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Combination Antitumor Therapy Based on Codelivery Nanosystems of Doxorubicin

Yuhan Bao , Zifeng Guo , Jintao Li , Mingzu Zhang , Jinlin He , Peihong Ni

Progress in Chemistry ›› 2023, Vol. 35 ›› Issue (8) : 1123 -1135.

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Progress in Chemistry ›› 2023, Vol. 35 ›› Issue (8) : 1123-1135 DOI: 10.7536/PC230114
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Combination Antitumor Therapy Based on Codelivery Nanosystems of Doxorubicin
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Abstract

Tumor has been one of the most common causes of death worldwide, while chemotherapy is still the major tool for antitumor treatment. As a broad-spectrum anthracycline-type antitumor drug, doxorubicin (DOX) has been widely used in different types of tumors in clinical practices. Nevertheless, its serious side effects, including cumulative cardiotoxicity and dose-limiting myelosuppression, present significant challenges to the clinical application. Researchers have long been committed to finding routes to reduce the toxic side effects of DOX, whereas the strategies of combination antitumor therapies based on codelivery nanosystems have received wide attention. They can realize the targeted enrichment and on-demand release of drugs in the lesion area, reducing the adverse reaction of DOX to normal tissues through drug combination and reversing the multi-drug resistance (MDR) of tumor cells to a certain extent. In this review, we focus on the recent progress on the DOX-based combination antitumor therapies together with other chemotherapeutic agents (camptothecin, paclitaxel, cisplatin), genetic drugs (pDNA, siRNA, miRNA), gas molecules (NO, O2, CO, H2S, SO2) or natural medicines (dexrazoxane, berberine, flavonoids). Besides, the current challenges and future trends of DOX-based combination therapies are also prospected.

Contents

1 Introduction

2 Combination therapy of DOX with other chemotherapeutic agents

3 Combination therapy of DOX with genetic drugs

4 Combination therapy of DOX with gas molecules

4.1 DOX in combination with NO

4.2 DOX in combination with O2

4.3 DOX in combination with CO

4.4 DOX in combination with H2S

4.5 DOX in combination with SO2

5 Combination therapy of DOX with natural medicines

6 Conclusion and outlook

Graphical abstract

Keywords

doxorubicin / antitumor therapy / combination therapy / codelivery nanosystem / tumor microenvironment

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Yuhan Bao, Zifeng Guo, Jintao Li, Mingzu Zhang, Jinlin He, Peihong Ni. Combination Antitumor Therapy Based on Codelivery Nanosystems of Doxorubicin. Progress in Chemistry, 2023, 35(8): 1123-1135 DOI:10.7536/PC230114

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1 Introduction

Cancer is a serious threat to human health, and its morbidity and mortality are increasing year by year in the world, which is one of the main causes of death in the world[1,2]. At present, cell therapy, immunotherapy and other emerging methods are not yet fully mature, surgery, radiotherapy and chemotherapy are still the three main means of cancer treatment[3,4]. Among them, chemotherapy is mainly through oral, subcutaneous or intravenous injection of anti-tumor drugs, which are distributed throughout the body through blood circulation and produce therapeutic effects after reaching a certain blood concentration in the body. However, chemotherapy drugs have obvious toxic and side effects on normal tissue cells in the human body while eliminating tumor cells, and long-term chemotherapy can easily lead to multidrug resistance (MDR) of tumor cells, which may even lead to recurrence and metastasis of tumors and greatly reduce the therapeutic effect[3,4].
The mechanism of MDR is complex, which can be roughly divided into cellular mechanism and non-cellular mechanism[5,6]. Cellular mechanisms mainly include increased drug efflux, decreased drug uptake, defects in apoptotic pathways, repair of damaged DNA, and autophagy, while non-cellular mechanisms are mainly related to the overexpression of ATP-binding cassette (ABC) transporters. P-glycoprotein (P-gp) is one of the important transporters in the process of drug efflux, which has been widely studied since its discovery. The overexpression of P-gp on the tumor cell membrane leads to the efflux of anti-tumor drugs against the concentration gradient and the decrease of intracellular drug concentration. At the same time, the efflux of a drug will also affect the therapeutic effect of other chemotherapeutic drugs, resulting in MDR of tumor cells. Studies have found that Combination therapy with two or more drugs has gradually become a new trend in cancer treatment, and appropriate Combination of drugs can regulate signaling pathways by different mechanisms.Restore the sensitivity of tumor cells to chemotherapeutic drugs, reverse the MDR of tumor cells, effectively reduce the dosage of drugs while reducing the toxic and side effects of drugs, and play a better anti-tumor effect than single drug treatment[7].
Doxorubicin (DOX), also known as Doxorubicin, is an anthracycline antibiotic with broad-spectrum anti-tumor activity. It was first isolated in 1969 when mutagenizing Streptomyces peucetius, which produces daunomycin. It has become one of the commonly used chemotherapy drugs for leukemia, lymphoma, breast cancer, uterine cancer, ovarian cancer and lung cancer[8,9]. According to the ClinicalTrials website, as of January 2023, there are 2457 clinical trials on DOX in the world, and many products (such as Adriamycin®, Doxil®, Myocet®, etc.) Have been approved for marketing in different countries. DOX is an orange-red crystalline powder with a density of 1.61 g/cm3 and a melting point of 205 ° C. It is soluble in dimethyl sulfoxide and tetrahydrofuran, insoluble in acetone, benzene, chloroform and ether, and can exist stably at normal temperature and pressure, but it needs to be stored in a dark and cool place. The water solubility of DOX is very low (~ 1.18 mg/mL), and its water solubility can be greatly improved (50.0 mg/mL) by converting it to the hydrochloride form (DOX · HCl)[9]. As shown in Fig. 1, DOX has an amphiphilic chemical structure containing a water-insoluble adriamycin unit and a water-soluble amino sugar unit.
It has been reported that DOX acts on nucleic acids in dividing cells for therapeutic purposes mainly through two mechanisms: (1) inserting between base pairs of DNA strands to inhibit DNA and RNA synthesis in rapidly proliferating cells by blocking replication and transcription processes[8,9]; (2) Production of iron-mediated free radicals to cause oxidative damage to cell membranes, proteins, and DNA. However, anthracyclines such as DOX can not only cause bone marrow suppression, but also damage the normal myocardial cell tissue of the human body, causing dose-cumulative cardiotoxicity and irreversible myocardial damage[10,11]. At the same time, it has also been reported that DOX can cause mitochondrial dysfunction in normal cells, produce a large number of reactive oxygen species (ROS), lead to oxidative stress, neuroinflammation and apoptosis, and ultimately induce cognitive dysfunction[12]. These toxic side effects largely limit the clinical application of DOX. As no other chemotherapy drugs have been found to completely replace anthracyclines, researchers have been committed to finding ways to reduce the toxic and side effects of anthracyclines for a long time, and the rapid development of nanotechnology in recent years has provided a powerful tool to solve these problems. More and more studies have shown that the combination of DOX with other chemotherapeutic drugs, gene drugs, gas molecules or natural drugs can reduce the toxic and side effects of drugs on normal cells and tissues, and can reverse the MDR of tumor cells to a certain extent, which is expected to achieve the synergistic therapeutic effect of "1 + 1 > 2"[13⇓~15]. By introducing targeting molecules and stimuli-responsive groups into the co-delivery carrier, the enrichment of the drug delivery system at the tumor site and the internalization of specific cells can be improved, and the drug can be rapidly released in the lesion area in response to endogenous (pH, hypoxia, redox, enzyme) or exogenous (light, heat, ultrasound) stimuli at the tumor site[16⇓⇓⇓~20]. In this paper, we will review the research progress of DOX combined with other chemotherapeutic drugs, gene drugs, gas molecules and natural drugs in the treatment of cancer in recent years, and look forward to its development trend.

