Opportunities and challenges for co-delivery nanomedicines based on combination of phytochemicals with chemotherapeutic drugs in cancer treatment

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Abstract

The therapeutic limitations such as insufficient efficacy, drug resistance, metastasis, and undesirable side effects are frequently caused by the long duration monotherapy based on chemotherapeutic drugs. multiple combinational anticancer strategies such as nucleic acids combined with chemotherapeutic agents, chemotherapeutic combinations, chemotherapy and tumor immunotherapy combinations have been embraced, holding great promise to counter these limitations, while still taking including some potential risks.

Nowadays, an increasing number of research has manifested the anticancer effects of phytochemicals mediated by modulating cancer cellular events directly as well as the tumor microenvironment. Specifically, these natural compounds exhibited suppression of cancer cell proliferation, apoptosis, migration and invasion of cancer cells, P-glycoprotein inhibition, decreasing vascularization and activation of tumor immunosuppression. Due to the low toxicity and multiple modulation pathways of these phytochemicals, the combination of chemotherapeutic agents with natural compounds acts as a novel approach to cancer therapy to increase the efficiency of cancer treatments as well as reduce the adverse consequences. In order to achieve the maximized combination advantages of small-molecule chemotherapeutic drugs and natural compounds, a variety of functional nano-scaled drug delivery systems, such as liposomes, host–guest supramolecules, supramolecules, dendrimers, micelles and inorganic systems have been developed for dual/multiple drug co-delivery. These co-delivery nanomedicines can improve pharmacokinetic behavior, tumor accumulation capacity, and achieve tumor site-targeting delivery.

In that way, the improved antitumor effects through multiple-target therapy and reduced side effects by decreasing dose can be implemented. Here, we present the synergistic anticancer outcomes and the related mechanisms of the combination of phytochemicals with small-molecule anticancer drugs. We also focus on illustrating the design concept, and action mechanisms of nanosystems with co-delivery of drugs to synergistically improve anticancer efficacy. In addition, the challenges and prospects of how these insights can be translated into clinical benefits are discussed.

Graphic abstract

Advantages of the combination of phytochemicals with chemotherapeutic drugs in cancer treatment.

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Introduction

In recent decades, although we have made significant progress in cancer treatment, the incidence and mortality of cancer are still among the highest in the world. Worldwide, an estimated 19.3 million new cancer cases and nearly 10.0 million cancer deaths occurred in 2020 [1]. To successfully cure cancer and completely control the development of advanced cancer diseases is still a major problem and challenge. Past studies have shown that most cancers are caused by factors such as genetic disorders, environment, nutrition, and metabolic stress [2].

The Food and Drug Administration (FDA) has already approved more than 300 chemotherapeutic agents, such as nivolumab, ipilimumab, pembrolizumab, 5-flurouracil (5-FU), Olaparib, taxol, vinca alkaloids as well as their derivatives, gemcitabine, methotrexate. Currently, most of the chemotherapeutic drugs used in the clinic are aimed at single targets of nucleic acids, proteins and carcinogenic signaling pathways. For example, platinum drugs (oxaliplatin, carboplatin, cisplatin) interfere with the synthesis and metabolism of nucleotides and cause DNA damage. Gefitinib, erlotinib, and icotinib target the tyrosine kinase target. Bevacizumab, sunitinib, and sorafenib inhibit angiogenesis. Even though we have developed hundreds of drugs for cancer treatment, cancer is an evolutionary process. When we give drug interventions, the tumour cells gradually adapt to the changing environment, similar to Darwin's theory of natural selection, which leads to further tumour development [3], [4].

