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Rational Design of Tumor Microenvironment Responsive Drug Delivery Systems

Xiaodong Jing , Ying Sun , Bing Yu , Youqing Shen , Hao Hu , Hailin Cong

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (6) : 926 -941.

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Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (6) : 926-941 DOI: 10.7536/PC200728
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Rational Design of Tumor Microenvironment Responsive Drug Delivery Systems
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Abstract

Chemotherapy is one of the most effective methods for cancer therapy in clinical practice, but the administration of chemotherapeutic drugs results in poor targeting of drugs to tumors and low utilization rates of drugs. While killing tumor cells, chemotherapeutic drugs also cause great damage to normal human cells, so chemotherapy is usually accompanied by serious side effects, such as nausea, vomiting, and hair loss. With the rapid development of oncology and nanomaterials, many nano-drug vectors have been used in the treatment of tumors. Nanometer drug vectors can improve the utilization rate of drugs and reduce side effects, which has become a research hotspot in the field of drug delivery. The tumor microenvironment responsive drug delivery systems have shown excellent performance in the controlled drug release, removal of the protective shell, and tumor targeting. In this paper, we discuss the common strategies for constructing tumor microenvironment responsive drug delivery systems based on abnormal biochemical indicators of tumor microenvironment or in tumor cells. The recent advances of tumor microenvironment responsive drug delivery systems are summarized. Finally, we outline the challenges and perspectives about the improvement of tumor microenvironment responsive drug delivery systems, aiming to provide a reference for the design and preparation of high-performance drug delivery systems.

Contents

1 Introduction

2 Design of microenvironment response vectors for tumor

2.1 Abnormal physiological indicators of tumor microenvironment

2.2 Design strategies of tumor microenvironment response vectors

3 Advances of microenvironment response vectors for tumor

3.1 pH responsive vectors

3.2 Redox responsive vectors

3.3 ROS responsive vectors

3.4 Anoxic response vectors

3.5 Enzyme responsive vectors

3.6 Other responsive vectors

4 Conclusion

Graphical abstract

Keywords

tumor microenvironment / drug delivery system / stimuli response / vector design / cancer therapy

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Xiaodong Jing, Ying Sun, Bing Yu, Youqing Shen, Hao Hu, Hailin Cong. Rational Design of Tumor Microenvironment Responsive Drug Delivery Systems. Progress in Chemistry, 2021, 33(6): 926-941 DOI:10.7536/PC200728

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1 Introduction

Chemotherapy (chemotherapy) is one of the most commonly used ways to treat malignant tumors, and its goal is to deliver anti-tumor drug molecules to tumor cells to inhibit or kill cancer cells[1]. Chemotherapeutic drug molecules can reach various organs in the body through blood circulation to inhibit the growth of cancer cells, but there are still many challenges in the process of chemotherapy, such as: (1) short blood circulation time, poor water solubility and low bioavailability of small molecule drugs, which limit the therapeutic effect of chemotherapy; (2) The effect of tumor-specific treatment is poor, which makes the cytotoxic drug molecules produce toxic side effects on the body (nausea, vomiting, diarrhea, constipation, alopecia, bone marrow suppression and liver and kidney function damage, etc.), and aggravates the pain of patients in the course of treatment; (3) Long-term chemotherapy can also cause multidrug resistance of tumor cells. In order to solve these problems, researchers have proposed Drug Delivery System (DDS), which is to load chemotherapy drugs into carriers for transportation. Generally speaking, there are five processes for nano-drug carriers to enter the human body through intravenous injection and play a role in tumor cells, namely: (1) circulation in vivo[2]; (2) accumulation at the tumor site; (3) infiltrating into the tumor tissue; (4) endocytosis; (5) Drug release plays a role[3]. These five processes together determine the therapeutic effect of chemotherapy, and any short board will greatly reduce the effect of chemotherapy. For example, doxorubicin liposomes can prolong the blood circulation of drugs for up to 30 hours, and can be accumulated to the tumor site in large quantities, but its efficacy is not much different from that of intravenous doxorubicin, the reason is that most of the doxorubbicin liposomes can not penetrate into the tumor, resulting in low uptake of liposomes by tumor cells[4][5]. Therefore, it is very important to further improve the drug permeability, cellular uptake and intracellular release efficiency, or to endow nano-drugs with more functionality, so that nano-drugs have higher anti-tumor activity. The tumor extracellular microenvironment is characterized by subacidity, anoxia and rich in secreted enzymes of tumor cells. At the same time, tumor cells also have high concentrations of reactive oxygen species (ROS), high concentrations of glutathione (GSH) and other biochemical indicators different from normal cells[6]. The design of nano-drug carriers that can respond to these abnormal physiological indicators in the tumor microenvironment and realize the enrichment and release of drugs in the tumor site has become a hot spot in the current cancer treatment[7,8]. In recent decades, with the continuous development of medical technology, nano-drug delivery systems have shown significant therapeutic effects in cancer diagnosis and treatment, and more and more nano-carriers (such as liposomes, albumin nanoparticles and polymer micelles) have been approved for clinical cancer treatment[9][10,11][12,13][14⇓⇓~17]. Compared with the simple use of chemotherapeutic drugs, the nano-drug delivery system shows many advantages: (1) by embedding small molecular chemotherapeutic drugs,Can improve the water solubility and the in vivo and in vitro stability of the drug, for example, the hydrophilic shell is helpful for the nanoparticles to escape the clearance mechanism of the body, prolong the circulation time in the body, and increase the accumulation amount of the drug at the tumor site[18]; (2) The size of the nanoscale carrier can make the drug better enriched in the tumor site through the Enhanced permeability and retention effect (EPR) of solid tumors, and effectively realize the passive targeting effect of the carrier on tumor tissues[19,20]; (3) connecting a ligand which has a specific targeting effect on tumor cells to the surface of the nano drug delivery system, and enabling the nano drug delivery carrier to have active targeting through the specific recognition of the ligand and a tumor cell receptor[21,22]; (4) Stimulus-responsive release of small molecular chemotherapeutic drugs can be achieved by using nano-drug delivery carriers, for example, small molecular chemotherapeutic drugs are embedded in the carriers by chemical or physical means, and the nano-carriers can maintain structural integrity in normal tissues.When the carrier reaches the tumor site, the nano-drug delivery system will depolymerize and release drugs under certain specific stimuli (such as pH, temperature, GSH, ROS, etc.), thus reducing the systemic toxicity and side effects caused by small molecule chemotherapy drugs[23][24]. Based on the advantages of nano-drug delivery carriers, this paper discusses the common strategies to construct tumor microenvironment-responsive carriers for abnormal biochemical indicators of tumor microenvironment.The research progress of tumor microenvironment responsive nano-drug carriers for tumor therapy in recent years was summarized, aiming to provide a reference for the design and preparation of high-performance nano-drug carriers.