2 DOX in combination with other chemotherapeutic agents

Single chemotherapeutic drug therapy usually can only temporarily delay tumor growth, and it is easy to cause MDR and reduce the efficacy, which promotes the research of combination chemotherapy to overcome MDR. The cocktail therapy for AIDS is a successful example of drug combination therapy, which shows that the combination of drugs can effectively control the disease. As one of the most commonly used chemotherapeutic drugs, DOX is often used in combination with other chemotherapeutic drugs, which can regulate different signaling pathways in tumor cells at the same time, effectively overcome MDR of tumors, and reduce systemic toxicity by reducing the dose of a single drug, thus playing a synergistic therapeutic effect[21].
Camptothecin (CPT) and paclitaxel (PTX) are natural antitumor drugs originally extracted from plants, and are also commonly used as first-line chemotherapeutic drugs in clinic, and have different antitumor mechanisms from DOX[22⇓⇓~25]. Therefore, the combination of DOX and these two drugs can simultaneously use different mechanisms for synergistic therapy. Our research group designed and synthesized the side chain reduction-sensitive CPT-dextran prodrug (Dex-ss-CPT) and acid-sensitive DOX-dextran prodrug (Dex-hyd-DOX) (Figure 2a), which effectively improved the water solubility of CPT and DOX, and the mixed nanomicelles formed by the co-assembly of the two prodrugs could achieve the synergistic therapeutic effect and inhibit the MDR of tumor cells to a certain extent[26]. Subsequently, we further coupled CPT and DOX to the end group and side chain of biodegradable polyphosphate, respectively, to prepare a pH/reduction dual stimulus-responsive prodrug nanoparticle, which can also release DOX and CPT simultaneously in the tumor microenvironment (TME)[27]. This polymeric prodrug strategy effectively improves the stability of the drug in the blood circulation, solves the problem of drug leakage, and can achieve site-specific controlled release of the drug in the TME[28,29]. Using a similar strategy, Li et al. Used reduction-sensitive disulfide bonds to connect DOX and PTX to the end of polyethylene glycol to prepare two polymer prodrugs, and then co-assembled to form mixed micelles to achieve drug co-loading and responsive release[30]. In addition, by adjusting the polymer chain structure to control the proportion of drug loading, the synergistic controlled release of different proportions of drugs can be achieved, and the therapeutic effect can be further improved[31].
Cisplatin (CDDP), also known as cisplatin dichloride, is effective for breast cancer, nasopharyngeal carcinoma, osteosarcoma and other tumors, and the combination therapy of DOX and cisplatin has also been widely studied. Cisplatin can induce biological alkylation reaction and cause DNA damage during tumor therapy, while DOX can act as an anthracycline topoisomerase Ⅱ (TOP2) inhibitor to prevent effective DNA repair to a certain extent, thus reflecting the synergistic therapeutic effect[32⇓~34]. However, the side effects and pharmacokinetic differences of the two drugs are still important problems to be overcome in the realization of combination therapy. In this regard, researchers suggest that nanoparticle systems have the potential to improve the current problems. Zhang et al. constructed a cross-linked nanogel based on natural hyaluronic acid (HA) in an aqueous system to co-load DOX and cisplatin. DOX was loaded on HA through electrostatic adsorption, while cisplatin could coordinate with the carboxyl group on HA to stabilize the nanoparticles (Figure 2b)[35]. The self-crosslinked nanogel shows good blood circulation stability and intratumoral enrichment ability, and can simultaneously transport DOX and cisplatin into tumor cells and release the drug in a weak acidic environment in the cells. The mouse tumor inhibition experiment showed that compared with the blank group and the combination of the two free drugs, the self-crosslinked nanogel showed more excellent performance of inhibiting the growth of osteosarcoma. Yang et al. Also used electrostatic adsorption and coordination to connect DOX and cisplatin with thermosensitive triblock copolymer to form nanogels, and cisplatin formed a compact three-dimensional crosslinked network shell around the DOX core, so that DOX and cisplatin could be released in parallel to maximize their synergistic therapeutic effects[36]. In addition, due to the good thermosensitivity of the designed triblock copolymer, the nanogel can form a macroscopic hydrogel after intratumoral injection, which further improves the intratumoral retention time of DOX and cisplatin.

