Introduction

Drug delivery systems (DDSs) for cancer treatment, which have been explored for many years, have been developed rapidly for their solubility, bioavailability, and targeting with their high drugloading rates, large specific surface areas and diverse surface functions [1,2,3]. However, further work has been hindered by low drug-loading rates, drug resistance, toxicity and immune responses induced by nanocarriers [4, 5]. Because most DDSs acted only as excipients with no direct effects, short and long-term toxicity can appear with their metabolites.

In addition, therapeutic effects can be reduced for the phagocytosis and clearance of nanoparticles (NPs) by the reticuloendothelial system (RES). Furthermore, DDSs can interact with cell surface-specific receptors resulting in adverse immune reactions. Nevertheless, natural products such as ginsenosides have been studied widely for the treatment of cancer and other diseases because of their chemical and biological properties including chemical diversity, specificity, and low toxicity, making them conducive to the development of DDSs [6].

Ginsenosides are a group of bioactive compounds extracted from Panax ginseng [7] (Fig. 1). As small-molecule substances, ginsenosides can resist diabetes, depression and cancer, offering better protective effects for cerebral ischemia, endothelial cell injury, and cardiovascular disease (CVD) [8,9,10,11]. Currently, ginsenoside Rg3 has been launched as a new drug in traditional Chinese medicine (TCM, Shenyi capsule) for the treatment of lung, breast, gastrointestinal (GI) cancers [12]. Researches have reported that the human body can develop resistance after multiple administrations of cancer therapy. Ginsenosides combined with cisplatin [13], adriamycin [14], vincristine [15] or other chemotherapy drugs can reverse multidrug resistance and improve the antitumor effects for lung and liver cancers. Ginsenosides have been proved to exhibit good anticancer activity and targeting ability, both as a drug and as an excipient compound simultaneously [190,191,192]. These NPs are usually sensitive to tiny changes related to tumor cells and TME (e.g., pH, redox state, enzymes) to release drugs, which also can be activated by external stimuli (e.g., light, heat, magnetic field, ultrasound) [193]. According to TME characteristics, conditionally sensitive NPs can achieve controlled drug release, only releasing drugs at tumor sites and stabilizing themselves under certain physiological conditions. pH-sensitive NPs (Rg3-loaded mPEG-b-P (Glu-co-Phe)) achieved CRC tumor targeting and Ph-stimulated drug release, as well as a longer circulation time in the blood, resulting in an increased tumor therapy and decreased side effects to other tissues or organs [88].

In addition, targeting NPs and microenvironment-sensitive NPs can reduce the toxicity and side-effects of ginsenoside nanomedicines. Hypoxia around the tumor tissue is caused by the lack of blood flowing through that tissue resulting from the exuberant metabolism [194]. Hypoxia-sensitive NPs can be designed to know the difference between the hypoxia environment of tumor tissue and the normoxic environment of healthy tissue. For example, although ~ 150-nm NPs exhibited good serum stability and passive tumor targeting, their weak tissue permeability can limit drug efficacy. In contrast, reducing particle size can increase tissue permeability while also reducing the stability of NPs in the blood circulation. Therefore, Designing NPs to achieve superior serum stability and permeability simultaneously is necessary.

A strategy based on the dissociation of tumor site NPs is worth pondering, which can not only increase the stability of NPs in the blood but also can enhance the tissue permeability [195]. Importantly, a human serum albumin anticancer drug modified by a hypoxia-sensitive azobenzene group has been fabricated, with a particle size of 100–150 nm. After reaching the tumor site, the azobenzene NPs groups disintegrated the NPs to < 10 nm, enhancing the role of tumor permeability and the curative effect.

Codelivery strategy

Combination drug therapy has synergistic therapeutic effects as compared with single chemotherapy drugs. Although it is common for multiple drugs to be applied for various diseases in the clinic, differences in physicochemical properties and pharmacokinetics may cause the drugs to fail to reach the same site at the same time, thus not achieving the optimum synergy. Therefore, it is necessary to determine the optimal ratio of drugs, which is complicated to investigate in vivo. Drug codelivery strategy provides a new possibility for the treatment of drug resistance in tumor cells.