2 Design of tumor microenvironment responsive vector

2.1 Abnormal physiological indicators of tumor microenvironment

Changes in some factors of the normal cell microenvironment can cause pathological changes and abnormal growth of tumor tissue. Fibroblast activating protein (immunosuppressive protein FAP +), bone marrow-derived suppressor cell supplementation and primary macrophage reprogramming provide a suitable environment for tumor growth and rapid proliferation of tumor cells.This results in local tissue hypoxia and angiogenesis, and the resulting changes in local blood flow, oxygen and nutrient uptake, and redox potential promote further tumor development and proliferation[25][26][27][28]. Recent studies have also found that gene mutations and extracellular chemical reactions in tumor cells can lead to significant metabolic abnormalities in tumor tissues compared with normal tissue cells.These include changes in the relationship between energy supply and demand in tumors (such as high anaerobic glycolysis, high oxidative phosphorylation), abnormal signal transduction (such as overexpression of hypoxia-inducible factor-1 (HIF-1)) and disorder of biomolecular metabolism (such as abnormal consumption of glucose, lactate and glutathione)[29][30][31]. These factors will directly lead to the acceleration of angiogenesis, nutrient absorption and adenosine triphosphate (ATP) production in the tumor site, and the enhancement of macromolecular biosynthesis and redox level, which will lead to the rapid proliferation, invasion and metastasis of tumors, and make tumor cells highly resistant to traditional treatment methods[32]. Figure 1 shows several abnormal biochemical markers in the tumor tissue microenvironment and tumor cells.

2.1.1 Slightly acidic environment

The change of pH value is one of the characteristics of human pathological tissues. Under normal physiological conditions, the pH of the extracellular matrix and blood is close to 7.4. The pathological sites of inflammation, infection or tumor will have a corresponding decrease in pH. The aggressive proliferation of tumor cells and the rapid formation of irregular blood vessels lead to the rapid lack of nutrients and oxygen in the tumor site, so that the lactic acid metabolites produced by glycolysis in tumor cells accumulate in the tumor stroma, resulting in the pH value of the extracellular environment of tumor cells decreasing to 6.5-7.2, and the pH value of endosomes and lysosomes in tumor cells further decreasing to 4.0-6.0[33][34]. This slightly acidic environment widely exists in various tumors, and plays an important role in the occurrence and development of tumors, especially in drug resistance. Based on this, a pH-responsive drug delivery system was designed to stabilize the carrier under normal physiological conditions, and when the carrier reached the tumor site, the slightly acidic environment triggered the carrier to swell, surface charge reversal or chemical bond rupture.O as to increase the accumulation of the carrier at the tumor site, promote the cell uptake and the specific release of the carrier drug, enhance the treatment effect of chemotherapeutic drugs and reduce the toxic and side effects of the drugs[35]. At present, there are two strategies to construct pH-responsive drug delivery carriers. One is to use polymers with ionizable groups, which can change their conformation and solubility at different pH values[36]. The other is the introduction of acid-sensitive cleavage structures, which can respond to cleavage in a slightly acidic environment. Table 1 summarizes commonly used acid-sensitive fracture structures. The two types of carriers can realize the responsive release of drugs from tumor sites, the removal of protective layers, the exposure of targeted molecules or the disintegration of carriers, so as to improve the efficiency of drug delivery[37⇓~39].

