Emerging transporter-targeted nanoparticulate drug delivery systems.

Transporter-targeted nanoparticulate drug delivery systems (nano-DDS) have emerged as promising nanoplatforms for efficient drug delivery. Recently, great progress in transporter-targeted strategies has been made, especially with the rapid developments in nanotherapeutics. In this review, we outline the recent advances in transporter-targeted nano-DDS. First, the emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery are reviewed. These include improvements in the oral absorption of protein and peptide drugs, facilitating the intravenous-to-oral switch in cancer chemotherapy. Secondly, the recent advances in transporter-assisted brain-targeting nano-DDS are discussed, focusing on the specific transporter-based targeting strategies. Recent developments in transporter-mediated tumor-targeting drug delivery are also discussed. Finally, the possible transport mechanisms involved in transporter-mediated endocytosis are highlighted, with special attention to the latest findings of the interactions between membrane transporters and nano-DDS.

Introduction

The ultimate goal of designing drug delivery systems is to achieve better therapeutic outcomes with lower side effects. Current approaches include improving the physicochemical properties of formulations and/or addressing the complex fates of drugs following in vivo delivery1., 2., 3., 4., 5., 6.. With the rapid developments in nanotechnology and carrier materials, nanoparticulate drug delivery systems (nano-DDS) show great progress in drug delivery over the past few decades3., 4., 5., 6., 7., 8., 9.. Drug molecules encapsulated in nanocarriers usually demonstrate totally different delivery characteristics instead of their intrinsic properties, due to the shielding effect of nano-DDS8., 10.. This permits development of more versatile drug delivery strategies as compared with only changing the physicochemical properties of compounds. Therefore, rationally designing various nanocarriers and making specific modifications on the nano-DDS can achieve more effective drug delivery.

Among the various delivery strategies in the field of nano-DDS, developing smart targeted nanocarriers has long been a research focus for pharmaceutical scientists11., 12.. The ideal drug delivery outcome must be precisely delivering the therapeutic agents to their sites of action, especially for anticancer drug delivery12., 13., 14.. Since most chemotherapeutic agents are cytotoxic compounds, which inevitably impose toxicity to the normal tissues, rational design of advanced nano-DDS with high efficiency and low toxicity is crucially important for anticancer drug delivery. There is also encouraging results for the prospects of nano-DDS targeting to the intestinal absorption site or specific organs (e.g., brain). These can significantly facilitate oral absorption or drug permeation of the blood—brain barriers (BBB)16., 17., 18., 19..

Traditional targeting strategies have mainly focused on modifying ligands on the surface of nano-DDS to recognize and interact with the specific receptors on cell membrane. So far, the strategy seems to be working, but the targeting efficacy has been greatly limited by the variability and heterogeneity of membrane receptors21., 22., 23.. Different patients with same disease may have different expression levels of receptors, and different receptors levels may also be found at different stages of the disease even for the same patient. Therefore, receptor-based targeting strategies have not been brought to clinics, and it is necessary to seek for new target sites to develop targeted nanocarriers. Recently, membrane transporters have become emerging target sites for efficient drug delivery24., 25., 26., 27.. Transporters for glucose, amino acids, vitamins and ions are essential for cell nutrition. In addition to these essential nutrients, transporters could also interact with a variety of drugs, thereby affecting the efficacy and safety of drugs. Due to the important roles for cell nutrition, the expression levels of transporters are less variable than those of receptors26., 27.. In some specific cases, such as in tumors, the expression level transporters are usually upregulated to meet the enormous nutrition demand for uncontrolled growth of tumor cells. Thus, transporters are an emerging target for designing tumor-targeting nano-DDS.

In the latest decades, the application of membrane transporters was not restricted to cancer therapy. Transporter-based drug delivery strategies have also been widely investigated in oral drug delivery and brain-targeting therapy24., 25., 26., 27.. Transporter-targeted prodrug strategies have been widely investigated, and several excellent relevant reviews have been published. Herein, we outline the recent advances in transporter-targeted nano-DDS (Fig. 1), including (i) emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery; (ii) recent advances in transporter-assisted brain-targeting nano-DDS; (iii) recent developments in transporter-mediated tumor-targeting drug delivery; and (iv) possible transport mechanisms involved in transporter-mediated endocytosis.

Figure 1

Emerging trends in the fields of transporter-targeted nano-DDS.

