Progress in clinical transformation of anti-tumor nano drugs

Cancer is one of the leading causes of human death. At present, the treatment of cancer still faces many challenges. Among them, how to accurately deliver drugs to tumor lesions to achieve targeted therapy is a major scientific problem that needs to be solved. With the rapid development of nano-biotechnology, anti-tumor nano drugs are expected to improve cancer treatment strategies and improve treatment effects. Studies have shown that nanomedicine can not only improve the specificity of tumor tissue and inhibit tumor growth by changing pharmacokinetics and tissue distribution, but also reduce the toxicity of drugs to normal tissues. In recent years, nanomedicine has shown great application value and development prospects in anti-tumor drug delivery and improvement of cancer treatment effects. Scientists use the latest nanotechnology to rationalize the design and regulation of the shape, size and function of nanomedicines, prolong the action time of nanomedicines, and also modify target molecules on the outer surface of nanomedicines to increase the amount of drug accumulation in tumor tissues. To achieve effective treatment of tumors and integration of cancer diagnosis and treatment. Nanomedicine can achieve targeted drug delivery and intratumoral drug delivery, avoid systemic non-specific release of drugs, improve drug pharmacokinetics and pharmacodynamics, and assist drugs in overcoming tumor cell resistance mechanisms. In addition to the conventional anticancer chemotherapeutic drugs, nanomedicines can also deliver peptides, proteins, nucleic acids and the like because they can protect the integrity and biological activity of biologically active substances during drug delivery.

Nano-drugs have many advantages in cancer treatment, including: 1) rational design and regulation of the shape, size and function of nanomedicines with nanotechnology to achieve optimal performance; 2) nanomedicine can realize integration of diagnosis and treatment 3) Nano-drugs are often preferentially enriched in tumor tissues; 4) Nano-drugs can reduce the toxic side effects of drugs; 5) Nano-drugs can make biological active substances in the process of drug delivery to achieve integrity and biological activity, not by enzymes degradation. The clinical transformation status of anti-tumor nano drugs was reviewed. The clinical application of anti-tumor nano drugs and some candidates in clinical trials were introduced, as well as some challenges and opportunities for anti-tumor nano drugs for tumor therapy.

The application of nano drugs in clinic

The development of nanomedicine began in the 1960s, and scientists proposed the use of nanolipid vesicles (ie, liposomes) for drug delivery. Since then, a large number of nano drug delivery systems have been developed in subsequent studies. The main development of nanomedicine can be summarized as follows: In 1976, Langer first proposed a delivery system for sustained release drugs. In 1980, Yatvin designed liposomes with pH-responsive drug release and active targeting for drug delivery. In 1986, Matsumura and Maeda proposed the enhanced permeability and retention effect (EPR effect), which is based on the pathological features of tumor vascular discontinuity and tumor lymphatic system. Nanomedicine can accumulate and remain in the tumor site. Within the tumor tissue. In 1987, Allen proposed that the modification of liposomes with polyethylene glycol (PEG) helps to reduce the elimination of phagocytic cells in vivo, and prolongs the blood circulation time of liposomes to provide more accumulation of liposomes in tumor tissues. opportunity. In 1994, Langer prepared the first long-cycle nanoparticle polyethylene glycol-poly(lactic-glycolic acid) nanoparticles. In 1995, loaded with the antitumor drug Doxorubicin (Dox), the polyethylene glycol modified liposome Doxil ® was approved by the US Food and Drug Administration as the first nano drug to be used in the clinic. Its indications include the ovary. Cancer, metastatic breast cancer, and AIDS-related Kaposi’s sarcoma (Figure 1). Since then, a variety of nano-drugs have entered clinical trials, some of which have been approved for clinical treatment of tumors. According to statistics, there are currently 15 kinds of nano drugs approved by the US Food and Drug Administration or the European Medicines Agency for cancer treatment, and more than 50 kinds of nano drugs in clinical trials. Among them, among the clinically approved nanomedicines, there are 10 kinds of liposomes, 2 kinds of polymer micelles, 2 kinds of nanoparticles, and 1 kind of inorganic nanoparticles. However, there is no polymer-drug conjugate. Clinical approval was obtained (Table 1). At present, anti-tumor nano-drugs can be roughly classified into liposomes, polymer micelles, nanoparticles and polymer-drug conjugates and inorganic nanoparticles according to their constitution