Currently, codelivery systems including liposomes, micelles, and inorganic NPs with same pharmacokinetics have overcome multiple drug resistance, providing a new possibility for the treatment of this resistance in tumor cells. Synergistic anticancer effects produced by codelivery are of significance for DDSs..

Liposomes embedded with ginsenoside and other drugs such as curcumin, PTX, and betulinic acid can significantly inhibit tumor growth [19]. Liposomes containing parthenolide, betulinic acid, honokiol and ginsenoside Rh2 have been found to be safer than cisplatin for the treatment of tumors [98]. In addition, it has been reported that ginsenosides, as chemotherapy adjuvant and membrane stabilizer combined with PTX, could inhibit the proliferation of gastric cancer cells and reduce side-effects, thus further improving the therapeutic effect for gastric cancer. The silanol hydroxyl group on the surface and adjustable pore size of MS are beneficial to the combination of ginsenoside CK and Rh2, which exerted excellent biocompatibility with normal hacaT skin cells and anticancer effect on HepG2, A549 and HT-29 colon cancer cells [111]. Furthermore, combination therapies have displayed potential applications for reducing side-effects and metastasis and for overcoming drug resistance. Multicomponent MEs consisting of etoposide, coix seed oil and ginsenoside Rh2 have been utilized to regulate a variety of signaling pathways to overcome drug resistance by inhibiting P-gp. Furthermore, Rh2 can relieve the inflammatory response and immune suppression caused by etoposide [122]. Thus, combination therapies of ginsenosides to overcome drug resistance and metastasis require further research.

Photodynamic and photothermal therapy enhancement

Much attention has been focused on PDT and PTT because of their advantages of being a noninvasive, precise treatment with strong specificity and high tumor destruction efficiency [196,197,215].

For example, fluorescent signal probes including NIR fluorescent dye ICG [216], up-conversion nanomaterials NaYF4: Yb/Er/Tm [217], GNP clusters (AuNCs) with a particle size of < 2 nm [218], and quantum dots recently have been designed for cancer imaging and therapy due to their biocompatibility and low toxicity [219]. In addition, NPs with iron, manganese, or gadolinium ions or iron oxide NPs for MRI imaging have been applied clinically [220]. Furthermore, acoustic waves from the contrast agents for photoacoustic imaging have been shown to be much safer than those of CT or PET [221]. More complex multimodal imaging for diagnosis and designing a treatment platform are needed. Therefore, the development of ginsenosides based on an integrated imaging and therapy delivery system must be explored further.

Multifunction as nanocarriers

Ginsenosides, as nanocarriers, have also shown multiple pharmacological functions, which are shown in Fig. 14 including antitumor effect improvement, side-effect attenuation, self-targeting delivery, biomimetic delivery, and immunomodulation.

Fig. 14
figure 14

Multifunction of ginsenosides as carriers

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Antitumor effect improvement and attenuation of side-effects

Most drug delivery carriers’ act only as excipients with no direct effects on the main drugs; however, short- or long-term toxicity may appear with their metabolites [108]. Ginsenosides have a potential application for being both adjuvant drugs and excipients simultaneously.

liposomes have been utilized to replace cholesterol for stabilizing the phospholipid bilayer. The liposome preparation formulations were simple without adding PEG or targeting ligand, which greatly simplified the technological production. Liposomes exerted a significant synergistic anticancer pharmacological activity with the chemotherapeutic drug PXT by targeting the GLUT on the surface of tumors [25,26,27].

Self-targeting delivery

Rh2, Rg3, and Rg5 ginsenoside liposomes can be accumulated in tumors for recognizing the GLUT receptor on the tumor cell membrane with stronger toxicities and targeting abilities. The curative effects of Rg5-PTX-liposomes have been confirmed with HGC-27, A549, and MCF-7 subcutaneous tumor models [27]. In addition, PTX-Rh2-lipo achieved excellent tumor targeting and anti-tumor activity of mouse breast cancer [25]. Rg3-PTX-liposomes inhibited tumor proliferation by activating the C6 glioma immune microenvironment via inducing the transformation of M2 TAMs into M1 in the TME [28].