3 Combination of DOX and gene drug

MDR and toxic side effects caused by long-term use of DOX limit the further development of drug therapy. With the in-depth understanding of the physiological mechanisms and cellular activities related to tumorigenesis, anti-tumor therapies have become more diversified and targeted[37]. Gene therapy refers to the use of appropriate vectors to introduce exogenous genes into tumor cells, through silencing the genes that regulate the function of tumor cells and down-regulating the expression of related proteins to achieve the purpose of eliminating tumor tissues. However, gene therapy is also limited by gene degradation, low cell transfection efficiency and short blood circulation time, so its application needs to rely on more efficient nano-carrier system[38⇓⇓⇓⇓⇓~44]. Chemotherapy with a single drug can only block one signaling pathway in the process of tumor growth, and it is difficult to achieve sustained and complete anti-tumor effect. Chemotherapy and gene therapy are used for combined anti-tumor, and specially modified nanocarriers are used to transport chemotherapeutic drugs and genes to tumor lesions at the same time, which can effectively inhibit tumor MDR, reduce drug dosage, reduce carcinogenic protein expression, and improve anti-cancer effect, with good prospects for development[45]. There are many types of nanocarriers for co-delivery of chemotherapeutic drugs and genes, including liposomes, nanoparticles, and polymeric micelles. These nanocarriers can increase the enrichment of chemotherapeutic drugs and genes in tumor tissues through enhanced permeability and retention (EPR) effect or active target direction, and then selectively release them at the lesion site[38,39].
Compared with normal cells, tumor cells are unable to undergo normal apoptosis, because the expression of tumor suppressor genes in tumor cells is often inhibited or down-regulated, and the induction of apoptosis requires the expression of tumor suppressor genes. P53 gene is the first discovered important tumor suppressor gene, which can slow down or monitor cell division, and its damage or mutation is closely related to the occurrence of many tumors.Therefore, the use of plasmid DNA (pDNA) has become a classical gene therapy, which can correct the disorder of human gene structure or function, inhibit the replication of pathogenic genetic material, and achieve the purpose of disease treatment. Zhang et al. Used acid-sensitive hydrazone bond to connect DOX to polyethyleneimine (PEI) to prepare PEI-hyd-DOX prodrug, and added pGL-3 plasmid to obtain PEI-hyd-DOX/pGL-3 co-carrier nanoparticles. The study found that the co-carrier system could reduce the toxicity of DOX and improve the transfection efficiency of pGR-3[46]. Nie et al. Used graphene oxide (GO) to immobilize PEI to form a GO-PEI skeleton, and then stacked DOX on the surface of GO through π-π bonds, while the negatively charged p53 gene could be co-loaded with the positively charged PEI chain segment through electrostatic interaction, and finally the DOX/GO-PEI/p53 complex was obtained[47]. The results showed that the co-carrier system released DOX faster under acidic conditions than under neutral conditions, and had lower toxicity than PEI/DNA nanoparticles, and the complex could release DOX and express p53 in sequence. Our research group used various reactions such as ring-opening polymerization, reversible addition-fragmentation chain transfer (RAFT) polymerization and "click" chemistry to construct a multifunctional carrier based on polyphosphate for co-loading DOX and p53 (Figure 3A), and the results showed that the carrier had good biocompatibility and could play a synergistic role in inhibiting tumor cell proliferation[48]. Targeted molecular bonding to the carrier surface will further increase antitumor efficacy, as tumor cells often overexpress certain specific receptors on their surface. Chen et al. Designed and synthesized an amidated cell-penetrating peptide (aTAT) -modified chitosan/polylysine graft copolymer for targeted delivery of p53 and DOX[49]. The results show that the targeted modification vector can effectively and actively target the tumor site, increase the tumor enrichment of the vector, achieve high gene transfection efficiency and drug delivery, and also has high anti-tumor effect in vivo.
Small interfering RNA (siRNA) is usually a double-stranded RNA of 20 to 25 nucleotides in length, which can inhibit the expression of specific genes by blocking their translation or transcription. Tumors are characterized by uncontrolled cell growth due to abnormalities caused by gene mutations, and overexpression of some genes is also one of the causes of tumors[50]. In addition, P-gp, an important transporter in drug efflux, is mainly encoded by MDR1 gene, and the overexpression of P-gp is the main cause of MDR in tumor cells. Therefore, the combination of specific siRNA and chemotherapeutic drugs can promote the synergistic effect of chemotherapy and gene therapy through targeted delivery, down-regulate the expression of specific genes or transporters, increase the accumulation of chemotherapeutic drugs in cells, and bring about stronger cell killing effect[42,51]. Shuai et al. Designed and synthesized a class of complex micelles composed of two block copolymers polyethyleneimine-poly (ε-caprolactone) and folate-polyethylene glycol-polyglutamic acid for targeted co-delivery of hydrophobic DOX and hydrophilic BCL-2 siRNA, which played a good synergistic effect in both human hepatocellular carcinoma cell Bel-7402 and mouse glioma C6[52,53]. Yin and Tang et al. Also combined hydrophobic interaction and electrostatic interaction to construct a multifunctional composite carrier based on modified chitosan for co-loading DOX and siRNA, which achieved good synergistic anti-tumor effect in cell and animal experiments[54,55]. Cheng et al. Prepared mPEG-PCL-g-PDMAEMA micelles for co-delivery of DOX and Cy5-siRNA by nanoprecipitation technique (Figure 3B), and the confocal images showed that both of them appeared not only in the cytoplasm of tumor cells but also in the nucleus, proving that the micelles had great potential as a carrier for efficient delivery of DOX and siRNA[56]. Li et al. Used PEI and PEG to modify molybdenum disulfide nanosheets with high near-infrared photothermal conversion efficiency, and co-loaded