2.1.2 Restoring Environment

Tumor cells have a large redox potential difference with the extracellular environment due to hypoxia and the production of some reducing molecules (such as reductase and glutathione)[40]. Glutathione (GSH) and glutathione disulfide (GSSG) are a major redox pathway in mammalian cells, which are mainly used to prevent cell damage induced by reactive oxygen species, maintain the stability of thiol-containing enzymes and maintain the integrity of cell membranes. GSH is a g-glutamine cysteinyl glycine tripeptide, the most abundant thiol in mammalian cells[41]. GSH is present at very low concentrations of 2 to 20 μM in blood or extracellular matrix. The rapid proliferation of tumor cells resulted in GSH levels in tumor tissues that were at least four times higher than those in normal tissues, reaching 0.5 to 10 mM[42]. This significant difference in GSH levels can be used to specifically trigger the controlled release of redox-sensitive nanoparticle drug delivery systems in tumor cells[43]. In addition to glutathione, some other biological reductants, especially some small molecules with high content in human plasma and cells, such as L-ascorbic acid, also play an important role in activating the release of redox-responsive nano-drugs[44]. Disulfide bonds (S — S) and diselenide bonds (Se — Se) can be rapidly cleaved by GSH (see Table 2) and are common structures for constructing reduction-responsive vectors. In the extracellular environment of low GSH concentration, the disulfide bond can remain stable, while in the intracellular environment of high reducing environment, the disulfide bond is quickly cut through the GSH-mediated thiol-disulfide exchange reaction, so that the nanocarrier is cracked and the drug is released[45]. Due to the difficulty of integrating diselenide bonds into polymers, the research and preparation of responsive nanocarriers based on diselenide compounds are limited to some extent[46].

2.1.3 Active oxygen enrichment environment

Reactive oxygen species (ROS) are a class of molecules with strong oxidative capacity, which are by-products of aerobic metabolism in vivo and special cell signaling transcription factors. ROS in organisms mainly include hydrogen peroxide (H2O2), singlet oxygen (1O2), superoxide radical (· O 2 -), hydroxyl radical (· OH) and nitric oxide (NO)[47]. In organisms, the continuous generation, transformation and consumption of ROS play a key role in various physiological processes. ROS is not only related to protein folding, signal transduction, cell proliferation, differentiation and migration, but also related to defense response, respiration and oxidative damage. H2O2 is the most typical ROS, which mainly comes from the single-electron reduction of oxygen molecules in biological cells, first forming superoxide, and then catalyzed by superoxide dismutase[48]. H2O2 have catalytic activity in a variety of reactions, and have been widely explored as an activation condition for drug release and a raw material for intracellular oxygen production[49,50][51,52]. Tumor cells produce higher concentrations of H2O2 than normal cells[53]. H2O2 can induce DNA damage and mutation, increase genetic instability, and increase the concentration of H2O2 can also activate HIF-1. Activated HIF-1 plays an important role in cell apoptosis, invasion, metastasis, angiogenesis and immortality[54][55][56]. If the level of H2O2 in the tumor cells is further increased, the tumor cells can be killed[57,58]. The high biological toxicity of H2O2 is largely due to its easy conversion to various types of active radicals, which disturb the redox metabolic balance, especially through the interaction with transition metal ions to produce highly reactive hydroxyl radicals. · OH has a high redox potential, which can react with the surrounding substances indiscriminately and cause oxidative damage to cells[59]. The main mechanism of 1O2 is to induce apoptosis, necrosis and autophagy[60]. Generally, low concentration of 1O2 can induce apoptosis, while high concentration of 1O2 can directly lead to cell necrosis. 1O2 plays an important role in the treatment of actinic keratosis, Bowen's disease, basal cell carcinoma and other diseases[61]. 1O2 is generally considered to be the main mechanism of PDT[62]. In the field of cancer therapy, combined with photodynamic therapy, photosensitizers located in mitochondria and nuclei are more likely to induce apoptosis, while photosensitizers located in cell membranes and lysosomes are more likely to directly cause cell necrosis[63]. Nitric oxide is one of the smallest and simplest biologically active molecules in nature. In living cells, nitric oxide synthase (NOS) catalyzes the production of L-arginine. In the field of tumor therapy, studies have found that nitric oxide is closely related to the occurrence and development of tumors, and this relationship is twofold. Low concentrations of nitric oxide less than 1 μM show anti-apoptotic effect and can promote angiogenesis, thereby increasing the supply of nutrients at the tumor site and promoting tumor growth[64]. High concentration of nitric oxide (1 μM ~ 1 mM) can cause oxidative stress and nitrosation stress in the body, which ultimately leads to deamination of DNA bases, nitrosation of enzymes, impairment of cell function, increased inflammatory response, inhibition of mitochondrial respiration and apoptosis[65]. Sensitive materials with ROS response usually contain reducing groups that can react with oxidizing substances, such as chalcogen elements, including sulfur-selenium-tellurium bonds, aromatic borate bonds, peroxyoxalate bonds, etc.Mercaptan and thioether groups can be oxidized into ketones by ROS, which are also commonly used reducing groups. Compared with sulfur compounds, selenium bonds have faster degradation rate and can react with oxidants and reductants in both directions[66,67][68][69,70]. In addition, ferrocene and the like can also be efficiently cleaved by ROS (commonly used ROS-responsive cleavage structures are shown in Table 3)[71].