Biomimetic delivery

The adsorption of opsonin proteins such as Ig and other complex proteins can enable NPs to be recognized and cleared easily by the mononuclear phagocytes. It has been demonstrated that the inhibited uptake of phagocytes by reducing the adsorption of these proteins can enhance the stealth effect of NPs [222].

PEGylated NPs can form steric hindrance on their surface through their hydrophilicity and spatial repulsion, thus decreasing protein adsorption and avoiding being removed by the monocyte phagocytic system [223]. Nevertheless, the increased blood circulation cycle of ginsenoside-embedded liposomes is achieved because Rh2, Rg3 and Rg5 can prevent the activation of the monocyte phagocytic system. It has been verified that the amount of Rh2 liposomes coated by protein corona was significantly lower than that of traditional liposomes [25]. The long circulating liposome fabricated with ginsenosides can reduce the adsorption of opsonins on their surface, thus exhibiting the stealth effect of ginsenoside and increasing the adsorption of apolipoprotein E, which can retard the absorption of macrophages to liposomes.

Immunomodulation

TME gradually has become the target of tumor treatment due to its important role in tumor development, diffusion, metastasis, and drug resistance. As compared to targeted tumor cells, one benefit of targeting nontumor cells in TME is that they are genetically more stable and, therefore, are less likely to form drug resistance. However, the difficulty of targeting nontumor cells to obtain good therapeutic effects involves reducing the toxicity to normal cells. Interfering with the TME of primary tumor cells or the premetastatic microenvironment of tumor cells can be effective for the treatment of malignant tumors prone to metastasis [224, 225].

The immunotherapeutic activities of ginsenoside liposomes have been reflected in improving the TME structure to enhance the drug permeability by reducing tumor vascular density. Some researchers have focused on transporting drugs to blood vessels with Rh2, Rh3 or Rg5 liposomes, which is important for tumor growth and metastasis [25, 26, 28]. Targeted stromal cells including cancer-associated fibroblasts and TAMs also have been utilized for cancer treatment [174]. Ginsenosides liposomes changed the immune-deficiency TME mainly through reducing the heterogeneous cells in the TME and enhancing the immune function by increasing the infiltration of CD8+ T cells. As a targeted stromal cells, TAMs easily differentiate into M2 phenotypes, which often have been associated with tumor metastasis and poor outcomes. Ginsenoside liposomes have played a role in reconstructing the TME by transforming TAM2 into TAM1 to promote the role of T cells by inhibiting the activities of signal transducers and transcription activators [25].

Multifunction as both drug and nanocarrier

Ginsenosides as a drug are commonly encapsulated into the core of NPs or modified on their surface. Ginsenoside Rg3, Rg5, and Rh2 have acted as carriers of nano lipid structures, substituting cholesterol for the similar structure. Therefore, ginsenoside DDSs not only can exhibit their multifunctionality as a drug but also can display their merits as carriers.

It has been verified that ginsenoside nanomedicines can increase anticancer efficacy and can exhibit synergistic anticancer effects with other chemotherapy drugs while decreasing the side-effects caused by these drugs, NPs, or cholesterol. In addition, the ligand-targeting ability of ginsenoside DDS for specific sites or their self-targeting ability for recognizing the GLUT receptor on the tumor cell membrane enable ginsenosides to be potential delivery systems. Furthermore, ginsenosides themselves are endowed with the delivery system’s stealth effect for the inhibition of the uptake of phagocytes and immune function by increasing the infiltration of CD8+ T cells and reconstructing the TME, strengthening tumor treatment.

Clinical application and translation

Ginsenoside nanomedicines have shown great application value and development prospects. Certain tumor therapeutic nanomedicines are in clinical trials, such as a G-PTX liposome loaded with ginsenoside and PTX, and have exhibited advantages for drug loading, tumor targeting, stability, and biological safety [27]. However, much remains to be explored before these therapies are truly mature. Several challenges must be solved before applying ginsenoside DDSs in clinical practice [226,227,228], including the synthesis and large-scale production of controllable and repeatable nanodrugs, the development of a safety evaluation, and the undertaking of clinical research.