DOX and siRNA to obtain a multifunctional nano-co-delivery system with chemical, genetic and photothermal therapy[57]. The results showed that the system had good biocompatibility, photoresponsiveness and stability, achieved faster drug release under low pH and near-infrared light triggering conditions, and had stronger killing effect on drug-resistant tumor cells. The above literature reports need to use hydrophobic interaction and electrostatic interaction to co-load DOX and siRNA, and the synthesis route of the vector involved is relatively complex. Recently, Wang and Yang et al. Developed a carrier-free nanoassembly PEG @ D: siRNA composed of a prodrug of PEG and DOX linked by an acid-sensitive hydrazone bond (PEG-hyd-DOX) and siRNA[58]. PEG-hyd-DOX prodrug can load siRNA through π-π stacking and electrostatic interaction to form carrier-free nanoassemblies with high drug content (siRNA content of 4.13%, DOX content of 21.67%). The findings suggest that this siRNA-loaded nanoassembly can significantly increase tumor-infiltrating T lymphocytes and enhance interferon-γ expression, thereby enhancing the immunogenic cell death effect of DOX prodrug, and finally significantly enhance the anti-tumor immune response and effectively inhibit tumor growth. Moreover, the facile synthetic route of this nanoassembly is expected to be a versatile strategy for the efficient preparation of co-loaded chemotherapeutic drugs and genes.
MicroRNA (miRNA) is a non-coding microRNA of 19-24 nucleotides in length, which can participate in the regulation of tumor cell dynamics by binding to complementary sequences of target messenger RNA (mRNA) and promoting its translational inhibition or degradation. The combination of miRNA with specific sequences and small molecule chemotherapeutic drugs can promote tumor cell apoptosis and autophagy, reverse tumor epithelial-mesenchymal transition, inhibit tumor angiogenesis, and down-regulate the expression of ABC transporters, thus showing synergistic anti-tumor effects[59]. Gao et al. Prepared a disulfide-cross-linked amphiphilic polyamino acid copolymer for co-loading DOX and miR-34a to synergistically treat prostate cancer[60]. The polyarginine on the outer side of the block copolymer structure has excellent endocytosis and gene compression ability, the hydrophobic octadecyl chain is used for loading DOX, and the pH-sensitive polyhistidine in the middle of the structure can be protonated in the cytoplasm to facilitate the release of drugs. The results showed that the composite micelle system not only reduced the cardiotoxicity of DOX, but also down-regulated the expression of silent information regulator 1 (SIRT1) and inhibited the proliferation of human prostate cancer cells DU145 and PC3, showing better anti-tumor effect than DOX or miR-34a administration alone. Torchilin et al. Designed a dual matrix metalloproteinase-2 (MMP-2) and reduction-sensitive prodrug micelle to deliver DOX and miR-34a[61]. The composite prodrug micelle mainly consists of three parts: DOX and PEG2k bonded by MMP-2-sensitive peptide, miR-34a and phospholipid bonded by disulfide bond, and PEG-PE modified by cell-penetrating peptide TAT. The results showed that the micelles showed strong cytotoxicity in HT1080 cells overexpressing MMP-2, and could release miR-34a molecules under the condition of high concentration of glutathione (GSH) reduction in tumor cells, which promoted the down-regulation of oncogenes such as Bcl2, notch1 and survivin. Shi et al. Recently reported an amphiphilic phosphorus-containing dendrimer micelle co-loaded with DOX and miR-21i for the combined treatment of triple-negative breast cancer (Figure 3C), verifying the synergistic efficacy of the co-loaded system in cell and animal trials[62]. The surface of the nanoparticle is modified by natural or biomimetic cell membrane materials, and the obtained cell membrane-coated nanoparticle not only retains the original physical and chemical properties of the nanoparticle,At the same time, the modified nanoparticles can be protected from the attack of the immune system by the function of proteins and polysaccharides on the surface of the cell membrane, so that the modified nanoparticles have longer circulation time in vivo and tumor targeting ability[63⇓⇓~66]. Paulmurugan et al. Constructed a cancer-platelet fusion membrane vesicle (CPMV) using cell membranes extracted from breast cancer cells and platelets, and loaded miRNAs (antimiR-10b and antimiR-21) with microfluidic technology to treat triple-negative breast cancer[67]. It has been found that CPMVs can efficiently recognize their source cells and avoid phagocytosis by macrophages. After systemic administration in mice, CPMVs showed longer circulation time and site-specific accumulation effect, and the delivered miRNA could improve the sensitivity of triple-negative breast cancer to DOX, thereby enhancing the synergistic therapeutic effect.
Suicide gene is an exogenous gene fragment that can express toxic substances from different sources in target cells, and targeted delivery of appropriate suicide genes to tumor cells or surrounding tissues can effectively cause their death[68]. Hajitou et al. Developed a non-pathogenic phage vector containing human adeno-associated virus DNA in the shell to combine with DOX for anti-tumor therapy. The results showed that DOX could promote the accumulation of suicide genes in the nucleus by destroying the stability of the nuclear membrane, thus changing the intracellular trafficking of the vector[69]. Genes can not only be used in cancer therapy, but also be designed as drug delivery carriers, which provides a new idea for the development of new drug delivery systems. Yang et al. First used the rolling circle amplification method to obtain long single-stranded DNA (lsDNA) from tumor cell-associated TK1 mRNA, and then self-assembled the lsDNA, fluorescent indicator probe HP, and DOX into DNA nanospheres (Fig. 3D), which can react with intracellular mRNA in two steps to release DOX, and can effectively overcome the efflux of drug-resistant cells, thereby improving the therapeutic effect of DOX[70]. Li et al. Used DNA tetrahedron as a carrier to co-load DOX and CpG oligonucleotides for immunotherapy, and the formed nanoparticles showed synergistic effects in enhancing immunostimulatory activity and improving anti-tumor efficiency[71].