Liposomes are two-layer spherical vesicles containing water-soluble inner chambers and vesicle shells formed by lipid molecules (such as phospholipids and cholesterol). They have a particle size, plasticity, good biocompatibility, low toxicity and low It is characterized by immunogenicity and can simultaneously load drugs with different affinity and hydrophobicity. Liposomes are one of the main classes of anti-tumor nano-drugs, and they are also the most successful nano-drugs in clinical transformation. They are widely used in the treatment of diseases such as cancer, inflammation and skin diseases. At present, liposome-encapsulated doxorubicin has been used in clinical treatment of ovarian cancer, metastatic breast cancer, Kaposi’s sarcoma and other tumors in many countries including China, and its trade name is Doxil ® . Doxorubicin is a chemotherapy drug, but it has cardiotoxicity, which affects its use in the treatment of tumors. Liposomes-encapsulated doxorubicin can effectively reduce the toxicity of doxorubicin and achieve the safety of clinical drugs. In addition to Doxil ® , a variety of liposome nano drugs are also approved for clinical treatment. These liposome nano drugs mainly include: 1) DaunoXome ® , a 50 μm diameter n- succinic liposome, Mainly used for the treatment of AIDS-related Kaposi’s sarcoma; 2) Myocet ® is a non-pegylated doxorubicin liposome with a particle size of 150 nm, mainly used for the treatment of metastatic breast cancer (Europe and Canada); 3) MM-398 ® , a irinotecan liposome with a particle size of 100 nm, is administered in combination with 5-fluorouracil and leucovorin, and is mainly used for the treatment of pancreatic cancer. In addition, a variety of liposome nano-drugs are in clinical trials, such as Themodox ® and Lipolatin in clinical phase III trials, and clinical phase II liposomes, such as Lipoxal and EndoTAG-1, in clinical practice. The liposomes of phase I include IHL-305 and LiPlaCis. Themodox ®It is a heat sensitive liposome of doxorubicin and is suitable for the treatment of hepatocellular carcinoma and breast cancer. Studies have shown that combined with radiofrequency ablation technology, Themodox ® can rapidly change the structure of the liposome when the ambient temperature rises to 40 ~ 45 ° C, forming a “small opening” to release doxorubicin. Lipolatin is a liposome preparation of the antitumor drug cisplatin, which is suitable for the treatment of non-small cell lung cancer. Studies have shown that the composition of cisplatin liposome contains an anionic lipid molecule dipalmitoylphosphatidylglycerol to assist cisplatin The plastid achieves transmembrane transport. In addition, Lipolatin has a long residence time in tumor tissues and an adverse reaction of inorganic substances during the treatment. Lipoxal is a liposomal formulation of oxaliplatin for the treatment of advanced malignancies. Phase I clinical results show that liposomal oxaliplatin variety of tumors, such as gastric and pancreatic cancer and the like, have a higher therapeutic activity, and only if the dose reached 350 mg · m ~ 300 -2 when Shows certain body toxicity, such as peripheral neurotoxicity. EndoTAG-1 is a cationic paclitaxel liposome. Its cancer treatment strategies include anti-tumor angiogenesis and anti-tumor cell growth. It is suitable for indications such as breast cancer, liver cancer and pancreatic cancer. IHL-305 is a PEGylated irinotecan liposome suitable for the treatment of advanced solid tumors. Preclinical studies have shown that IHL-305 treatment has shown anti-tumor activity in a variety of tumor models, such as colon cancer, non-small cell lung cancer, small cell lung cancer and prostate cancer, and can significantly improve the survival rate of tumor-bearing mice. LiPlaCis is a liposomal formulation of cisplatin with a phosphatase A2 (PLA2) responsive release drug for advanced solid tumors. However, the results of clinical phase I indicate that LiPlaCis has significant side effects such as nephrotoxicity, so its clinical trial has been terminated. At present, a variety of liposome-based nanomedicines have been approved and entered clinical trials because liposomes are a relatively mature clinical drug model with low risk and successful liposome formulations. The reference and preparation techniques are relatively mature.