So we have to find new drugs to treat this kind of resistance. Coupled with the toxicity and non-targeting of these conventional chemotherapeutics, the treatment of cancer has been greatly restricted. In more recent years, phytochemicals have attracted many people's interests as new treatment options for the development of chemoprevention and cancer treatment. Since most of the established anti-cancer drugs are mostly derived from natural substances, we focused our attention on phytochemicals. The extracts of most natural products have shown good anti-cancer activity, with multiple targets and mild effects, which gives us more choices in the treatment of cancer. For example, baicalin, magnolol, evoline, quercetin, erianin, honokiol, thymoquinone (TQ), shikonin, elemene, tocotrienol (T3), gambogic acid, triptolide [5], [6], piperine, resveratrol, tetramethylpyrazine [7], SFN, and ursolic acid affect the development of malignant tumors in many ways [8], [9]. By down-regulating oncogenes and up-down suppressor genes, they promote cell apoptosis and autophagy. A variety of death methods such as pyrolysis, necrosis, ferroptosis, etc., induce the growth cycle of cancer cells to stagnate, promote their senescence, inhibit tumor angiogenesis and EMT pathways and other ways to inhibit the development of cancer [10] (Fig. 2). Honokiol can effectively prevent the growth of a multiple of tumors, this phytochemical is able to regulate diverse molecular targets [11], [12]. Resveratrol is a non-flavonoid polyphenol, which has the effects of anti-tumor cell proliferation, metastasis, epigenetic changes and inducing cell apoptosis, as well as increasing sensitivity to chemotherapeutics [13]. phytochemicals erianin exerts its anti-cancer effects by inhibiting cell migration and inducing Ca2+/CaM-dependent ferroptosis [14].

Due to the many limitations in the application of chemotherapy drugs, chemotherapy sensitization is a good strategy to break this limitation. This strategy is to use chemotherapy drugs in combination with another or more drugs to overcome their tumor effects. The choice of sensitizing drugs should have low toxicity and multi-targets, which can enhance the sensitivity of cancer cells to chemotherapy drugs through inhibiting signaling pathways involved in chemotherapy resistance. Phytochemicals have shown the potential to play this role in many ways. Numerous research findings have illustrated that the combination of chemotherapeutic drugs and phytochemicals can achieve synergistic sensitization, reverse drug resistance, and reduce the toxicity burden and side-effects of chemotherapeutic drugs [15]. In terms of mechanism, the development of chemotherapy resistance includes the reduction of drug uptake by tumor cells, the activation of DNA repair mechanisms, the abnormal expression of drug-resistant proteins, as well as the overexpression of transporters that causes increased drug outflow. The phytochemicals we take can make up for this defect to a certain extent and raise the effectiveness of chemotherapeutic drugs [15], [16]. For example, combined with sulforaphane can reduce the dose of CIS or 5-FU, and at the same time enhance the cytotoxicity of these drugs to HNSCC-CSC, with minimal impact on normal cells [17]. Curcumin combined with anticancer drugs to treat glioblastoma multiforme (GBM) cells reduces their self-renewal, differentiation and malignant properties [18].

Despite the advantages of combination therapy over monotherapy, clinical outcomes remain suboptimal. At the same time, we should consider the clinical feasibility of the combined treatment plan we have adopted, such as the water solubility and bioavailability of drugs, the targeting drugs, and the duration of drugs at the tumor site [19]. Nanomedicine, a drug delivery system with a size of 1–1000 nm, is mainly used to improve the balance between the efficacy and toxicity of combined or embedded chemotherapeutic drugs. Therefore, based on nano-carriers, jointly deliver chemotherapeutic drugs and phytochemicals to the tumor site to reach the purpose of precise treatment. Combined anti-cancer therapy based on nano-drugs can synergistically improve the anti-tumor effect through multi-target therapy, reduce the dosage of each therapeutic agent and reduce side effects [20]. Development of liposomal nanocarriers, which have highly encapsulated hydrophobic flavonoid apigenin to enhance the effect of chemotherapy [21]. HA-DOX-STS-lipo accumulates more as well as improves anti-tumor efficacy in MDA-MB-231 xenograft tumor models that express high levels of CD44 [22]. Nanovesicles have natural cell targeting ability by maintaining the topological structure of plasma membrane proteins. Nanovesicles loaded with chemotherapeutic drugs can enter tumor tissues and reduce tumor growth [23]. Nano-drug co-delivery is the co-delivery of two or more therapeutic agents in a single nano-carrier system. Two or more drugs are loaded into a single nano-carrier at the same time, which may synchronize the biodistribution and pharmacokinetics of different drugs. So as to achieve a synergistic effect [24]. Gold nanoparticles (AuNPs) are used to load phytochemicals (curcumin, quercetin and paclitaxel), AuNPs (b-AuNPs). The combination of AuNPs-Cur, AuNPs-Tur, AuNPs-Qu and AuNPs-Pacli has good anti-tumor activity [25]. The nanomedicine method can make cyclosporine A and gefitinib co-deliver and enhance the therapeutic effect of drug-resistant lung cancer [26]. Biodegradable nanoparticles mediated erlotinib (ELTN) and Federatinib (FDTN) co-delivery to treat ELTN-resistant non-small cell lung cancer (NSCLC) by inhibiting the JAK2/STAT3 signaling pathway [27]. The drug micelles co-carrying paclitaxel and cisplatin exhibit superior anti-tumor activity than single drugs or their mixtures [28]. In ovarian cancer models, the co-delivery of wortmanning and cisplatin nanoparticles can synergically improve radiotherapy and chemotherapy and reverse platinum resistance [29]. Recent studies have shown that nano-carrier drug delivery systems have greatly improved the effectiveness of drugs in the treatment of cancer (Fig. 3).