4 Combination of DOX and gas therapy

Gas therapy, as a new therapeutic strategy, has been paid more and more attention in cancer treatment. Many gaseous molecules, such as O2, CO, NO, H2S, and SO2, play important regulatory roles in various physiological processes of cells, tissues, or organisms, and thus exhibit great potential in the treatment of a variety of diseases, including tumors[72⇓⇓⇓⇓~77]. Studies have shown that appropriate concentrations of physiologically relevant gas molecules can effectively reduce the Warburg effect of tumor cells, inhibit the proliferation of tumor cells and accelerate their apoptosis without damaging normal cells, so as to achieve the therapeutic effect of cancer. In addition, it has been found that some physiologically active gas molecules can cooperate with other conventional cancer treatment methods through different mechanisms to improve the efficacy. A variety of nanosystems have also been designed to co-carry DOX and gas molecules (or donor molecules capable of producing gas) to achieve combined treatment of tumors.

4.1 DOX combined with NO therapy

NO is the first gaseous signal molecule discovered, which is related to a large number of physiological metabolic processes in organisms. Endogenous nitric oxide is mainly produced by L-arginine in organisms under the catalysis of nitric oxide synthase. Physiological concentrations of nitric oxide can regulate protein kinase signaling pathways, ATP-dependent potassium channels and so on. The overexpression or dysfunction of ABC transporters on the tumor cell membrane is one of the important causes of MDR. For example, P-gp can use the energy released by the hydrolysis of ATP to pump hydrophobic chemotherapeutic drugs from the cytoplasm to the outside of the cell. A large number of studies have shown that a certain concentration of NO can down-regulate the expression of P-gp by binding to the heme group, reduce the leakage of drug molecules, and thus effectively reverse MDR to improve the anti-tumor effect[76,78]. Therefore, one of the strategies to use nitric oxide in tumor therapy is to release a higher concentration of nitric oxide to the lesion site, and to use nanoparticles to co-carry chemotherapeutic drugs and various nitric oxide donors to achieve anti-tumor combination therapy[76]. Chen et al. Used biocompatible poly (ethylene glycol) -poly (lactic-co-glycolic acid) block copolymer (mPEG-PLGA) to co-carry ultraviolet-visible light-responsive NO donor N, N '-di-sec-butyl-N, N' -dinitroso-1,4-phenylenediamine (BNN6) and DOX to obtain a new nano-drug delivery system mPEG-PLGA-BNN6-DOX, and studied its performance of overcoming MDR of tumor cells[79]. The mPEG-PLGA-BNN6-DOX maintains good stability under physiological conditions, but can release NO under the stimulation of ultraviolet-visible light, and the generated bubbles further destroy the shell of the nanoparticles to release DOX. NO enhances the chemotherapeutic effect of DOX by reversing the MDR of tumor cells, greatly improving the synergistic antitumor efficiency. Yao et al. Proposed a photothermal responsive NO release system based on thermosensitive S-nitrosothiol (SNO) for co-loading DOX, which induced mitochondrial dysfunction through NO, thereby blocking ATP synthesis, reducing ATP-dependent drug pumping process, and ultimately improving the effect of DOX chemotherapy[80]. In addition, combination therapy can also adopt a prodrug strategy to integrate NO donors into polymers. Hu et al. Constructed a class of amphiphilic triblock copolymers PEG-b-PNORM-b-PEG containing N, N '-dinitroso-p-phenylenediamine (DNP) motifs in the main chain for co-loading DOX by polycondensation[81]. Under visible light irradiation, the DNP motif can release NO to inhibit the activity of P-gp and reverse the MDR of tumor cells, while the micelle dissociates to release DOX (Fig. 4A), showing a combined killing effect on tumor cells. Dong et al. Combined poly (amino acid) copolymer containing SNO motif in the side chain with poly (dopamine) nanoparticles to prepare a near-infrared/pH dual-responsive nanocomposite co-loaded with NO donor and DOX[82]. Under the irradiation of near-infrared light, PDA produces photothermal effect to release NO from SNO motifs, which down-regulates the expression of P-gp, reverses MDR of tumor cells and improves the efficacy of DOX. In vivo experiments showed that the combination of DOX and NO showed excellent anti-tumor effect in the mouse model of adriamycin-resistant MCF-7/ADR breast cancer cells.