Nanomicelle refers to a polymer molecular aggregate having a “core-shell” structure with a particle size of 10 to 200 nm self-assembled by an amphiphilic block polymer in an aqueous solution. During the micelle formation process, the hydrophobic drug molecules act synergistically with the polymer segments and are encapsulated into the hydrophobic core to form drug-loaded nanomicelles. PEG is the most commonly used hydrophilic polymer in the nano-micelle hydrophilic shell. The dense polyethylene glycol shell on the surface of the micelle can effectively prevent the nano-micelle from being non-specifically adsorbed or recognized by plasma proteins or macrophages, and prolonged. The blood circulation time of nanomicelles. Currently, clinically approved nanomicelles are Genexol-PM ® and Paclical ® , both of which are nanomicelle pharmaceutical preparations of paclitaxel. Genexol-PM ® has an average particle size of about 20 to 50 nm and is formed by self-assembly of polyethylene glycol-polylactic acid block polymer, which is suitable for the treatment of metastatic breast cancer (Korea). Paclical ® has an average particle size of about 20 to 60 nm, and its ammophore structure introduces the amphiphilic surfactant XR-17 (a vitamin A analogue) that can be metabolized by the body. It is suitable for the treatment of ovarian cancer (Russia ). The results of the study show that Paclical ® has a significantly higher drug loading than the current commercially available paclitaxel formulations, Taxol ® and Abraxane ® . Therefore, Paclical ® supports the use of high-dose treatments for cancer patients, and it is associated with Abraxane ®Almost consistent pharmacokinetic behavior ensures the safety of the patient during treatment. In addition, a variety of new nanomicelles are in clinical trials. These nanomicelles are mostly prepared from biocompatible polyethylene glycol-polyamino acid block polymers, such as polyethylene glycol-polyaspartate. And polyethylene glycol-polyglutamic acid and the like. The polymer nanomicelles entering the clinical trial mainly include: 1) NK105 (clinical phase III), paclitaxel-loaded polyethylene glycol-polyaspartic acid nanomicelle (85 nm), suitable for breast cancer and gastric cancer. Clinical trial results show that NK105 shows good anti-tumor activity against breast cancer, and can significantly reduce the side effects caused by paclitaxel (such as neutropenia, etc.), and its overall response rate (ORR) 25% (clinical phase II data); 2) NC-6004 (clinical phase III), cisplatin-loaded polyethylene glycol-polyamino acid nanomicelles (20 nm) for the treatment of pancreatic cancer. Studies have shown that NC-6004 has a disease control rate of 64.7% for pancreatic cancer (clinical phase II data) and has a higher tolerated dose, only when NC-6004 is administered at a dose of 120 mg·m -2Cisplatin-related organism toxicity occurs; 3) NK012 (clinical phase II), polyethylene glycol-polyamino acid nanomicelles loaded with 7-ethyl-10-hydroxycamptothecin (SN38) (20 nm) For three-negative breast cancer. Clinical phase II studies have shown that NK102 has a positive effect on patients with relapsed small cell lung cancer, ORR is 22%; 4) NK911 (clinical phase II), doxorubicin-loaded polyethylene glycol-polyaspartic acid nanomicelle (40nm) for a variety of solid tumors. Studies have shown that the area under the plasma efficacy curve (AUC) of NK911 is twice that of free doxorubicin, and NK911 only causes mild nausea and vomiting, and does not cause serious side effects such as bone marrow suppression; 5) NC-4016 (clinical Phase I), cisplatin-loaded polyethylene glycol-polyamino acid nanomicelles (30 nm), suitable for a variety of solid tumors. Preclinical studies have shown that the plasma AUC of NC-4016 is about 1000 times higher than that of oxaliplatin. It has high anticancer activity in mouse colon cancer, human pancreatic cancer, gastric cancer and melanoma in animal models. None of the mice in the treatment showed significant systemic neurotoxicity.


