Abstract
Poor targeting of therapeutics leading to severe adverse effects on normal tissues is considered one of the obstacles in cancer therapy. To help overcome this, nanoscale drug delivery systems have provided an alternative avenue for improving the therapeutic potential of various agents and bioactive molecules through the enhanced permeability and retention (EPR) effect. Nanosystems with cancer-targeted ligands can achieve effective delivery to the tumor cells utilizing cell surface-specific receptors, the tumor vasculature and antigens with high accuracy and affinity. Additionally, stimuli-responsive nanoplatforms have also been considered as a promising and effective targeting strategy against tumors, as these nanoplatforms maintain their stealth feature under normal conditions, but upon homing in on cancerous lesions or their microenvironment, are responsive and release their cargoes. In this review, we comprehensively summarize the field of active targeting drug delivery systems and a number of stimuli-responsive release studies in the context of emerging nanoplatform development, and also discuss how this knowledge can contribute to further improvements in clinical practice.
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Background
Cancer is one of the leading causes of death worldwide, and despite the current arsenal of anticancer strategies, the number of patients is continuously increasing [1, 2]. Statistics have shown that one in 6 women and one in 5 men worldwide develop a tumor in their lifetime [3, 4] which accounts for nearly 1 in 6 deaths. The main reason behind the poor treatment efficacy is the low targeting ratio of therapeutics which can also induce severe side effects on healthy tissues [5, 6]. Therefore, there is an urgent need for site-specific delivery of therapeutic agents to the tumor region. For this reason, nanotechnology-based formulations have been the focus of a large body of research as effective approaches for overcoming the bottlenecks of undirected biodistribution, undesired side effects and high-dose administration [7].
With the increased uptake in nanomedicine, various versatile nanoformulations with excellent biocompatibility and pharmacokinetic properties, such as micelles, liposomes, nanoparticles, and nanoemulsions, have exhibited great potential for the delivery of novel anti-cancer drugs (Fig. 1) [8,9,10]. These nanoparticles can effectively address the poor water solubility and undesired adverse effects often observed during the delivery of therapeutic agents and prolong their blood circulation time for enhanced tumor accumulation, thereby markedly facilitating their use as therapeutic agents for tumor therapies [10,11,12]. Importantly, these novel nanomedicines generated by encapsulating specific therapeutic agents in nanocarriers can achieve satisfactory tumor targeting by utilizing the EPR effect-mediated passive targeting strategy [55].
Folate receptor (FR)-mediated active targeting
FRs, a class of glycoproteins, have been classified into three subtypes namely FRα, FRβ and FRγ. It should be noted that FRα and FRβ can closely bind to the tumor cell membrane via a glycosylphosphatidylinositol anchor, while FRγ has only been reported in hematopoietic cells [4, 56,57,58]. Among them, FRα is the most widely generated FR subtype and is overgenerated in various tumor cells, especially in breast, lung, kidney, cervical, and ovarian cancer [59,60,61]. Moreover, FR can transport folate into tumor cells via the receptor-mediated endocytosis process [62]. For this reason, a number of FA-based nanoplatforms have been prepared for increased internalization of therapeutic agents by tumor cells [63,64,65]. In one example, Murgia et al. prepared an organic/inorganic hybrid nanoplatform modified by FA-chitosan conjugates to load upconverting NaYF4 nanoparticles and daunorubicin for tumor therapy [62]. The FA modification significantly improved the cellular uptake of the nanoparticles, and an in vivo xenograft model also showed a positive antitumor effect. In another example, Wang et al. designed an FA-conjugated chitosan loaded rutin prepared palladium nanoplatform for FA-mediated targeting treatment. The introduction of FA into the designed nanoplatform significantly improved the endocytosis efficiency of the nanoparticles in breast cancer cells. The designed nanoplatform was shown to considerably suppress cell proliferation as evidenced by a cell viability assay [66]. Mechanistically, FRs can identify and bind to extracellular FA-modified nanoparticles and then transport them into the tumor cells through a FR-mediated endocytosis process [67]. In these nanoparticles, the FA portion is used as a tumor-targeting ligand. On binding to the FR on tumor cells, the cell membrane can invaginate and pinch off to form endosomes which subsequently reach lysosomes or other organelles. The drug-encapsulated nanoparticles can dissociate from the FR and effectively release the encapsulated drug at the TME for tumor treatment.