Transporter-targeted nano-DDS to improve oral absorption

Oral drug delivery has long been considered a natural and safe administration route, due to its good compliance16., 28., 29., 30.. However, a wide range of drugs cannot be administrated orally, since multiple barriers may be encountered during oral absorption process. These include water insolubility, inferior stability, poor drug permeability, and complex gastroenteric environments (e.g., pH and metabolic enzymes). For example, the successful oral delivery of insulin would be profoundly important for diabetic patients, but orally-administered insulin has poor stability, resulting in inefficient oral absorption. Furthermore, developing new strategies to facilitate the intravenous-to-oral switch in cancer chemotherapy has also attracted increasing attention. In recent years, great progress has been made in designing transporter-targeted nano-DDS to improve oral absorption of peptide drugs and anticancer drugs16., 32..

Improving oral absorption of protein and peptide drugs

Oral delivery of large-molecule proteins and peptide drugs has long been a great challenge, due to their poor oral absorption caused by inferior stability and low permeability33., 34.. More recently, nano-DDS seems to be a viable approach by encapsulating proteins or peptides into nanocarriers35., 36., 37.. Although nano-DDS could significantly improve the stability of proteins and peptides via a shielding effect, the oral absorption is still limited by the unsatisfactory permeability capability across the intestinal wall. Various types of gastrointestinal transporters have been found to play important roles in essential nutrient uptake, and these transporters exist as natural targets for the efficient oral delivery of proteins and peptide drugs36., 37., 38., 39., 40., 41..

Bile acid transporters are widely expressed throughout the intestinal tract and have been investigated for oral delivery of proteins and peptide drugs, such as insulin39., 40., 41.. For instance, Dr. Gan׳s research group developed deoxycholic acid-modified nanoparticles (DNPs) to overcome multiple intestinal barriers for oral insulin delivery (Fig. 2). Deoxycholic acid-conjugated chitosan was designed and synthesized as the transporter-targeted carrier material into which insulin was encapsulated as DNPs. Insulin-loaded DNPs were effectively internalized through apical sodium-dependent bile acid transporter-mediated endocytosis, thus surmounting multiple barriers of the intestinal epithelium. More importantly, the stability of insulin in the epithelium was significantly improved due to the endosomal escape of DNPs. Intracellular trafficking and basolateral release of insulin also occurred by interactions with a cytosolic ileal bile acid-binding protein. As a result, the oral bioavailability of insulin was improved to 15.9% in type I diabetic rats after loading the lyophilized powder of DNPs into enteric capsules. These results suggest that bile acid transporter-mediated endocytosis could play key roles in oral delivery of insulin by addressing the multiple barriers across the intestinal epithelium.

Figure 2

Schematic illustration of transepithelial transport of insulin from DNPs to overcome multiple barriers of the intestinal epithelium by exploiting the bile acid pathway. Reprinted with the permission from Ref. 39. Copyright © 2017 Elsevier Ltd. DNPs, deoxycholic acid-modified nanoparticles; ASBT, apical sodium-dependent bile acid transporter.

Amino acid transporters have also been used for targeting insulin delivery. Specific transporters expressed in the small intestine are known to transport l-amino acids against a concentration gradient Based on this rationale, l-valine-conjugated polylactic-co-glycolic acid (PLGA) nanoparticles were developed for oral delivery of insulin. Cellular uptake experiments demonstrated that l-valine-conjugated PLGA nanoparticles showed distinct advantages over the non-modified nanoparticles. Furthermore, the in vivo hypoglycemia test in streptozotocin-induced diabetic rabbits revealed that l-valine-conjugated PLGA nanoparticles could effectively reduce blood glucose levels in a sustained manner with clear therapeutic superiority vs. the non-modified nanoparticles. The results suggest that l-valine-conjugated NPs are a promising nanoplatform for oral delivery of insulin across the intestinal wall.

Facilitating the intravenous-to-oral switch in cancer therapy

Most anticancer drugs are administrated intravenously, leading to poor compliance and high potential side effects16., 17.. Therefore, there is presently an intense research focus to discover methods for facilitating the intravenous-to-oral switch in cancer chemotherapy. The common barriers hindering oral absorption of anticancer drugs include low water solubility, poor stability in the gastrointestinal tract, and limited permeability across the intestinal wall16., 17.. For example, the oral delivery efficiency of the taxane drugs (paclitaxel, docetaxel and cabazitaxel) is greatly limited by their low water-solubility, poor stability in gastrointestinal tract and good affinity with drug efflux pump P-glycoprotein (P-gp) transporter. Although most transporters expressed in gastrointestinal tract helps to promote the oral absorption of drugs, the P-gp efflux pump acts in the opposite way. Formulating chemotherapeutic agents into nano-DDS could significantly improve their water solubility and chemical stability in gastrointestinal tract, but the permeability of noncarriers remains unsatisfactory. Therefore, despite the promising application prospects of nano-DDS in oral chemotherapy, there is still a long way to further improve the permeability across the intestinal endothelial cells.

