands, antibodies, etc. to bind to target cells to actively target liposomes to the target site is an effective solution. Responsive release liposomes constructed by utilizing the difference between the tumor microenvironment and the physiological environment of normal cells are another important solution. At present, new functionalized liposomes, dominated by targeted modified liposomes and stimulus-responsive liposomes, have become a hot topic in liposome research.

Targeted Modified Liposomes

Targeted Liposomes Modified with Aptamers Aptamers are short single-stranded DNA or RNA sequences that can fold into complex secondary and tertiary structures and bind to various target molecules with high affinity and specificity. Aptamers have attracted widespread attention due to their small size, low immunogenicity, ease of manufacture and chemical modification. Researchers have developed a liposome drug delivery system functionalized with AS1411. AS1411 is a G-quadruplex aptamer that has a strong binding affinity to nucleolar proteins and is used for targeted anticancer chemotherapy. Compared with non-targeted liposomes, AS1411 aptamer-functionalized liposomes with doxorubicin as a payload increased cellular internalization and cytotoxicity against breast cancer cells and improved antitumor efficacy against xenograft breast tumors in athymic nude mice. Other researchers have designed an aptamer-liposome chimera. The chimera can specifically bind to prostate cancer cells expressing prostate-specific membrane antigen because of the incorporation of an RNA aptamer. Studies have shown that the chimera has significant prostate cancer cell binding specificity and gene silencing effects in vitro, and promotes the regression of prostate cancer in vivo, but nucleic acid aptamers are easily degraded by nucleases in vivo, so its stability needs to be paid attention to in research.

Peptide-modified Liposomes

Peptides are an important class of bioactive substances involved in growth, development and metabolism in the body, with the advantages of easy preparation, small molecular weight, high selectivity and high biocompatibility. In the study of targeted preparations, peptides are often used as ligands to improve the selectivity of preparations through receptor mediation. Commonly used peptides include RGD cyclic peptide, iNGR peptide, AG73 peptide, etc. In addition, there are cell-penetrating peptides such as BR2 peptide, R8 peptide, GALA peptide, etc. Some researchers have used RGD and TAT peptides to double-ligand modify liposomes to increase the targeting of liposomes. Double modification leads to enhanced targeting levels of liposomes inside and outside blood vessels, thereby improving the therapeutic effect of liposomes loaded with doxorubicin, but also increasing the clearance rate of liposomes. Although there are many studies on peptide-modified liposomes, no peptide-modified liposomes have been successfully marketed due to limiting factors such as the targeting universality of peptides.

Antibody-modified Liposomes

Antibody-modified liposomes are currently the most promising targeted modified liposomes because antibodies have a high degree of specific recognition ability. The large number of tumor-targeted antibodies currently on the market have also fully verified their effectiveness, safety and specificity, and have accumulated a lot of preliminary research foundation for the study of antibody-modified liposomes. Someone prepared a new CD24-targeted drug delivery system for advanced ovarian cancer by modifying the surface of cisplatin liposomes with CD24 (cluster of differentiation 24) monoclonal antibodies. Cell experiments also confirmed the specific uptake of cisplatin liposomes modified with anti-CD24 monoclonal antibodies by Caov-3 cells, a drug-resistant ovarian cancer cell line. In addition, someone prepared a targeted immunoliposome coupled with integrin b6 (ITGB6) monoclonal antibodies to target malignant colon epithelial cells. Compared with liposomes, the cellular internalization level of ITGB6-targeted immunoliposomes in ITGB6-positive colon cancer cells was significantly enhanced. Although antibody-modified liposomes have entered the clinical trial stage, there are still no related products on the market due to the insufficient stability and easy inactivation of antibodies.

Ligand-modified Targeted Liposomes

Some abnormally expressed antigens or receptors are produced on the surface of tumor cells or tumor vascular endothelial cells. Modified liposomes attach themselves to tissue receptors which causes them to gather at tumor tissue locations and enables drugs to reach their target actively. The most researched targeting ligands presently consist of folic acid, transferrin (Tf), hyaluronic acid, epidermal growth factor and carbohydrates. Scientists created PEG liposomes which target folic acid receptors to deliver medication to breast cancer cells that have folate receptors. Folic acid-modified liposomes demonstrate their potential for tumor therapy by specifically targeting tumor cell mitochondria to increase ROS levels and disrupt mitochondrial transmembrane potential. Although ligand-modified targeted liposomes show broad application prospects in tumor-targeted drug delivery systems, the overexpressed receptors in tumor cells are also expressed in normal tissues, which will lead to a small amount of distribution of the preparation in normal cells, which is also a key problem that needs to be solved for such preparations.

Stimulus-responsive Liposomes

Stimulus-responsive liposomes can be induced by the special environment inside and outside the tumor cells to localize and concentrate to reduce the systemic distribution of drugs.Tumor microenvironments show distinct features when compared to normal tissues through unique conditions like acidic pH and redox potential specificity. Liposomes demonstrate responsiveness to external stimuli including sound waves and heat along with light and magnetic fields. The triggering conditions for stimulus response allow classification into pH-sensitive liposomes and redox-sensitive liposomes along with thermosensitive liposomes ultrasound-responsive liposomes light-responsive liposomes and magnetic-responsive liposomes.

Biomimetic Liposomes

Since a cell membrane coating technology using red blood cell membrane as membrane material was first reported in 2011, cell membrane as a natural membrane material has attracted more and more attention in the field of nanomedicine. Cell membrane-coated liposomes have the characteristics of high biocompatibility, strong targeting ability, and simultaneous multi-drug delivery. Many types of membranes have been used to construct biomimetic nanoliposomes for cancer treatment, including membranes of red blood cells, macrophages, white blood cells, platelets, cancer cells, bacteria, stem cells, etc. Natural killer cells (NK) have the ability to directly target cancer cells through inhibitory and activating receptors on the cell surface, and can release membrane-destroying proteins (perforins) and proteolytic enzymes (granzymes), thereby causing target cell lysis and death. Liposomes generated by NK cell membrane infusion and fusion can be used for targeted drug delivery, and have successfully achieved targeting capabilities for human breast cancer cells. The researchers developed a biomimetic mesoporous FeSAZs/DDP nanosystem (CSD) for enhanced nanocatalytic therapy/chemotherapy by simultaneously encapsulating the chemotherapy drug cisplatin with high peroxidase activity and metal-based SAZs (single-atomnanozymes, SAZs) into the cancer cell membrane. CSD can evade immune recognition and actively target tumor sites, upregulating endogenous H₂O₂ levels, leading to mitochondrial damage and intolerance to chemotherapy drugs. However, the preparation of biomimetic liposomes requires the extraction and integration of natural biological components. The batch-to-batch variability of natural components may lead to unstable quality of different batches of drugs, and these factors need to be fully considered during research.