2.1.4 Anoxic environment

The growth and proliferation of human cells can not be separated from adequate oxygen and energy supply. In human tissues with normal oxygen supply, 90% of the energy of cells is provided by aerobic oxidation reactions in mitochondria, and the remaining 10% depends on glycolysis. However, in tumor tissues, due to the aggressive proliferation of a large number of solid tumors, the internal metabolism and oxygen consumption are accelerated, but the new vascular network can not be established for oxygen supply or the new vascular structure and function are abnormal.These irregular blood vessels have "blind ends" and high permeability, which leads to the extravasation of blood components into the tissue space and increases the viscous resistance of blood flow. These factors make the supply of oxygen far from enough, thus creating a local anoxic tumor microenvironment. Hypoxia-inducible factor (HIF) is an upstream transcriptional regulator of tumor angiogenesis, energy metabolism, invasion, proliferation and metastasis related genes, and is also a key factor in various hypoxic responses in tumors[72,73]. Tumor cells can change their biological behavior by activating HIF signaling pathway and inducing various hypoxic responses. Tumor hypoxia, as a stress factor, can increase the level of regulatory transcription factors (such as HIF-1α), increase the ability of tumor cells to invade, proliferate and resist apoptosis, make them more prone to local and distant metastasis and increase the resistance to chemotherapy, leading to the aggravation of cancer and less than the expected therapeutic effect[74]. In the design of hypoxia-responsive carriers, most of them use nitroaromatic-based nanocomposites, which usually contain nitroaromatic functional groups or azo derivatives. Hydrophobic 2-nitroimidazole can be converted into hydrophilic 2-aminoimidazole through a series of selective biological reduction reactions under hypoxia conditions, so it is widely used in the development of hypoxia-induced drug release materials. For example, nitrobenzyl chloroformate has been developed as a hypoxia-sensitive molecule for breaking down and releasing drugs under hypoxic conditions[75].

2.1.5 Nvironment for overexpression of enzymes

Enzymes play an important role in most of the body's physiological processes. Studies have shown that the pathology of neoplastic diseases is related to enzyme dysfunction or dysregulation of its expression. Among them, the expression and activity of protease, phospholipase and other enzymes in tumor tissues are significantly higher than those in normal tissues, which has an important impact on the occurrence and development of tumors[76]. Based on this characteristic, it is of great significance to design and develop enzyme-responsive anti-tumor nano-drug delivery systems, which can help to achieve the controlled release of drugs in tumor sites[77,78]. Matrix metalloproteinases (MMPs), hyaluronidase (HAase) and cathepsin B have been widely studied[79][80,81][82,83]. The construction of enzyme-responsive drug delivery systems is mostly based on ester bonds or short peptide sequences that can be degraded by proteases or esterases. For example, the glycine-phenylalanine-leucine-glycine (Gly-Phe-Leu-Gly) sequence is a commonly used enzyme-responsive short peptide sequence. The sequence can be degraded by cathepsin B overexpressed in tumor cells[84].

2.1.6 Other

ATP is the "monetary molecular unit" of intracellular energy transfer and the basic molecule of cell signal transduction and metabolism. The unlimited proliferation of tumor cells requires a large amount of energy to maintain growth and metabolism, resulting in different ATP concentrations in and out of tumor cells. The ATP concentration in extracellular fluid is less than 5 μM, while the ATP concentration in cells is as high as 1-10 mM[85,86]. Various ATP-responsive nanoparticle drug delivery systems can also be designed by using the significant difference in ATP between intracellular and extracellular.

2.2 Design Strategy of Tumor Microenvironment Responsive Vector

The abnormal biochemical indexes of the tumor microenvironment are used as stimulating factors to make the drug carrier in a "dormant" state when circulating in vivo, and once the drug carrier accumulates at the tumor site and enters the tumor microenvironment, the special microenvironment makes the carrier "awake" to enhance the uptake of tumor cells and accelerate the release of drugs, thereby improving the effect of chemotherapy[87]. At present, the design goals of tumor microenvironment stimulus-responsive carriers are mainly to accelerate drug release, promote drug uptake by tumor cells and improve tumor penetration. As shown in fig. 2, the design strategy can be summarized as follows: (1) sensitive chemical bond breakage triggers the cleavage of the released drug or carrier to achieve controlled release of the drug; (2) removal of the outer protective layer of the carrier by microenvironmental response to increase the efficiency of cellular uptake of the carrier, such as removal of a polyethylene glycol (PEG) shell or by carrier surface charge reversal; (3) reexposure of functional molecules promotes drug uptake by cells; (4) controlling the enrichment and penetration of the vector in the tumor site through the responsive change of the size of the vector.

2.2.1 In response, the chemical bonds are broken and the carrier is cleaved

Through the unique microenvironment of tumors, some sensitive chemical bonds can be broken responsively or some compounds can be cleaved responsively. The anti-tumor drug is Graf onto that carrier through microenvironment-sensitive chemical bond, the chemical bonds are stable in a normal tissue environment, and after the anti-tumor drug reaches a tumor site, the chemical bond are responsively broken by a special tumor microenvironment, so that the grafted chemotherapeutic drug is released[88,89]. Another strategy is to introduce sensitive chemical bonds into the matrix from which the vector is constructed. The breakage of sensitive chemical bonds triggered by abnormal biochemical indicators in the tumor microenvironment will lead to the collapse of the carrier, thus releasing the drug encapsulated in the carrier[90].