As mentioned above, a wide range of gastrointestinal transporters have been found to play important roles in essential nutrient uptake, and these transporters exist as natural targets for efficient oral delivery of both large-molecule proteins and small-molecule anticancer drugs. Among them, various types of transporters have been utilized for oral delivery of chemotherapeutic agents, including bile acid transporter, peptide transporter 1 (PepT1), organic cation transporter-2 (OCTN2), and sodium-dependent vitamin C transporter 1 (SVCT1)42., 43., 44., 45., 46., 47., 48., 49., 50., 51., 52.. Dr. He׳s research group has made notable contributions in the field of transported-targeted anticancer drug delivery. Recently, they have published several research papers. These include: (i) PepT1-tageted nano-DDS. Dipeptide-modified PLGA nanoparticles were designed and developed to facilitate oral docetaxel delivery; (ii) OCTN2-targeted nano-DDS. OCTN2 exists in small intestine as a Na+-coupled absorption transporter where it mediates l-carnitine uptake. To exploit this, l-carnitine-modified PLGA nanoparticles containing encapsulated paclitaxel were shown to effectively target OCTN2 on enterocytes to improve the oral absorption of paclitaxel; and (iii) SVCT1-targeted nano-DDS. Ascorbate-modified PLGA nanoparticles were reported to target SVCT1 on epithelial cells for efficient oral delivery of therapeutic agents, and the targeting process and intracellular delivery fate of ascorbate-modified PLGA nanoparticles were documented and illustrated.

Bile acid transporter-based nano-DDS have also been used for oral drug delivery47., 48., 49., 50., 51., 52.. For instance, taurocholic acid (TCA)-modified nanostructured lipid carriers (NLCs) were developed to improve oral bioavailability of curcumin by targeting bile-acid transporter. In situ intestinal perfusion results showed that TCA-modified NLCs could significantly improve the absorption rate and permeability of curcumin. In vivo pharmacokinetic studies revealed that TCA-modified NLCs showed a 15-fold higher area under the curve (AUC) in rats when compared with the unmodified NLCs after oral administration. In addition to facilitating oral absorption of chemical compounds, TCA-modified nano-DDS was also successfully applied to improve oral delivery of therapeutic siRNA. An AuNP-siRNA-glycol chitosan-TCA nanosystem was developed to selectively deliver Akt2 siRNA and for treatment of colorectal liver metastases. The prepared TCA-modified nanosystem protected siRNA from degradation in the gastrointestinal environment, facilitated siRNA transport across enterocytes and enhanced accumulation of siRNA in liver. In vivo pharmacological experiments showed potent therapeutic activity against colorectal liver metastases after oral administration of Akt2 siRNA-loaded TCA-modified nanoparticles. These results suggest that transporter-targeted nano-DDS provides a versatile platform for both chemotherapeutic drugs and therapeutic genes.

Transporter-based brain-targeting nano-DDS

Drug delivery to the central nervous system (CNS) is still challenging due to the blood—brain barrier (BBB)53., 54.. The BBB is a natural defense barrier protecting the brain from harmful substances. Since only selected, neutral, lipophilic small molecules can diffuse into the CNS from blood, most drugs have traditionally been thought to be impermeable to the brain. However, smart active targeting nano-DDS makes it possible to deliver many drugs to the brain. Approaches include receptor-and transporter-mediated targeting55., 56., 57., 58., 59.. Herein, the emerging transporter-based brain-targeting nano-DDS is discussed, with special attention on the latest findings of specific transporter-based nanotechnology approaches.

Targeting to choline transporter

Choline, a polar and cationic molecule, plays key roles in biosynthesizing several important endogenous substances, such as lecithin. Choline is also important for brain development. However, this charged cation does not readily diffuse across the cell membrane. Therefore, a specific transport mechanism is required on plasma membranes to meet the cellular needs for choline. Similarly, the choline transporter is also necessary to deliver choline across the BBB from plasma to brain tissues. Based on this rationale, the choline transporter has been widely investigated and applied in brain-targeted drug delivery, resulting in development of several choline or choline derivative-modified nanocarriers61., 62., 63., 64..