Nanoparticles refer to nanoparticles having a size in the nanometer scale, and their structures are mainly composed of a shell, an inner core, and an active material (drug, etc.). The properties of nanoparticles (such as stability, blood half-life, etc.) are mainly determined by the physicochemical properties of the shell material and nanoparticles, which often determine the type of pharmaceutically active substance loaded by the nanoparticles. Nanoparticles can carry a wide variety of active substances, such as anti-tumor drugs, siRNA, proteins and contrast agents. Currently, nanoparticle nanomedicines that have received clinical approval are Abraxane® and Transdrug ® . With annual revenues of approximately $967 million, Abraxane ® is one of the major success stories for nanopharmaceutical development. Abraxane ® is a paclitaxel-bound albumin nanoparticle with an average particle size of approximately 130 nm. The indications are pancreatic cancer and metastatic breast cancer. In clinical treatment, Abraxane ® not only maintains the anti-tumor efficacy of paclitaxel, but also eliminates the toxicity associated with the emulsifier Cremophor ® EL in the commercial paclitaxel formulation Taxol ® . Pharmacokinetic studies show that, Abraxane based ® activity mediated albumin transport pathway – targeting “ligand receptor”, Abraxane ® paclitaxel tumor volume of distribution and rate of clearance is higher than the Taxol ® , and of Abraxane ® Maximum tolerated dose (MTD) than the Taxol ® height of about 50%. Transdrug ®It is a doxorubicin nanoparticle preparation developed by BioAlliance based on Transdrug technology. Its carrier polymer material is polyisocyanurate, which is suitable for clinical treatment of hepatocellular carcinoma. In addition, a variety of nanoparticles are also in clinical trials. Among them, the nanoparticles in clinical phase II trials mainly include DHAD-PBCA-NPs and CRLX101, and the nanoparticles in clinical phase I have Nanoxel ® and Docetaxel-PNP. DHAD-PBCA-NPs is a mitoxantrone nanoparticle suitable for hepatocellular carcinoma. CRLX101 is a nanoparticle formed by encapsulating camptothecin with polyethylene glycol-polylactic acid. CRLX101 can be combined with bevacizumab, and studies have shown that this combination therapy has high anti-tumor activity and is well tolerated in metastatic renal cell carcinoma. In addition, CRLX101 is also suitable for the treatment of non-small cell lung cancer. Nanoxel ® is a non-albumin-bound paclitaxel nanoparticle with a size of about 10 to 50 nm and is suitable for advanced breast cancer. Nanoxel ® significantly improves the pharmacokinetics of paclitaxel, while reducing anti-tumor efficacy while reducing side effects such as allergic reactions and fluid retention. Docetaxel-PNP is a docetaxel nanoparticle suitable for a variety of solid tumors. The results show that Docetaxel-PNP has a blood half-life of 1.5 to 2 times that of the anti-tumor drug, Taxotere, which is more conducive to the accumulation of docetaxel in tumor tissues, so Docetaxel-PNP has better therapeutic effect and lower Clinical toxicity. China has also made progress in the research and development of nano-drugs such as nanoparticles. So far, a total of five pharmaceutical companies in China (Zhengda Tianqing, Shijiazhuang Group, Jiangsu Hengrui, Qilu Pharmaceutical and Hunan Kelun) have successively obtained clinical approvals for various paclitaxel-binding albumin injections, and have successively entered clinical trials. Among them, there are 5 kinds of new drugs in class 1.6, one class of new drugs in class 2.4, and seven kinds of new drugs in class 3.4.