2.2.2 Responsive to the removal of the PEG layer

Functional molecules are modified on the surface of the nano-drug carrier by chemical bonding or physical adsorption, which can change the hydrophobicity and stability of the nano-carrier, help the carrier escape the recognition and phagocytosis of the reticuloendothelial system, thus effectively prolonging the circulation time in vivo and enhancing the targeting effect of the carrier[91⇓~93]. PEGs are widely used in biomedical engineering and drug delivery systems due to their good biocompatibility. PEGylation of the carrier surface is a common modification method of nano-drug carriers. PEG-modified nano-drug carriers can significantly enhance the solubility and stability, improve the pharmacokinetics of drugs, and reduce the toxic and side effects on the human body. However, PEGylation of the carrier surface can reduce the endocytosis of nanomedicines[94]. The tumor microenvironment is utilized to design a carrier which can responsively remove the PEG-protective layer at the tumor site, thereby improving the uptake rate of the nano-drug by the tumor cells[95⇓~97]. Binding PEGs to sensitive chemical bonds and stimulus-triggered charge reversal are common dePEGylation strategies, such as acid-triggered bond cleavage, which can result in the removal of the PEG chain and the exposure of the targeted ligand.

2.2.3 Responsive to charge reversal

In human plasma, most proteins have negative charges, and the nano-carriers with positive charges on the surface have strong adsorption capacity to human proteins, which will lead to the nano-carriers being easily recognized and phagocytized by phagocytes after entering the human body and removed from the blood, which greatly reduces the bioavailability of drugs. Designing the carrier surface to be neutral or electronegative can extend the circulation time of the carrier in vivo. However, because the cell membrane is usually electronegative, the nanoparticles with positive surface charge are more easily taken up by cells, while the nanoparticles with negative surface charge will reduce the uptake efficiency of cells under the action of electrostatic repulsion[98,99]. By designing the nano drug carrier with the surface charge which can be adjusted intelligently, the nano drug carrier can respond to the special microenvironment of the tumor tissue to realize charge reversal after reaching the tumor site, and the surface charge of the nano carrier is responsively changed from the neutral and negative charge which is favorable for long circulation to the positive charge which is favorable for acting with the cell membrane[99⇓~101]. Han et al. Linked alkylated protoporphyrin (Pp IX) and dimethylmaleic anhydride (DMMA) modified cationic nuclear localization sequence (NLS) peptide through PEG.The negatively charged PAPP-DMMA nanocarrier can respond to the tumor microenvironment and quickly change into a positively charged PAPP nanocarrier, thus exposing the cationic NLS peptide and promoting the uptake of Pp IX by tumor cells[102]. Shen et al. Recently reported a gamma-glutamyltranspeptidase (GGT) -responsive polymer-camptothecin (CPT) conjugate (PBEAGA-CPT) (shown in fig. 3) that achieves deep penetration of tumor tissue by transendocytosis[103]. When the conjugate passes through the vascular endothelial cells or extravasates into the interstitial space of the tumor tissue, the gamma-glutamyl group on the conjugate can be cleaved by gamma-glutamyl transpeptidase highly expressed on the cell membrane surface, and the positively charged primary amine is exposed. The positively charged conjugates achieve a deep and uniform distribution across the vascular endothelium and across cells at the tumor site through endocytosis and transendocytosis mediated by caveolae, and at the same time, the disulfide bonds at part of the bonding sites are cleaved by glutathione, releasing camptothecin, leading to tumor cell apoptosis.

2.2.4 Activation of functional molecules in response to

Cell membrane is the main barrier between cells and the extracellular environment, which plays an important role in maintaining the stability of the intracellular environment. It is also because of the existence of cell membrane, an important natural barrier, that many macromolecules are difficult to enter cells through the cell membrane, which is a major obstacle to targeted drug delivery at this stage. Grafting molecules with penetrating or targeting functions to the carrier can greatly improve the drug delivery efficiency of the drug delivery system[104]. For example, Cell-penetrating peptides (CPPs) are a class of short peptides with strong penetration into cell membranes, which can be used to modify liposomes, nanoparticles and other drug delivery systems to promote cell uptake[105,106]. Although CPPs can efficiently carry nano-drugs into cells, they are degraded by enzymes in plasma and lack of specificity for tumor receptors. CPPs are modified by compounds sensitive to tumor microenvironment.By masking the transmembrane activity before reaching the target site and activating CPPs in response to the microenvironment (pH, ROS, GSH, etc.), CPPs can be prevented from penetrating normal cells and being degraded by blood components before reaching the target site. This strategy can not only achieve targeted therapy of tumors, but also greatly accelerate the efficiency of drug delivery[107]. Xiang et al. modified the siRNA-loaded liposomes with CPPs, in which the polyanion domains (histidine, glutamic acid) acted as inert molecules and protected the CPPs by using a hydrazone bond as a stimulation-responsive cleavage bond[108]. As shown in Figure 4, when the liposome reaches the tumor site through the EPR effect, the acidic environment breaks the hydrazone bond and activates the membrane penetrating functional molecules CPPs, so that the CPPs carry the liposome into the cell quickly, which accelerates the intracellular release of the drug and improves the anti-tumor effect of the drug.