4.2 DOX combined with O2 therapy

Hypoxia is one of the main characteristics of TME, which is essentially caused by the imbalance between local oxygen supply and oxygen consumption. Because of the abnormal structure of new blood vessels in the tumor site, the blood flow rate can not be regulated, and the persistent hypoxia makes the distribution of blood vessels uneven, and the distance between blood vessels exceeds the diffusion distance of O2, resulting in difficulties in the transport of O2. At the same time, the rapid proliferation of tumor cells consumes a large amount of O2, so that the TME is in a state of hypoxia (< 5 mmHg)[83]. This property up-regulates hypoxia-inducible factor-1α (HIF-1α) at the tumor site, leading to overexpression of P-gp and the generation of MDR[84]. Therefore, in order to improve the delivery ability and therapeutic effect of chemotherapeutic drugs, researchers proposed that co-loaded O2 donors and DOX should be released after targeted delivery to tumor tissue cells, hoping to improve the chemotherapeutic effect by increasing the concentration of O2 in the lesion site. Xiang et al. Designed a nanoparticle system co-loaded with DOX and capable of producing O2 (DOX-CaO2/MnO2), which could expose the water-sensitive inner core through the destruction of superficial glycerol monostearate by lipase highly expressed in tumor cells, release DOX and produce O2 by the CaO2/MnO2 system, and increase the local O2 concentration to down-regulate the level of HIF-1α and inhibit the expression of P-gp[85]. It further promotes tumor cell apoptosis and releases nanoparticles with exposed inner core, thus releasing DOX and O2 more completely. Free DOX can diffuse through the extracellular matrix, while O2 can promote drug penetration by reducing the sedimentation of extracellular matrix collagen, and both can accelerate the induction of tumor cell apoptosis when they reach the deep region of the tumor.
Photodynamic therapy (PDT), as another conventional tumor treatment strategy, is often used in combination with chemotherapy through co-delivery of drugs and photosensitizers. The mechanism of PDT is that the photosensitizer consumes O2 and generates cytotoxic singlet oxygen (1O2) to kill tumor cells, so the therapeutic effect of PDT is also closely related to the content of O2 in the tumor site. Zhang et al. Designed an amphiphilic molecule composed of perfluorocarbon chain (PFC), photosensitizer IR780 and hydrophilic PEG chain (F-IR780-PEG) to co-carry DOX and O2, and the formed nanoparticles could release O2 after aggregation at the lesion site, which played a role in down-regulating HIF-1α and P-gp expression[86]. At the same time, the 1O2 produced by near-infrared light irradiation can not only kill tumor cells, but also trigger the fragmentation of IR780 to release DOX, achieving the synergistic anti-tumor effect of PDT and chemotherapy (Fig. 4B). However, this PFC-based O2 delivery process is mainly driven by concentration gradients, with poor controllability and difficulty in achieving high O2 concentrations. Recently, Li et al. Designed a photothermal-controlled "oxygen bomb" ”(PSPP-Au980-D), which integrates PDT, photothermal therapy and chemotherapy, for the programmed level synergistic treatment of hypoxic orthotopic pancreatic cancer[87]. In the structure of the PSPP-Au980-D carrier, the core PFC can carry a high concentration of O2(2.25±0.22 mg/g), the middle layer is composed of silicon phthalocyanine and polystyrene, which can be used as photosensitizers for PDT, and the shell is composed of gold nanorods, thermosensitive poly (N-isopropylacrylamide) and DOX, which are responsive to photothermal reagents in the near infrared II region. They first used 980 nm laser to irradiate the PSPP-Au980-D, and the photoheat generated by it triggered the release of O2 and injected hypoxic TME, accompanied by local hyperemia and DOX release. PDT was then achieved by irradiation with a 680 nm laser to produce 1O2. The experimental results show that the programmed cascade therapy strategy based on the multifunctional carrier can effectively inhibit the growth of hypoxic tumors under the conditions of low light intensity and DOX dosage.