Polymer-drug conjugate

Polymer-drug conjugates (PDCs) refer to drug carriers formed by the coupling of an active drug molecule and a polymer by chemical covalent bonds. The polymer materials used in polymer-drug conjugates are highly soluble, non-toxic and non-immunogenic in aqueous solutions, mainly including poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) ), polyethylene glycol, polysaccharide polymers (such as hyaluronic acid, dextran, etc.) and polyglutamic acid. At present, there are no clinical approvals for PDCs nanomedicine, but a variety of PDCs nanomedicine are in clinical trials. PK1 (FCE28068, PHPMA-Dox conjugate) was the first N-(2-hydroxypropyl)methacrylamide-based polymer-drug conjugate to enter clinical phase I assessment. Clinical phase I studies have shown that PK1 exhibits anti-tumor activity in non-small cell lung cancer, colorectal cancer, and drug-resistant breast cancer, but clinical phase II studies have shown that PK1 only exhibits anti-tumor effects in breast cancer patients and non-small cell lung cancer patients. active. N-(2-hydroxypropyl)methacrylamide-based polymer-drug conjugates entering clinical evaluation are also PK2 (PHPMA-Dox-galactosamine, clinical stage I/II), PNU-166945 (PHPMA) -PTX, clinical stage I) and PNU-166148 (PHPMA-CPT, clinical stage I) and the like. Among them, the PK2 structure introduces a galactosamine structure that targets the hepatocyte asialoglycoprotein receptor (ASGR), which is suitable for the treatment of primary liver cancer, but it is caused by galactosamine. PK2 accumulates in normal liver cells, resulting in greater toxicity. In addition, the clinical trial results of PNU-166945 and PNU-166148 are also unsatisfactory, both of which show significant toxicity in the course of cancer treatment, such as cystitis. The PEG-based polymer-drug conjugates in clinical trials include Prothecan (PEG-CPT, Clinical Phase I), etc. Prothecan has a camptothecin content of about 1. 7%, plasma half-life for up to 72h, during which the anti-cancer activity against a variety of solid tumors was maintained, and its dose-limiting toxicity was mainly characterized by neutrophil and thrombocytopenia. The polysaccharide polymer-drug conjugates in clinical trials include AD-70 (Clinical Phase I) and the like. Among them, AD-70 is the first dextran-drug conjugate to enter clinical trials. The molecular weight of dextran carrier is about 70,000 g mol.-1 , the drug loaded is doxorubicin. However, since dextran is easily taken up by the endothelial reticular system, AD-70 exhibits large toxic side effects such as hepatotoxicity and thrombocytopenia. The polyglutamic acid-drug conjugates in clinical trials include Xyotax ® (Clinical Phase III) and the like. Xyotax ® is a conjugate of polyglutamic acid ( Mw =17000 g/mol) with paclitaxel, which has a drug loading of up to 37%. Studies have shown that Xyotax ® has a good pharmacokinetic profile and shows high antitumor activity against a variety of tumor models, such as non-small cell lung cancer and ovarian cancer.

Inorganic nanoparticles

Inorganic nanoparticles have been widely concerned by researchers in the field of nanomedicine. Compared with organic nano-drugs, inorganic nanoparticles have characteristics such as good size and shape controllability and large specific surface area. In addition, due to the inherent properties of inorganic nanoparticles, such as surface plasmon resonance and magnetic responsiveness, inorganic nanoparticles are widely used in the fields of heat treatment, thermal imaging and magnetic resonance imaging, and have great applications for the integration of nano drug diagnosis and treatment. prospect. Common inorganic nanoparticles include magnetic nanoparticles, silica nanoparticles, nanocarbon materials, and quantum dots. Feraheme is a semi-synthetic superparamagnetic iron oxide nanoparticle that has been clinically approved for the treatment of iron deficiency anemia in patients with chronic kidney disease. In addition, Feraheme can also be applied to magnetic resonance imaging angiography. At present, a variety of inorganic nanoparticles are also in the clinical trial stage, and its application areas include tumor imaging and thermal therapy. Cornell Dots is a polyethylene nanoparticles modified with polyethylene glycol and cRGDY peptides and 124I radiolabeled for imaging of melanoma and brain tumors; AuroLase is a PEG-modified silica-gold nanoparticle for Photothermal therapy for metastatic lung cancer. Although inorganic nanoparticles have made great progress in the field of nanomedicine in recent years, their biosafety has been a potential problem and requires biosafety evaluation.

Active targeting of nanomedicine

Active targeting refers to the introduction of active targeting molecules to increase the targeted enrichment of nanomedicines at the site of the lesion and the internalization of tumor cells. The identification of tumor biomarkers is the basis for active targeting of nanopharmaceutical ligand selection and design. Common target molecules are antibodies, non-antibody target molecules, nucleic acid aptamers, and the like. The antibody target molecule mainly includes a monoclonal antibody, an antigen-binding fragment and the like, and the non-antibody target molecule mainly includes a vitamin, a polysaccharide, a polypeptide and the like. Tumor tissue targets can be divided into tumor cell targets and tumor endothelial cell targets. Tumor cell targets refer to transferrin receptors, folate receptors, and glycoprotein receptors that are overexpressed by tumor cells. Tumor endothelial cell targets refer to vascular endothelial growth factor (VEGF), α v β 3 integrin and vascular cell adhesion factor-1 (VCAM-1), which are overexpressed by tumor endothelial cells . At present, nano-drugs are mostly non-active targeted nano-drugs, and their drug-forming properties have been confirmed by clinical trials. However, there is still a lack of active targeted nano-drugs on the market, mainly due to the lack of significant differences in clinical trial results. Compared with active targeting, the accumulation of passively targeted nanomedicine in tumor tissue is determined to a greater extent by the physicochemical properties of the nanomedicine. Therefore, even if the targeting ligand is deleted, the targeting of the nano drug to the tumor tissue can be achieved by optimizing the physicochemical properties of the nano drug, or can be non-specifically taken up by the tumor cell. On the other hand, active targeting can promote the specific uptake of nanomedicine by cancer cells. Therefore, the development of active targeting nanomedicine remains a hot topic in the field of nanopharmaceuticals.