2.2.5 Responsive to implementation of carrier size Chan

Nanocarrier size plays an important role in the enrichment, infiltration, internalization and nuclear internalization of tumor tissue. In the EPR effect, particles with a diameter of less than 400 nm can easily infiltrate into the tumor stroma from the blood vessels[109]. Nanoparticles in the size range of 10 to 100 nm can effectively evade liver clearance and renal filtration. Particles of small size penetrate the tissue more easily than particles of large size, but do not stay in the tissue well because they can participate in the blood circulation again[110]. However, large-sized particles can achieve enhanced tissue retention, but it is difficult to penetrate into the tumor tissue. Therefore, utilizing the tumor microenvironment to responsively change the size of nanoparticles is an effective way to enhance the tumor enrichment, penetration, internalization and nuclear uptake of nanocarriers. Zhang et al. Prepared a nano-drug complex with ultra-high drug loading rate by self-assembly of photosensitizer DVDMS, chemotherapeutic drug doxorubicin (DOX) and ferric ions in vitro on a large scale through a one-pot method. The particle size of the nano-drug complex is about 140 nm, which can achieve effective accumulation in tumor sites through EPR effect[111]. The nano-drug complex can respond to the weak acid environment of the tumor, disintegrate to form 5-10 nm ultra-small nanoparticles, realize the effective penetration of the drug in the tumor site, and significantly enhance the therapeutic effect of the chemotherapeutic drug DOX. Tan Weihong et al. Designed a size-adjustable assembly (ApFA) containing ferrocene and DNA polymer, which solved the contradiction between EPR effect and spatial uniform penetration in carrier size[112]. The assembly with a size of about 100 nm will be rapidly enriched at the tumor site through the EPR effect. When it is exposed to the tumor microenvironment, the ferrocene component in the assembly will undergo a Fenton-like reaction, resulting in a significant shrinkage of the size to 10 nm, which improves the tumor penetration ability of the assembly while releasing highly toxic hydroxyl radicals to achieve effective anti-tumor therapy in vivo (as shown in Figure 5).

3 Research progress of tumor microenvironment responsive vector

3.1 pH-responsive carrier

The pH-sensitive drug delivery system can have efficient intelligent delivery performance by flexibly utilizing the pH gradient difference between normal tissue and tumor tissue cells. Deng et al. successfully constructed a new type of multifunctional yolk-shell nanoparticles with tumor microenvironment responsiveness by combining gold nanostars with photothermal properties in the near infrared region II and biodegradable zeolite imidazole framework material (ZIF-8), which can respond to tumor microacid environment and degrade[113]. ZIF-8 was degraded in the slightly acidic environment of the tumor, and the chemotherapeutic drug (doxorubicin hydrochloride) loaded in the cavity showed responsive release. At the same time, the heat generated by 1064 nm laser irradiation can dissociate the Zn-O coordination of ZIF-8 in Au @ MOF, which accelerates the release of DOX and shows excellent synergistic anti-tumor effect. Nie et al. Linked integrin-related protein (CD47) and signal regulatory protein (SIRPα) to M1 phagocyte-derived exosomal antibody carrier via pH-responsive linkage (benzimide linkage)[114]. As shown in fig. 6, aCD47 molecules are highly expressed on the surface of tumor cells, so that the exosomal vector bonded with the CD47 antibody has an active targeting function, and in a slightly acidic environment of the tumor, the benzoimide bond is responsively broken, and the released CD47 and SIRPα can block anti-phagocytosis signals between the tumor cells and macrophages,The phagocytosis of macrophages to tumor cells was enhanced, and the specific release of antibodies was also realized, while the exosomes derived from M1 macrophages also promoted the polarization function of M2 macrophages, which greatly enhanced the synergistic anticancer effect of the drug delivery system.

3.2 Redox responsive carrier

Because the concentration of GSH inside and outside the tumor cells and in the blood may be thousands of times different, the redox sensitive drug delivery system has good response speed and targeted release ability in the tumor cells. Yang et al. used bilirubin and polyethylene glycol as carrier materials to entrap disulfide bond coupled drug dimers (SL @ BRNPs), the dimerization of drugs significantly increased the drug loading, and the introduction of disulfide bonds made the drug dimers have GSH response ability.The drug activity is only activated in an environment rich in GSH, so that the cytotoxicity caused by the non-specific release of the drug can be reduced, and a good anti-tumor combined therapeutic effect is achieved by combining the tumor targeting penetration promoting peptide iRGD and the immune checkpoint blocking antibody (anti-PD-L1)[115]. Ding Baoquan et al. Developed a drug delivery system based on DNA nanostructure (TODP), which connected the linear tumor therapy gene p53 with disulfide bonds, inserted DOX into the base pairs of DNA double strands, and achieved the specific release of DOX and p53 in tumor cells through GSH response, thus realizing the combined treatment of gene and chemotherapy[116]. Liu Hong of Shandong University prepared a kind of copper-amino acid self-assembled nanoparticles (Cu-CysNPs). After the nanoparticles were endocytosed by tumor cells, they first reacted with local GSH to reduce Cu2+ to Cu+[117]. Subsequently, the Cu+ reacts with the local H2O2 in a Fenton-like manner to produce cytotoxic hydroxyl radicals, and the reaction rate of the Fenton-like reaction is increased in a weakly acidic tumor microenvironment to further induce apoptosis of tumor cells,Cu-Cys nanoparticles showed relatively high cytotoxicity to cancer cells and low toxicity to normal cells due to the continuous redox reactions triggered by the high expression of GSH and H2O2 in tumor cells (as shown in fig. 7). The results showed that Cu-Cys NPs could effectively inhibit drug-resistant breast cancer without causing significant systemic toxicity.
Diselenide bonds have smaller bond energies and are more sensitive than disulfide bonds. Behroozi et al. Reported a novel debathable micelle based on an amphiphilic triblock copolymer in which a diselenide is used as a redox-sensitive bond[118]. The diselenide bond, located at the junction of the hydrophilic-hydrophobic chains, allows complete destruction of the micelles by redox reactions, resulting in efficient drug release in the tumor environment. The system delayed tumor growth and reduced toxicity in a breast cancer tumor model after intraperitoneal injection in mice. Jia et al. Developed a nano-drug with tumor-targeting effect and local tumor sensitive response to release NO[119]. They co-loaded the glutathione S-transferase (GSTπ) -responsive drug NPQ (NO donor) and AIE red dye QM-2 into the nano-micelles, and then covered the nano-micelles with a GSH-sensitive shell to obtain a new organic-inorganic composite nano-drug (QM-NPQ @ PDHNs). The QM-NPQ @ PDHNs nano-drug can respond to the over-expression of GSH and GSTπ at the tumor site, the outer organic silicon shell is biodegraded, NPQ is released, and NO is further released inside the tumor, thereby reducing the damage to normal tissues of a human body.