Nanodrug synthesis and large-scale production

Repeatable synthesis methods and controllable quality are prerequisites for drug clinical transformation. Some multifunctional nanodrugs (e.g., layer-by-layer, self-assembly NPs) involve multiple or complex synthesis steps. Therefore, it is difficult to synthesize nanodrugs with the same qualities quickly, accurately and repeatedly. Microfluidic technology might help solve the problem of inconsistent effects from laboratory research to clinical experiments given its high-speed self-assembly, narrow size distribution, and good repeatability [229].

In addition, monodisperse NPs with highly controllable size, shape, chemical composition, surface properties, and drug loading capacity can be synthesized using a nonwetting template complex method [230]. To carry out a comprehensive quality control for nanodrugs and carrier materials, more research on their formulation technology and stability are necessary. Furthermore, corresponding quality control methods must be established, optimized, and verified. The research and development of a GMP-compliant preparation process and equipment for the large-scale production of nanodrugs will be required.

Safety evaluation and clinical research

As compared with traditional small-molecule or biological macromolecular drugs, ginsenoside nanodrugs are different in their variety and physical and chemical properties. Hence, to achieve a clinical transformation, we must focus on evaluating the biocompatibility and safety of NPs in vivo. Safety assessment first requires the completion of high-throughput cytotoxicity testing, including for oxidative stress, surface membrane, and mitochondrial damage, lysosomes, autophagy, and inflammatory corpuscles. Animal models with different species are needed to study the pharmacokinetics, biodistribution, efficacy, and safety of nanomedicines [226]. It will be necessary to carry out preclinical studies on ADME, toxicokinetics, acute toxicity, immunology, and drug-specific toxicity of drugs in vivo, as well as to design standard operating procedures for safety evaluation method.

Certain correlations and differences exist between the toxicological results of experimental animals and the adverse reactions of the human body. Although animal models are commonly used to evaluate safety, the safety responses of animals and humans are different and can be affected by many factors, such as the differences of cytochrome P450 and enzymes. There also are differences among the animal models themselves. For example, the rat model is more sensitive than is the mouse model for predicting the GI toxicity of chemotherapy and targeted therapy. Some models, such as the genetically engineered and patient-derived xenotransplantation mouse model, can accurately simulate the heterogeneity of human tumors [231, 232].

Another challenge is clinical trials. After the completion of a preclinical safety assessment, it will be necessary to evaluate and manage patient side-effects and adverse events to evaluate toxicity in the human body, so as to facilitate the successful clinical transformation of the drugs.

Conclusion and prospects

The ideal DDS maintains a drug concentration in a certain range or specifically delivers a drug to target organs and tissues after a single administration while minimizing the drug’s concentration in other regions and reducing the immune response in vivo. Ginsenosides have been an important component of cancer drugs for a long time. The research on and development of ginsenoside DDSs have provided a certain prospect for tumor treatment, but the antitumor mechanisms of some nanodrugs require further research. Only with a reasonable research strategy, comprehensive preclinical evaluation and strict clinical trials can more antitumor drugs be developed.

The antitumor effects of a ginsenoside DDS for lung, colon, and liver cancer cells, as well as the inhibitory effects on tumor xenografts in mice, have been investigated. Although the nano-delivery systems can increase drug concentration in the blood, only a few studies have explored in depth the distribution of ginsenosides or their metabolites in tumor tissues or organs. The research on ginsenoside DDSs is still in the preclinical stage, and no DDS has been launched successfully. Although NPs have achieved progress, the clinical transformation of nanodrugs for cancer treatment remains a focus.

To simulate the real clinical environment as much as possible, it is necessary to further explore the mechanism and pharmacokinetics of a ginsenoside DDS in vivo to inhibit cancer metastasis and to combine chemical sensitizers to eliminate the resistance of the body to ginsenosides. Furthermore, the therapeutic effects can be maintained by a combination of ginsenosides and classical chemotherapy drugs, the dosage of which can be reduced. Although still in the early stages of research and development, a multifunctional DDS for diagnosis, treatment, and prognosis will require evaluating its efficacy in vivo, which is worthwhile research. The development and improvement of new dosage forms show a great potential in cancer treatment.