4.3 DOX combined with CO therapy

As a stable and freely diffusible gas signal molecule, the physiological effects of CO are closely related to its concentration. At low concentration, CO participates in the growth, angiogenesis and metabolism of tumor cells through the heme oxygenase-1/CO system[88]. At high concentrations, it combines with hemoglobin to produce carboxyhemoglobin, which reduces the oxygen carrying capacity of blood and leads to tissue hypoxia. It has been reported that a certain concentration of CO can produce a large amount of ROS to kill tumor cells by enhancing mitochondrial respiration and increasing O2 consumption[89]. Therefore, appropriate concentration of CO can effectively treat inflammation, tumor and other diseases. However, considering that CO can cause cytotoxicity to other normal tissues when used as a drug, how to release and use CO at a fixed point becomes the key to the study[90]. Wang et al. Innovatively proposed an "Enrichment-triggered activation" prodrug strategy based on bioorthogonal click chemistry to achieve the specific release of CO and DOX at the target site[91]. Simply put, the concentration of the two components involved in the click reaction in the blood circulation is low, which makes the reaction between them very slow, and the non-specific release of the corresponding parent drug is very small. When the targeting molecule enriches the two-component reactant to the target site, the reaction rate between the two components increases due to the significant increase in the local concentration of the reactant, resulting in the specific release of a large number of parent drugs at the target site. Studies have found that CO can effectively protect normal cells while enhancing the sensitivity of tumor cells to chemotherapeutic drugs. Shen et al. Reported that a magnetic carbon nanoparticle modified by manganese carbonyl was used to load DOX, and manganese pentacarbonyl bromide was used for CO storage and controlled release, which realized the combination therapy of CO and DOX with near-infrared response, and significantly improved the efficacy of DOX[92]. Yang et al. Used near-infrared responsive mesoporous carbon nanoparticles to CO-carry DOX and triiron dodecacarbonyl (FeCO). After the nanocarrier absorbs near-infrared light, the heat stimulates the thermosensitive FeCO to release CO, which improves the sensitivity of tumor cells to DOX through the iron death pathway and enhances the synergistic therapeutic effect[93][94]. Recently, Zheng et al. Constructed a self-assembled nanocarrier containing nitrophenyl ether and 3-hydroxyflavone (3-HF) derivatives for entrapping DOX. The CO-carrier system can trigger 3-HF derivatives to release CO and achieve controlled release of DOX under light (Fig. 4C), so as to achieve the effect of combined treatment of tumors[95].

4.4 DOX combined with H2S therapy

H2S is an endogenous gas signaling molecule, which usually exists in various mammalian tissues and cells, mainly produced by cystathionine-γ lyase, cystathionine-β-synthase and 3-mercaptopyruvate sulfurtransferase, and has many physiological functions such as anti-oxidation, anti-inflammatory, promoting vasodilation and so on[96⇓~98]. Similar to CO and NO, low concentration of H2S can induce vasodilation, reduce blood pressure and anti-inflammatory effects. However, high concentrations of H2S can impair the viability of cells by inhibiting mitochondria, activating apoptotic signals and acidifying the intracellular environment, and then lead to apoptosis[99]. In addition, some studies have found that H2S can reduce myocardial reperfusion injury, promote angiogenesis and treat cardiac fibrosis, which is a potential gas cardioprotective agent[100,101]. As an endogenous gas, the tumor site will produce a certain concentration of H2S, but because of its low content, it shows a cancer-promoting effect, so it is necessary to deliver more H2S to the lesion site to achieve the effect of tumor treatment. Fruttero et al. Synthesized a series of small molecule prodrugs (H2S-DOXOs) composed of DOX and H2S donors, and found that they exhibited lower cardiotoxicity than DOX alone, while having higher killing efficiency on U-2OS osteosarcoma cells overexpressing P-gp[102]. Subsequently, in order to further enhance the tumor targeting performance of small molecule prodrugs, they coupled H2S-DOXOs with sodium hyaluronate with CD44 targeting function to prepare active targeting polymer prodrug (HA-Lsdox), which can reverse MDR and show very good synergistic anti-tumor ability[103]. Lukesh et al. Designed a H2O2 responsive H2S/DOX co-delivery system to release H2S through carbonyl sulfide hydrolysis for cardioprotection and synergistic antitumor therapy[104]. Chen et al. Developed a tumor-specific lipase-responsive DOX drug carrier, which can release H2S through the reaction of diallyl trisulfide with GSH at the lesion site (Figure 4D), improving the therapeutic effect of DOX[105]. In addition, H2S present at the tumor site can also participate in chemotherapy as a trigger for stimulus-responsive antitumor drug delivery carriers[106].

4.5 DOX combined with SO2 therapy

SO2 is one of the main air pollutants in traditional cognition, which can cause serious damage to the respiratory system. Recent studies have shown that mammals can produce SO2 in the metabolism of sulfur-containing amino acids through the transamination of aspartate aminotransferase, making it another important gaseous signaling molecule[107]. Low concentrations of SO2 can play a positive role in physiological regulation, while high concentrations of SO2 have high toxicity to cells and are closely related to the occurrence of many diseases. Under physiological conditions, SO2 can undergo a series of redox processes related to free radicals, some of which have strong oxidation and can cause serious oxidative damage and even induce apoptosis, so SO2 has been widely concerned in inhibiting tumor growth in recent years[108]. Taking advantage of the high concentration of GSH in TME, Chen and Xiao et al. Linked a GSH-responsive small molecule SO2 prodrug, 2,4-dinitrobenzenesulfonamide, to the side chain of PEGylated poly (L-glutamic acid) (Fig. 4E) or dextran, respectively.The amphiphilic polymer prodrug was prepared and co-assembled into DOX-loaded nanoparticles in water. The in vitro drug release results showed that the drug-loaded nanoparticles could simultaneously release SO2 and DOX under reducing conditions[109,110]. The SO2 released in situ in tumor cells increases the concentration of ROS in cells, resulting in oxidative damage of tumor cells, which can cooperate with DOX to kill tumor cells. The two drug-loaded nanoparticles have shown highly effective combination therapeutic effects in the MCF-7/ADR mouse model and the treatment of subcutaneous and metastatic melanoma in mice, respectively, providing a new technology to combat tumor MDR.