3.3 Active oxygen responsive carrier

The high level of ROS produced by cancer cells provides a variety of ideas for the intelligent design of ROS-responsive drug delivery systems[120]. Zhang et al. designed a poly prodrug platform, which improved the drug loading efficiency through the strategy of conjugation with acid-labile bonds, and used thioketal bonds as the response part of intracellular ROS stimulation, so that the DOX-loaded nano-drug delivery system could be rapidly cracked under the stimulation of high levels of intracellular ROS to promote the rapid release of DOX[121]. The preparation has remarkable improvement in pharmacokinetics and biodistribution, the tumor accumulation is increased by 2.69 times, the systemic toxicity is greatly reduced compared with free DOX, and the preparation has the advantages of efficient cell uptake, preferential tumor accumulation, controlled release behavior and the like. Zheng et al. reported a stable polymeric siRNA assembly nanoparticle drug carrier bound using triple interactions (electrostatic, hydrogen bonding, and hydrophobic), as shown in fig. 8[122]. Compared with the traditional carrier which is combined only by electrostatic interaction, the addition of hydrogen bonds and hydrophobic interaction improves the physiological stability of the nano-drug, and the angiopep-2 short peptide is used to mediate the active targeting of the drug, which is internalized into tumor cells and then degraded by ROS response, thus realizing the precise targeted release of siRNA.
Wang et al. Reported a pH/ROS dual responsive nano-drug delivery system[123]. As shown in fig. 9, the system comprises beta-lapaquone (Lap), a pH-responsive polymer (PEG-PDPA-PDA), a hydrophobic drug (PEG-PtkDOX) and a Fe3+, and the PEG-PDPA-PDA fragment is converted from hydrophobic to hydrophilic in a weakly acidic environment of tumor cells, so that the carrier is rapidly cracked,At The same time, the entrapped Lap and the Fe3+,Lap complexed with dopamine (PDA) can actively produce H2O2. On the one hand, the Fe3+ and H2O2 can produce highly toxic hydroxyl radical through Fenton-like reaction.On the other hand, the surge of intracellular ROS level can further trigger the release of anti-tumor drug DOX linked by thioacetal bond, and this nano-drug delivery system with cascade reaction can effectively inhibit tumor growth.

3.4 Hypoxia responsive carrier

Tumor hypoxia responsive nano-drug delivery system can responsively activate and release drugs under hypoxia conditions. As shown in Fig. 10, the micelles prepared by combining polyethylene glycol and the anticancer drug combretastatin A-4 by using the azo bond as a linker for hypoxia response can release the drug in an anoxic microenvironment[124]. A diblock copolymer poly (lactic acid-azobenzene) -poly (ethylene glycol) with hypoxia response self-assembled into a polymer in an aqueous medium, and the polymer can exist stably under normal oxygen concentration conditions, but can be rapidly decomposed in an anoxic environment[125].
Tumor anoxic microenvironment can not only be used for responsive cleavage of chemical bonds, but also for targeted therapy of tumors. Sun Xun et al. Of Sichuan University used a facultative anaerobic strain VNP2009 with low toxicity as a biotherapeutic agent and drug carrier.The synergistic photothermal agent polydopamine is used for tumor targeting therapy, which not only achieves significant tumor targeting effect, but also eliminates the tumor in situ (as shown in Figure 11)[126].

3.5 Nzyme-responsive vector

Based on the fact that the activity and expression of some enzymes in tumor tissues are significantly higher than those in normal tissues, many studies have been devoted to the design and development of enzyme-responsive nano-drug delivery systems to achieve controlled drug release[127]. Cheng et al. developed a dendritic multiresponsive nanoparticle drug delivery vehicle for blocking tumor-specific metabolism[128]. The nano carrier breaks through the physiological barrier and cell factor of tumor drug resistance, prolongs the blood circulation time and improves the passive targeting efficiency by using the PEGylation coronoid,Matrix metalloproteinase (MMPs) response is used to enhance the tumor penetration and cellular uptake of the carrier, GSH response in the cell matrix can achieve precise drug release, and pH response in the lysosome can achieve nuclear delivery of the drug. Zhang et al. developed a novel enzyme-responsive PEGylated lysine peptide Dendrimer-gemcitabine conjugate (Dendrimer-GEM) nanoparticle, in which glycylphenylalanylglycine tetrapeptide (GFLG) can be cleaved by the enzyme, enabling faster release of the drug gemcitabine (GEM) in the tumor cell environment[129]. Compared with free GEM drugs, it showed stronger therapeutic effect and lower toxicity, significantly inhibited the growth of tumor volume, and no significant adverse reactions were observed after histological analysis. Kern et al. used reversible addition-fragmentation chain transfer (RAFT) polymerization to prepare diblock polymer micelles by introducing FKFL (four amino acids) linker which can be degraded by cathepsin B (as shown in fig. 12).Apoptosis of tumor cells is induced by the specific cleavage of the FKFL junction structure by cathepsin B, which releases the BIM peptide, a peptide therapeutic, in the target cell's endolysosome[130].