As reported in previous studies, we provide a systematic overview of phytochemicals and phytochemicals in synergistic sensitization, reversal of drug resistance and reduction of toxic side effects from the perspective of their combined use in cancer therapy. And a detailed summary of the mechanism through which phytochemicals work. Concurrently, the delivery system is linked to nanomedicines to maximise the combined anti-tumour effect of synergistic phytochemicals and chemotherapeutic agents based on a nano-co-delivery system, and an overview of its nano-co-delivery system is presented. Finally, some opportunities and challenges in how to translate these insights into clinical benefits are discussed.

Section snippets

2.Materials and methods

We searched English databases, including PubMed, Web of Science, and GeenMedical, then we screened relevant literature published in China and abroad. The databases were searched using the following terms: [“bioactivecompounds” OR“ Natural compound” OR“ natural product” OR“ traditional Chinese medicine” OR“ herb-medicine” AND“ cancer”]. Nanomedicine co-delivery is retrieved in the database using the following terms: [“nanomedicines ”AND“ cancer”]. According to the situation of different databases,

Rationale and advantages of combination therapy

Currently, the most common anticancer strategies include surgery, chemotherapy, radiotherapy, immunotherapy, molecularly targeted therapies, and so on. Among these approaches, chemotherapy is still one of the most effective methods. However, the conventional chemotherapeutic drugs show the limited efficacy for cancer treatment due to the tumor heterogeneity, the dose-limiting toxicity for cancer patients and the occurrence of drug-resistant. Therefore, the combined treatment of chemotherapeutic

Approaches of combination therapy

Combination therapy, a treatment that combines two or more drugs, is a new strategy for cancer treatment [38]. The combination of phytochemicals and chemotherapeutic improves efficacy compared to the mono-therapy, this is because drug combinations target key pathways in a synergistic or additive manner to achieve optimal effects. Currently available combination therapy approach can be divided into two classes of therapeutic approach: Simultaneous therapy and Sequential therapy. Here, we have

Co-delivery nanomedicines for the combination of phytochemicals and chemotherapeutic drugs

Combined therapies can be challenging by many limitations, among which targeting to the precise cancerous tissue with minimal side effects are particularly challenging due to presence of highly organized physical, physiological and enzymatic barriers, leading to the limited drug partitioning and distribution to the target site and non-selective tissue toxicity. Moreover, a successful co-delivery of phytochemicals and chemotherapeutic drugs can be limited by the varying physiochemical and

Synergistic effect of combination therapy

Honokiol is important active ingredient of traditional Chinese medicine Magnolia officinalis, which has multiple pharmacological effects, including antibacterial, antioxidant, antithrombotic, anti-cancer, anti-inflammatory, liver protection, and so on [48]. In lung cancer, honokiol combined with paclitaxel synergistically kill H1650 (paclitaxel-sensitive), H1299, and H1650/PTX cells (intrinsic and acquired paclitaxel-resistant, respectively) by inducing paraptosis [49]. Honokiol also inhibits

Synergistic effect of combination therapy

Honokiol exert a wide range of anticancer activities in colorectal cancer in vitro and in vivo by modulating multiple signaling pathways and acting synergistically in combination with chemotherapeutic agents [81]. The combined treatment of honokiol and cisplatin could synergistically inhibit the proliferation of CT26 cells [82]. Honokiol combined with oxaliplatin enhanced anti-cancer effects in HT29 cells by inhibiting COX-2,VEGF protein levels and phosphorylation of AKT,ERK1/2 and NF-ΚB P65