Currently, only a few active targeted nanomedicines have entered clinical trials. These nanomedicines mainly include: 1) MCC-465 (Clinical Phase I), a F(ab’)2 fragment modified by human monoclonal antibody GAH, modified doxorubicin immunoliposome, which can specifically bind to the stomach, Intestinal tumor tissue is combined. Studies have shown that MCC-465 has no obvious anti-tumor effect on GAH-negative Caco-2 tumors, but has obvious anti-tumor effect on GAH-positive WiDr-Tc and SW837 tumors; 2) SGT-53 (clinical stage I), anti-tumor Transferrin receptor single-chain antibody fragment (TfRscFv) modified liposome nanocomplex for p53 gene delivery, wherein TfRscFv actively targets tumor cell transferrin receptor. Studies have shown that SGT-53 significantly enhances the sensitivity of tumor cells to radiotherapy/chemotherapy; 3) BIND-014 (clinical phase II), loaded with docetaxel, nanoparticles that specifically target prostate specific membrane antigen (PSMA) . Studies have shown that BIND-014 has a good inhibitory effect on a variety of tumor models (such as prostate cancer, non-small cell lung cancer, etc.), and its pharmacokinetic behavior is significantly better than free docetaxel, with lower systemic toxicity. 4) CALAA-01 (Clinical Phase I, Termination), a nanoparticle formed by cyclodextrin and adamantane-polyethylene glycol, is the first active targeted siRNA nanomedicine to enter clinical trials. CALAA-01 surface-modified human transferrin (hTf) specifically targets the transferrin receptor, but unfortunately, CALAA-01 related clinical trials have been discontinued for reasons of preparation cost and safety. Although the clinical transformation of nanomedicine with active targeting is progressing slowly, the development and exploration of active targeted drug delivery systems will be an important direction for future nano drug development. Because the active targeting of nano-drugs specifically recognizes tumor cells, it can improve the accuracy of tumor treatment and reduce unnecessary side effects on normal tissues and organs. At the same time, according to the modification of different target molecules on the outer surface of ordinary nano drugs, the application range of nano drugs can be broadened, and different tumors can be targeted according to different target molecules, thereby improving the targeting and effectiveness of nano drugs on a single tumor. .

The challenge of nanomedicine in clinical transformation

Nanomedicine faces many challenges in the clinical transformation process, including the construction of pharmacokinetic models, the design of nanomedicines and the evaluation of biological properties. Rationalization of the physicochemical properties of nanomedicine contributes to nanomedicine immune escape, tumor extravasation and diffusion, cell targeting and internalization, and controlled release of drugs. The physicochemical properties of nanomedicine are often designed and determined based on a simplified nanopharmaceutical pharmacokinetic model. The model believes that based on the EPR effect, nanomedicines with sufficiently long circulating half-lives can accumulate more efficiently in tumor tissues. Based on this model, nanomedicine design focuses on inhibiting or reducing nanomedicine’s opsonin adsorption, reticuloendothelial uptake, and renal clearance to maximize circulatory half-life. However, more and more studies have shown that this model oversimplifies the physiological barriers, tumor microenvironment and their effects on the organization of nanomedicine, accumulation and penetration in tumor sites. A rational pharmacokinetic model plays a crucial role in the design of nanomedicine. Considering tumor tissue as a unique and complex organ, constructing an accurate theoretical model of pharmacokinetics, and delving into the “cause and interaction mechanism of nanomedicine being taken up by mononuclear macrophage system” “The power of nanomedicine targeting tumor tissue Key scientific issues such as “study mechanism” and “how to quantify and adjust various factors of tumor microenvironment to improve the targeted transportation of nanomedicine”. In this way, we can understand the tumor mechanism and the differences between different tumors from multiple angles, and design the optimal nano drugs and treatment plans.