For instance, a choline-modified doxorubicin (DOX)-PEG polymer conjugate was created in a micellar formulation for brain targeting and glioma therapy. Micelles optimized to contain 20% choline demonstrated favorable cellular uptake, pharmacokinetics and biodistribution, resulting in potent in vivo antitumor activity. A choline-modified nano-DDS also showed promise for brain-targeting gene delivery and glioma MRI diagnosis. A choline transporter-targeting nano-DDS was also developed for efficient combination of gene therapy and chemotherapy. A complex was prepared by intercalating DOX into TNF-related apoptosis-inducing ligand (TRAIL) DNA plasmid. This DOX-TRAIL complex was then condensed with a choline derivative-modified nano-DDS for BBB penetration and glioma dual-targeting drug delivery. The transporter-targeting co-delivery nano-DDS showed higher cellular uptake efficiency and cytotoxicity than unmodified nanoparticles, resulting in synergistic combination therapy.

Targeting to OCTN2 transporter

The OCTN2 transporter is overexpressed on both brain capillary endothelial cells and glioma cells65., 66.. It plays key roles in transporting l-carnitine from blood to brain across the BBB65., 66.. Long-term exposure of bovine brain capillary endothelial cells to carnitine resulted in a high accumulation of long-chain acyl carnitines, and acetyl-l-carnitine is of critical importance for brain function and energy supply65., 66.. Therefore, the OCTN2 transporter has attracted increased attention for rational design of brain-targeting prodrugs and nano-DDS.67., 68. For instance, Dr. Sun׳s research group developed l-carnitine-modified nano-DDS to target glioma cells for drug delivery across the BBB (Fig. 3). l-Carnitine was conjugated to poly (lactic-co-glycolic acid) (PLGA), and then l-carnitine-modified PLGA nanoparticles were prepared for glioma-cell targeting. Modification of l-carnitine significantly improved the uptake of nano-DDS PLGA in the BBB endothelial cell line hCMEC/D3 and in the glioma cell line T98G. Moreover, significant improvement of brain accumulation of l-carnitine-modified PLGA nanoparticles was observed. Therefore, OCTN2 transporter-mediated brain-targeting strategy holds bright prospects for new drug delivery systems able to penetrate the BBB.

Figure 3

Graphic illustration of the composition of l-carnitine-conjugated nanoparticles with varied lengths of PEG spacers, and OCTN2-mediated BBB transcytosis and glioma targeting. Reprinted with the permission from Ref. 68. Copyright © 2017 Taylor & Francis Group.

Recent study suggested that more than one transporter is involved in the brain accumulation of l-carnitine. In addition to OCTN2 transporter, the amino acid transporter ATB0,+ also functions in carnitine transport, and the expression of ATB0,+ transporter in bovine brain capillary endothelial cells was confirmed by using RT-PCR technology. These results suggest that ATB0,+ could be used for brain-targeting drug delivery. Thus l-carnitine-modified nano-DDS could be also utilized as a dual-targeting nanoplatform by simultaneously targeting to OCTN2 transporter and ATB0,+ transporter.

Targeting to glucose transporter

Glucose transport and utilization is critically important for brain activity. Although glucose is an essential nutritional substance for brain, it cannot be synthesized by the brain. As a result, the glucose transporter is overexpressed on the BBB to maintain the continuous high glucose and energy demands of the brain. As such, the glucose transporter could also serve as a therapeutic target for drug delivery to the brain. In recent years, a wide range of glucose transporter-based targeting strategies have been developed, including glucose transporter-targeted nano-DDS69., 70., 71.. For instance, glucose-derived cholesterols were designed and synthesized, and glucose-modified liposomes were prepared with coumarin 6 loaded. The in vivo biodistribution results suggested that glucose-modified liposomes demonstrated distinct advantages over the unmodified liposomes in terms of specific accumulation of coumarin 6 in brain. Due to the simultaneous overexpression on both the BBB and glioma cells, the glucose transporter could be used for dual-targeting drug delivery. For instance, a derivative of glucose (2-deoxy-d-glucose)-modified nano-DDS was developed for simultaneously targeting the BBB and glioma cells, resulting in efficient glioma treatment.