3.6 Other responsive vector

In recent years, researchers have designed ATP-responsive nano-drug delivery systems based on the difference of ATP in and out of tumor cells. Kataoka et al. designed a polyion complex (PIC) micelle modified by phenylborate, in which siRNA was encapsulated by the interaction of ribose and phenylborate[131]. At the level of ATP outside the tumor cells, the cross-linking of siRNA makes the micelles very stable. After entering the tumor cells, the intracellular ATP level is high, which makes the ribose on ATP competitively bind with phenylboronic acid, resulting in the destruction of the micelles and the intracellular release of siRNA triggered by ATP. Biswas et al. Prepared a kind of ATP-responsive protein nanotubes, which can achieve sustained and controlled release of drugs[132]. The nanotubes are used to prevent the biodegradation of drug molecules in the tubular structure by coordinating the connection of chaperone proteins and magnesium ions (Mg2+). After uptake by tumor cells, the conformation of the chaperone protein changes due to ATP hydrolysis (to adenosine-50 '-diphosphate, ADP), causing the nanotubes to cleave, releasing the drug within the tube.

4 Conclusion

In this paper, the design of nano-drug delivery system is discussed from the perspective of tumor microenvironment response strategy. The design of nano-drug delivery system can not only improve one of the five steps of chemotherapy drug delivery (blood circulation, accumulation, penetration, internalization and drug release), but also comprehensively utilize the tumor microenvironment to develop multi-responsive nano-drug delivery system and improve the drug delivery efficiency of multiple steps at the same time. It can also be combined with exogenous stimulus response to artificially introduce external stimulus signals (light, magnetic field, electric field, ultrasound, etc.) To achieve precise control of the function of the drug delivery system in time and space. Reasonable design of drug delivery system can overcome the difficulties encountered by many traditional chemotherapeutic drugs, bring new ideas for the treatment of tumors, and have important clinical application prospects in improving the efficacy of traditional chemotherapy, reducing the side effects of drugs, reducing the drug resistance of tumor cells and alleviating the suffering of patients during chemotherapy. Although responsive drug delivery systems based on tumor microenvironment have been reported, there are still many challenges in the clinical treatment of tumors. On the one hand, there are great differences in the microenvironment of different types of tumors, different tumor growth processes and different individual tumors.Even normal cells share some of the characteristics of the tumor cell microenvironment, and the complex interactions between the tumor extracellular matrix and tumor cells remain unclear. On the other hand, in the study of drug delivery system materials, the in vivo solubility and biocompatibility of materials have not been fully studied. Therefore, the construction of preclinical models to study the tumor microenvironment and the development of new and multi-functional monitoring systems to monitor the pharmacokinetic process, toxicological characteristics, distribution and metabolism of drug delivery systems in humans will greatly promote the development of drug delivery systems.It is of great significance to accelerate the development of drug delivery system from research and development to clinical treatment.
With the deepening of the study of tumor microenvironment, the design of nano-drug delivery system is no longer limited to the passive response to the stimulation of tumor microenvironment, but also gradually goes deep into the active regulation of some indicators of the microenvironment.For example, by delivering oxygen to the tumor site to alleviate the hypoxia of tumor tissue, neutralizing the slightly acidic environment of tumor tissue to regulate its pH value, and actively regulating immune cells to increase the phagocytosis of cells[133]. Compared with direct induction of tumor cell apoptosis, the method of active regulation of microenvironment has less toxic and side effects, and can cooperate with existing therapies to enhance the efficacy. In addition, from the research and development of nano-drug delivery systems to the production process, the complexity of responsive drug delivery systems also poses great challenges in productivity and quality control, such as how to optimize the various physical and chemical characteristics of nanoparticles (including size, shape, charge distribution, stability, diffusion performance, surface functionalization and interaction with organisms).How to improve the manufacturing process of drug delivery systems, make nanomaterials with high quality, replicable, and can be applied to commercial preparation on a large scale, are all the problems that pharmaceutical enterprises should strive to study.

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Funding

National Natural Science Foundation of China(51703105)

National Natural Science Foundation of China(21675091)

National Natural Science Foundation of China(21874078)

Natural Science Foundation of Shandong Province(ZR2017BEM012)

Taishan Young Scholar Program of Shandong Province(TSQN20161027)

Major Science and Technology Innovation Project of Shandong Province(2018CXGC1407)

Key Research and Development Project of Shandong Province(2016GGX102028)

Key Research and Development Project of Shandong Province(2016GGX102039)

Key Research and Development Project of Shandong Province(2017GGX20111)

China Postdoctoral Science Foundation(2018M630752)

Innovation Leader Project of Qingdao(168325zhc)

Postdoctoral Scientific Research Foundation of Qingdao

First Class Discipline Project of Shandong Province

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