Transferrin (Tf) receptor-mediated active targeting
As the critical Fe3+ pool in the body, Tf plays an important role in Fe metabolism and delivery. To meet the growing requirements of Fe for maintaining cell growth and division, transferrin receptors (TfR) are frequently overexpressed on the surface of a number of tumors including pancreas, breast, prostate, colon, and lung cancer, with high affinity to Tf [68,69,70,71]. This has prompted scientists to use the TfR as an active targeting site in the design of novel anti-cancer delivery platforms. TfR can be employed either for Tf-mediated targeting and internalization of therapeutic agents or to block normal receptor function, resulting in cell death [72,81]. It can block cell cycle arrest and reduce angiogenesis by disturbing downstream HER2 signaling activity. The interaction between TZ and HER blocks receptor cleavage and activates the response of Ab-dependent cellular cytotoxicity and receptor degradation following internalization of the TZ-HER2 complex. Pertuzumab (PZ), another humanized mAb, has been used to suppress heregulin-mediated activation of HER2 phosphorylation and tumor proliferation [82]. Nanoparticles functionalized with anti-HER2 Abs or its fragments can be effectively used for specific delivery of therapeutic agents to HER2-overexpressed tumor cells by the HER2 receptor-mediated endocytosis process [83] which enhances therapeutic efficacy with fewer side effects.
Estrogen receptor-mediated active targeting
Estrogen is a steroid hormone that plays a critical part in maintaining reproductive system function, bone homeostasis, brain development, and cardiovascular remodeling [84]. Among the three forms (estrone (E1), estradiol (E2), and estriol (E3)), E2 is the crucial for the progression of breast, endometrial, and ovarian cancers [85, 86]. Estrogen function relies primarily on its binding and subsequent activation of two structurally different estrogen receptors (ERα and ERβ) [87]. Therefore, these related receptors are considered members of the nuclear receptor superfamily.
It has been reported that following intracellular uptake of estrogen-modified nanoparticles by receptor-mediated endocytosis, intracellular ERs can carry these nanoparticles toward the nucleus for nuclear targeting [88]. Furthermore, these receptors have been found overexpressed on several tumor cell surfaces. In a recent application, Kapara and co-workers [89] reported a straightforward and non-destructive 3D surface-enhanced Raman spectroscopy (SERS) imaging strategy to track the cellular internalization of AuNPs modified with an anti-ERα Ab in MCF-7 cells. It was found that these modified nanoparticles were effectively internalized by tumor cells using the ERα receptor-mediated endocytosis process for enhanced tumor treatment.
Cluster of differentiation (CD) receptor-mediated active targeting
The CD receptor family comprises surface receptors mainly present on cancer stem cells (CSCs), including CD14, CD22, CD36, CD44, and CD133, which can be used as promising delivery targets against tumor metastasis. Among them, CD44, a transmembrane adhesion glycoprotein, has been commonly used to target receptors for targeted tumor treatment [90,91,92]. Hyaluronic acid (HA), a ligand with good biocompatibility, has been widely used in CD44 receptor-mediated active targeting delivery systems. It can be readily obtained due to its abundance as a natural polymer compared with polymers that require multiple step chemical synthesis [93, 94]. HA-functionalized nanoplatforms can effectively deliver therapeutic agents to tumor cells through CD44 receptor-mediated active targeting, with an excellent cytotoxic profile and tumor kill. For example, Kim et al. [94] reported a HA modified, trio-stimuli receptive and on-demand triggerable nanoplatform for multimodal cancer treatment. These HA-enveloped nanoparticles effectively suppressed tumor growth in comparison to groups without HA modification. In general, HA is modified on the surface of nanoparticles to specifically bind to CD44 receptors that are overexpressed in tumor cells, thus mediating tumor endocytosis. In addition, HA has the tendency to be degraded to smaller fragments in the presence of hyaluronidase which is also abundantly present in the TME [95]. The versatile characteristics of HA as a targeted and enzyme-responsive ligand make it a promising candidate for application in specific drug delivery systems.
Other receptor-mediated active targeting systems
In addition to the receptors mentioned above, other receptors have also been used to design targeted anti-cancer nanoplatforms, including chemokine, biotin, and luteinizing hormone-releasing hormone (LHRH) receptors [96,328]. For example, the elimination of indolequinones can be achieved under hypoxic environments with the aid of the DT-diaphorase NQO1, which is overexpressed in various cancer cells and plays a crucial role in bioreduction [405]. Once administrated, the prepared nanoplatforms circulate in the bloodstream to access various tissues or organs. During this circulation, these nanoplatforms can interact with biomacromolecules (including carbohydrates, proteins, nucleic acids, and lipids) which can coat the nanoplatforms, leading to a surface or biomolecule corona, which alters the surface properties of the nanoplatforms, affects their therapeutic effects, and can induce protein unfolding [406,407,408,409]. Stimuli-responsive nanoplatforms are effective but can still be affected by their physiological environment. For example, most carbon nanomaterials (such as carbon nanoparticles and nanotubes) and metals (such as MnO) can act efficiently in acidic environments but generate ROS near tumors which can lead to cancer progression and metastasis [410, 411]. Notably, ROS-responsive nanoplatforms tend to be rapidly phagocytized due to their special surface properties [412, 413].