Targeting to LAT1 transporter

The LAT1 transporter is also overexpressed both on the BBB and glioma cells, which could be used for brain-targeting drug delivery. For example, a glutamate-d-α-tocopherol polyethylene glycol 1000 succinate copolymer (Glu-TPGS) was synthesized to modify docetaxel (DTX)-loaded liposomes to enhance the BBB penetration and glioma therapy. Glu-TPGS modified liposomes demonstrated effective higher cellular uptake, cell cytotoxicity and BBB penetration vs. unmodified formulations in vivo. These results suggested that LAT1 transporter-mediated brain-targeting strategy provides another new option in designing brain glioma-targeting nano-DDS.

In summary, although the BBB is a major impediment to drug delivery in brain, various types of nutrient transporters open a window across this barrier to facilitate brain-targeting drug delivery for treating central nervous system diseases. Of greatest relevance may be that several important transporters (e.g., glucose transporter and LAT1 transporter) are overexpressed on both the BBB and glioma cells, which providing the possibility of efficient treatment of brain glioma tumors71., 72., 73..

Transporter-mediated tumor-homing drug delivery

Cancer remains an enormous challenge to human health74., 75., and many efforts have been made to address the consequences of malignant tumors75., 76., 77., 78., 79., 80., 81.. One of the most characteristic features of tumor cells is uncontrolled and progressive proliferation, accompanied by the requirements for very large amounts of nutrients to maintain such abnormal growth. As a result, various types of nutrient transporters overexpressed on tumor cells. These overexpressed membrane transporters as ideal natural targets for tumor-homing anticancer drug delivery25., 82.. Herein, the recent trends in transporter-based tumor-targeting nano-DDS are discussed, focusing on targeting to the overexpressed membrane transporters on tumor cells and the emerging transporter-based dual-targeting strategies.

Targeting to the overexpressed membrane transporters on tumor cells

Due to the wide overexpression of various transporters on tumor cell membranes, various transporter-mediated tumor-homing nano-DDS have been developed, including the glucose transporter83., 84., 85., LAT1 transporter72., 86., OCTN2 transporter, amino acid transporter88., 89. SLC6A14 and ATB0,+, and secreted protein acidic and rich in cysteine (SPARC). Among them, glucose transporter-targeted anticancer drug delivery strategies have been attracting increased attention, and several nano-DDS has been developed for efficient cancer therapy, including polymeric nanoparticles and nanomicelles83., 84., 85.. For instance, redox-responsive tumor-targeting tri-layer nanomicelles were developed for hepatocellular carcinoma therapy (Fig. 4). The nanomicelles were modified with dehydroascorbic acid (DHAA) for specific recognition of the glucose transporter overexpressed on hepatocarcinoma cells. As expected, these nanomicelles demonstrated significantly improved cellular uptake and accumulated distribution in hepatocarcinoma tumors, resulting in enhanced anticancer efficacy.

Figure 4

Illustration of stepwise synthesis, GLUT1-mediated endocytosis and GSH-triggered 3 intracellular drug release of DPL(s-s)P/DOX micelles. Reprinted with the permission from Ref. 85. Copyright © 2015 American Chemical Society.

Amino acid transporters have also been widely explored as potential targets for cancer therapy, including SLC6A1488., 89. and ATB0,+, and LAT172., 86.. These specific transporters were found to be overexpressed in a wide range of tumors, including breast cancer, lung cancer, hepatocarcinoma and glioma86., 87., 88., 89.. A common strategy is to modify nano-DDS with specific amino acids recognizing and targeting the relevant transporter, thereby facilitating cellular uptake and tumor accumulation of nanoparticles. For example, glutamate-modified PLGA nanoparticles could readily recognize and bind with LAT1, promoting tumor accumulation and anticancer activity of chemotherapeutic agents. In addition, lysine-modified liposomes demonstrated good targeting ability to ATB0,+, facilitating tumor-homing delivery of DTX for hepatocarcinoma therapy.

Transporter-based dual-targeting strategies

Despite the tumor-targeting ability of transporter-based nano-DDS, tumor cells are heterogeneous in many aspects.91., 92., 93.. The expression level of specific transporters may vary in different tumors or even in different regions in the same tumor87., 90.. Different expression levels have be found at different growth stages of one tumor87., 90.. Therefore, rational development of dual-targeting nano-DDS may be a solution to the challenges of tumor heterogeneity.