The biological evaluation of nanomedicine can be divided into in vitro cytological assessment and zoological assessment. In vitro evaluation experiments help to deepen understanding of nanoparticle-cell interactions, and it is necessary to conduct in vitro evaluation of nanomedicines to determine their biocompatibility before conducting animal experiments. However, the porous plate environment used in conventional cell culture processes lacks the complexity of living tissue and blood fluidics and does not fully mimic the complex physiological barrier between the organism and the nanomedicine. The bionic “organ/tumor chip” can avoid the drawbacks of current in vitro cell experimental models. Incorporating tumor-type spheres into microfluidic channels can investigate the effects of interstitial flow, cell action, and nanoparticle size on tumor accumulation and diffusion behavior of nanomedicines. The in vivo properties of nanomedicines include pharmacokinetics, biodistribution, biocompatibility, and biosafety. These properties must be accurately assessed by animal models. At present, the difference between preclinical research results and clinical trial results in nanomedicine research is a recognized obstacle, which is largely due to the lack of animal experimental models that accurately reflect human cancer conditions during nanomedicine development. A variety of tumor models are currently available in nanomedicine research, including subcutaneous and orthotopic tumor models based on tumor cell lines, human tumor xenograft models, and genetically engineered mice. However, none of the above tumor models can fully accurately reflect the symptoms of human malignancies. Moreover, passive targeting effects due to EPR effects are often more pronounced in animal models than in human cancer patients. In addition, considering the high mortality rate of metastatic tumors, it is also important to evaluate the EPR effect, penetration and targeting of nanomedicines in human metastatic tumor models. With the continuous development of animal models that accurately mimic human tumor heterogeneity, such as high-fidelity human tumor xenograft models, humanized mouse models and genetically engineered mouse models of invasive metastases, and nanomedicine in large mammalian models Further evaluation in monkeys, dogs and pigs, etc., believes that the status quo of clinical conversion of nanomedicine will also be greatly improved.

Another challenge in the clinical transformation of nanomedicine stems from the increasing complexity of the chemical, production, and pharmaceutical manufacturing quality management practices involved in nanomedicine from preclinical research to subsequent clinical development and commercialization. For complex nanomedicine, its mass production poses higher requirements and challenges for current pharmaceutical companies’ production units and manufacturing processes. When nanopharmaceutical formulations involve multiple steps or complex processes, their large scale and reproducible preparation will be more difficult. In fact, the transformation from laboratory development to clinical use is almost always accompanied by optimization of nanomedicine formulation parameters and even process changes. Therefore, it is particularly important to make forward-looking considerations for the subsequent large-scale preparation of nanomedicine design. .

in conclusion

The development and clinical transformation of nanomedicine is both a challenge and an opportunity. In order to promote the clinical transformation of nanomedicine, the mechanism of action of nanomedicine in the human body should be further explored. The key to efficient and targeted delivery of nanomedicine to tumor tissue lies in the accumulation of nanomedicine at the tumor site, the interaction of nanomedicine with tumor cells and tumor microenvironment. How to rationalize the design of nanomedicine to increase system stability, improve tissue distribution, how to overcome a series of in vivo biological barriers of nanomedicine, improve its tumor tissue targeting, tumor penetration and tumor cell internalization ability; how to overcome the genetic diversity of tumors Sexuality, heterogeneity, and drug resistance of tumor cells; how to overcome the off-target effects of nanomedicine; and how to carry out large-scale reproducible preparation and screening of nanomedicine and other key scientific issues in the field of nanomedicine need to be resolved. Moreover, the clinically approved nanomedicines are mostly loaded with existing anti-tumor active small molecule drugs, while new therapeutic agents (such as siRNA, mRNA and gene editing) and novel molecular entities (such as kinase inhibitors) It is expected to be included in the development of a new generation of nanomedicine. In addition, due to the lack of relevant evidence for EPR effects in human tumors, deeper understanding of tumor heterogeneity and EPR markers will help maximize the therapeutic effects of nanomedicines. Therefore, clinically relevant tumors and tumors with EPR effect responsiveness can be preferentially used as tumor models for nano drug research. At the same time, nanomedicines can also be developed for applications such as intratumoral delivery of nanomedicines or tumor microenvironment imaging that are not based on EPR effects. With the deepening of research, more nano-drugs will enter clinical trials in the future, and they will be approved for the treatment of cancer patients, improve the therapeutic effect of cancer, reduce the side effects of treatment, and improve the public health.