In the future, there is an urgent need to control the physicochemical features of nanoparticles to improve their targeting ability, especially their morphology, particle size distribution and surface chemistry. For example, new surface modification strategies need to be explored to confer novel multifunctionalities to the nanoparticles. Moreover, in order to improve the antitumor effects of nanoparticles the development of alternative reactions, formulations, or constructs containing stimulus components aimed at producing multiple strategies for highly effective combination cancer treatment should be a focus. Importantly, these new generation targeting strategies should be explored for an in-depth understanding of key parameters, such as their pharmacokinetics, biodistribution and nano-bio interfacial interactions, as such outcomes have a significant impact on cancer treatment. Furthermore, there are possibilities to develop novel stimuli-responsive modalities for better encapsulation of agents as well as their controlled release to further increase their therapeutic index with few side effects. It is forecast that nanoscale biomaterials comprising biocompatible lipids, polymers or inorganic materials in conjugation with targeting groups will have tremendous scope for transporting pharmaceutical active ingredients to their specific target sites for improved therapeutic purposes. Such versatile targeted nanoparticles will find broader application possibilities and will aid in the role out of personalized/precision medicine.
Availability of data and materials
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Abbreviations
- EPR:
-
Enhanced permeability and retention
- HA:
-
Hyaluronic acid
- TME:
-
Tumor microenvironment
- FRs:
-
Folate receptors
- Tf:
-
Transferrin
- FA:
-
Folate acid
- EGFRs:
-
Epidermal growth factor receptors
- HER2:
-
Human epidermal growth factor receptor 2
- DOX:
-
Doxorubicin
- PTX:
-
Paclitaxel
- TGF-α:
-
Transforming growth factor-α
- IFP:
-
Interstitial fluid pressure
- MOF:
-
Metal organic framework
- UIC:
-
Ultrasound-mediated inertial cavitation
- POxs:
-
Poly(2-oxazo line)s
- PMVE:
-
Poly (methyl vinyl ether)
- NMR:
-
Nuclear magnetic resonance
- GOx:
-
Glucose oxidase
- AZO:
-
Azobenzene
- Ce6:
-
Chlorin e6
- NQO1:
-
NAD(P)H quinone dehydrogenase 1
- GSH:
-
Glutathione
- PEG:
-
Polyethylene glycol
- CA IX:
-
Carbonic anhydrase IX
- Ab:
-
Antibody
- ATP:
-
Adenosine triphosphate
- TZ:
-
Trastuzumab
- PTT:
-
Photothermal therapy
- PDT:
-
Photodynamic therapy
- CDT:
-
Chemodynamic therapy
- RT:
-
Radiotherapy
- CAT:
-
Catalase
- ROS:
-
Reactive oxygen species
- RNS:
-
Reactive nitrogen species
- MR:
-
Magnetic resonance
- MMP:
-
Matrix metalloproteinase
- TaOx:
-
Tantalum oxide
- RBCs:
-
Red blood cells
- ICD:
-
Immunogenic cell death
- PNIPAAm:
-
Poly-N-isopropylacrylamide
- PNVCL:
-
Poly(vinyl caprolactam)
- PK:
-
Protein kinase
- ICP-OES:
-
Inductively coupled plasma optical emission spectrometry
- CD:
-
Cluster of differentiation
- ECM:
-
Extracellular matrix
- CPT:
-
Camptothecin
- DOTAP:
-
1,2-Dioleoyl-3-trimethylammonium-propane
- AQ4N:
-
Banoxantrone dihydrochloride
- DTD:
-
DT-diaphorase
- TKIs:
-
Tyrosine kinase inhibitors
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This work was supported by Guangdong Basic and Applied Basic Research Foundation (No. 2019B030302012), National Key Research and Development Project (No. 2020YFA0509400, and 2020YFC2002705), and National Natural Science Foundation of China (No. 81821002, 81790251, 82102738, 82103168, and 82003098).
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ZS, CH and NX designed this manuscript. HL and TT drafted the manuscript and drew the figures. EN revised the manuscript. ZH, LZ and JY checked the manuscript. All authors reviewed the manuscript. All authors read and approved the final manuscript.
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Tian, H., Zhang, T., Qin, S. et al. Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies. J Hematol Oncol 15, 132 (2022). https://doi.org/10.1186/s13045-022-01320-5
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DOI: https://doi.org/10.1186/s13045-022-01320-5