5 Combination of DOX and natural medicine

As mentioned above, the antitumor effect of DOX itself has been recognized, but the dose-cumulative cardiotoxicity limits its wide clinical application. Therefore, finding suitable cardioprotective drugs has also become a way to expand the clinical application of DOX. Dexrazoxane, as a clinically approved cardiotoxic protective drug, can prevent the cardiotoxicity of anthracycline chemotherapy while maintaining the anti-tumor activity of the drug[111]. However, because the cardiotoxicity of DOX has the characteristics of dose accumulation, the therapeutic intervention time of dexrazoxane is still controversial, and there are some side effects, so the cardioprotective drugs of anthracycline chemotherapy drugs such as DOX are still being studied[112].
With the development of research, the cardioprotective effect of natural compounds has been paid more and more attention. Natural compounds in some plants can enhance the efficacy and reduce the cardiotoxicity of DOX, and their combination with DOX can enhance their clinical application value. Flaxseed, a common health food, has been shown to have the same level of preventive effect as Perindopril on DOX-induced cardiotoxicity[113]. Costantini et al. Found that the combination of phenolics (PEFSO) extracted from linseed oil and DOX could inhibit the proliferation of MCF-7 and MDA-B231 breast cancer cells at the same time, and reduce the effective dose of DOX to reduce its toxic and side effects[114]. Berberine, the main component of Rhizoma Coptidis, has its own anti-tumor and cardioprotective effects, and its combination with DOX can prevent the heart injury caused by Berberine, but its mechanism is not yet clear[115]. The existing experiments show that the cardioprotective effect of berberine may involve multiple mechanisms. Su et al believed that berberine may show cardioprotective effect by increasing the level of intracellular Ca2+ and reducing mitochondrial dysfunction[115]. Xiong et al. Found that berberine could protect cardiomyocytes through the SIRT1/p66Shc-mediated pathway[116]. Zhang et al. Have recently shown that low doses of berberine have cardioprotective effects by stabilizing Bcl-xL protein levels affected by DOX and dissociating Bcl-xL and Beclin1 to restore mitophagy in cardiomyocytes[117].
Oxidative stress is one of the main mechanisms of DOX-induced cardiotoxicity[118]. DOX activates NADPH oxidase (NOX) in the heart to produce excessive ROS, which causes DNA damage, p53 protein phosphorylation and cardiomyocyte apoptosis, and ultimately leads to different degrees of myocardial disease[119]. Karimi et al. Found that natural flavonoid small molecules such as Luteolin, Quercetin and Paeoniflorin can reduce the generation of ROS by generating stable free radicals and preventing the aggregation of NOX subunits (mainly NOX2 and NOX4), and ultimately effectively attenuate the cardiotoxicity caused by DOX, thus becoming a better "antioxidant" to participate in the adjuvant treatment of chemotherapy[120]. However, it is not known whether the combination of flavonoids and DOX will produce drug-drug interactions. Researchers examined the pharmacokinetic characteristics of this type of therapy through in vitro experiments of drug-metabolizing enzymes, and found that the consequences of drug-drug interactions depend on whether the enzyme inhibitors are reversible, that is, the drug-drug interactions produced by the use of class I and class II chemotherapy-related CYP-metabolizing enzymes are not the same[121]. At the same time, current studies have shown that the bioavailability of flavonoids in human body is low, and there is still a long way to go before they are put into clinical use[120].

6 Conclusion and prospect

Anti-tumor combination therapy is a widely concerned research direction in recent years, which is expected to overcome the common problems of tumor heterogeneity, complexity and drug resistance in traditional chemotherapy, and minimize the toxic and side effects on normal tissues and organs on the basis of achieving synergistic therapeutic effect. In this paper, the broad-spectrum anti-tumor drug DOX is used as the core, and its combined anti-tumor treatment system with other chemotherapeutic drugs, gene drugs, gas molecules and natural drugs is summarized. The different components of these combination therapy strategies can eliminate tumor cells through their own mechanisms, and the stimuli-responsive targeted therapy system can be designed with the help of the characteristics of TME to achieve site-specific drug release at the lesion site.
However, while the current combination therapy strategy has made some progress, it also faces many challenges. (1) In addition to the combination treatment strategies summarized above, there are many other options. For example, the combination of DOX and protein drugs, anti-vascular therapy drugs, immunotherapy drugs, photodynamic therapy reagents, etc., the drug combination that can target primary tumors and metastatic tumors respectively, the drug combination that can target tumor tissues and circulating tumor cells, etc.[122⇓~124]; (2) How the co-loaded drug carrier maintains high stability and less drug leakage in the blood circulation, and how it can overcome the obstacles of dense extracellular matrix and high tissue osmotic pressure to efficiently penetrate into the tumor tissue and release drugs after reaching the tumor site[125⇓~127]; (3) Anti-tumor drug combination is not a simple superposition of drugs, but requires full consideration of the mechanism of action of different drugs, cell kinetics, drug toxicity, as well as the timing of drug administration, dose optimization, drug interactions and other issues, rigorous analysis and experiments to obtain the optimal solution of the combination strategy; (4) With the rapid development of combination therapy, many nanosystems with different functions have emerged. However, considering the complexity of biological systems and the metabolism of nanomaterials, it is necessary to develop nanosystems with simple structures and fewer components to reduce their uncertainty in vivo, which is also conducive to the next step of clinical translation[128]. Anti-tumor combination therapy is an emerging field with broad application prospects. Although it still faces many difficulties, it is believed that with the vigorous development of interdisciplinary integration of tumor biology, nanotechnology and targeted drug delivery, more breakthroughs will be made in the near future.

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Funding

Natural Science Foundation of the Jiangsu Higher Education Institutions of China(20KJA150009)

Undergraduate Training Program for Innovation and Entrepreneurship, Soochow University(202110285025Z)

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