Synergistic effect of combination therapy

Chrysin is a naturally occurring flavonoid found in many plants, honey and propolis and has a number of pharmacological activities such as anti-cancer, pro-apoptotic, anti-angiogenic, anti-metastatic, immunomodulatory and antioxidant properties [123]. Study demonstrates synergistic enhancement of cisplatin and sorafenib in hepatocellular carcinoma by chrysin. The combination of chrysin and cisplatin increased the phosphorylation and accumulation of P53 through activation of ERK1/2 in Hep G2

Synergistic effect of combination therapy

Thymoquinone (TQ) is a main effective monomer isolated from black cumin that has been used for the treatment of hypertension, asthma, dysentery and eczema for thousands of years [147]. In addition, several studies have demonstrated its anticancer potential [148]. For example, the combination of TQ (6.25 μM, 12.5 μM and 25 μM) with paclitaxel (10 μg/mL), induced higher cytotoxicity to breast cancer cell 4 T1 in vitro [148]. Another study indicated that TQ combined with gemcitabine had

Synergistic effect of combination therapy

Thymoquinone (TQ) significantly enhanced the anti-tumor effect of cisplatin-induced gastric cancer by inhibiting PI3K/AKT signaling pathway, activating mitochondrial pathway, up-regulating PTEN gene and down-regulating P-glycoprotein in vitro and in vivo [189]. In addition, thymoquinone also enhances 5-fluorouracil-induced apoptosis of gastric cancer cells and inhibits tumor growth by enhancing the activation of caspase-3 and Caspase-9 [190].

Licochalcone A (LCA) is a kind of flavonoids

Synergistic effect of combination therapy

Genistein is a soy-derived isoflavone with a variety of pharmacological activities that can have a synergistic effect with chemotherapeutic agents. The combination of 5-FU and genistein significantly reduces final xenograft tumor volume by inducing apoptosis and autophagy compared to 5-FU alone, and confirms that genistein can be used as an adjuvant therapy for pancreatic cancer [221].

6-Shogaol, a bioactive ingredient of ginger root (Zingiber officinale), is a medicinal plant having

Synergistic effect of combination therapy

Phytochemicals can also have a synergistic effect in other cancers. In glioblastoma, TQ combined with temozolomide has synergistic killing effect on U87MG cells and significantly reduced the invasion of U87MG cells [241]. In human urothelial carcinoma, honokiol significantly enhanced the cytotoxicity of 5-FU and showed a synergistic effect with 5-FU in Urothelial Cell Carcinoma cells [242]. In malignant glioma, honokiol enhanced the apoptosis induced by temozolomide through a mitochondrial

Clinical study on combined treatment of phytochemicals and chemotherapeutic drugs

Prolonged treatment with chemotherapeutic agents during clinical therapy can be limited by lack of efficacy, drug resistance, metastasis and severe side effects, ultimately leading to poor patient outcomes. In recent years, a lot of basic research has been conducted on phytochemicals and the results have shown that they have pharmacological activities such as inhibiting the proliferation, migration and invasion of cancer cells and promoting apoptosis. The combination of chemotherapeutic drugs

Current challenges and perspectives

We analyze the pros and cons of various oncology therapies in terms of the future prospects of oncology treatment with chemotherapeutic drugs combined with phytochemicals in nano-co-delivery systems. We also present the current challenges of such combinations.

The incidence and mortality of cancer are increasing year by year, and currently our main treatments for tumors include, surgery; chemotherapy; radiation therapy; targeted therapy; biotherapy; immunotherapy; and gene therapy. Surgical

Conclusions

The occurrence and development of malignant tumor are multi-step, multi-factor accumulation process as well as the number of cases and mortality rate are increasing year by year. Therefore, cancer therapy still remains a major challenge so far. Currently, surgery is the main treatment, supplemented by chemotherapy. But chemotherapy has many disadvantages, such as insufficient efficacy, drug resistance, metastasis, and undesirable side effects, and so on. Compared with traditional single

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was financially funded by the grants National Natural Science Foundation of China (No. 81874380 and 82022075 to Xinbing Sui, No. 81973662 to Jinming Zhang), Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars (No. LR18H160001, to Xinbing Sui), Sichuan Provincial Natural Science Foundation for Distinguished Young Scholars (No. 2019JDJQ0049, to Jinming Zhang), Zhejiang Provincial Natural Science Foundation of China (LQ21H160038, to Jiao Feng), and

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