Recently, several transporter-based dual-targeting drug delivery strategies have been reported87., 90.. For example, the expression of both OCTN2 and ATB0,+ on colon cancer cells was greater than on normal colon cells, leading to the development of dual-targeting l-carnitine-modified nano-DDS to target both transporters for colon cancer chemotherapy. l-Carnitine-modified nano-DDS showed distinct improvement in cellular uptake and cytotoxicity of 5-fluorouracil in colon cancer cells (HCT116 and HT29 cells), resulting in enhanced antitumor efficacy in a 3D spheroid model. In addition, the combination of transporter- and receptor-mediated tumor-homing drug delivery strategies could also effectively address the problems of tumor heterogeneity and enhance antitumor activity. For instance, it was found that both the colon cancer cells and M2 macrophages overexpressed secreted protein acidic and rich in cysteine (SPARC) and mannose receptors (MR). Therefore, mannosylated albumin nanoparticles were designed to target both SPARC and MR, thereby acting on both cancer cells and M2 macrophages. The dual-targeting nanosystem significantly improved the therapeutic outcomes. Therefore, transporter-based dual-targeting nano-DDS holds promising prospects in response to tumor heterogeneity.

Interactions between membrane transporters and nano-DDS

As discussed above, there is sufficient evidence for advantages of transporter-targeted nano-DDS for efficient drug delivery. These nano-DDS with specific modifications could effectively recognize and bind to the targeted transporters, and the nano-DDS could be internalized into cells via transporter-mediated endocytosis. Such a transporter-mediated cellular uptake mechanism of nano-DDS is definite. In addition, the mechanisms by which nano-DDS affects the expression levels of transporters have also attracted more attention in recent years42., 72., 86., 87., 88., 89.. Thus, illuminating the interactions between membrane transporters and nano-DDS is important for rational design of high-efficient transporter-based nano-DDS.

According to the recent studies42., 72., 86., 87., 88., 89., two possible fates of transporters in transporter-mediated cellular uptake were found: (i) recycling back to the cell membrane. Once the nano-DDS dissociates from the transporters, they can recycle back to cell membrane, which is important for maintaining the sufficient levels of transporters (Fig. 5)42., 72., 86., 87., 88., 89.; and (ii) degradation within endosome/lysosomes. If the transporter-mediated cellular uptake is an endosome-dependent pathway, the structure of transporter can be destroyed in endosome/lysosomes, which will decrease the transporter levels on cell membrane. So far, recent studies demonstrated that the two routes simultaneously exist42., 72., 86., 87., 88., 89.. For instance, the LAT1 protein of tumor cells incubated with LAT1-targeted nanoparticles were decreased at the beginning of cellular uptake, but the membrane LAT1 transporter increased once the nanoparticles were removed from the uptake medium, verifying evidence for the first situation. Moreover, there was some evidence found for the degradation of transporters within cells87., 88., 89..

Figure 5

(A) Competitive study in hPepT1-Hela cells in the presence of typical substrate GlySar (GS); (B) Influence of proton in the culture medium on the cellular uptake of dipeptide modified NPs in hPepT1-Hela cells; The variation of relative PepT1 mRNA expression versus β-actin (C) and the variations of membrane and cytosol PepT1 protein expression (D,E) after treatments with NSPV1000 NPs for different time over 24 h. Data are shown as mean±SD. P<0.05,P<0.01 vs. C6/DTX solution group or control group, P<0.05, P<0.01, n=3; (F) The schematic illustration of hypothesized mechanism of PepT1-mediated endocytosis. Reprinted with the permission from Ref. 42. Copyright © 2018 Taylor & Francis Group.

Conclusions and perspectives

Transporter-targeted nano-DDS has emerged as a promising nanoplatform for efficient drug delivery. The basic strategies are modifying nano-DDS with specific substrates of transporters, including natural substrates (e.g., choline, glucose, carnitine, vitamins and amino acids) and derivatives. In this paper, we reviewed the recent developments in transporter-targeted nano-DDS on the emerging transporter-targeted nano-DDS developed to facilitate oral drug delivery, transporter-assisted brain-targeting nano-DDS, transporter-mediated tumor-targeting drug delivery, and the specific transport mechanisms involved in the transporter-mediated endocytosis.

However, despite the rapid developments and promising application aspects of transporter-targeted nano-DDS, several concerns should be addressed in the future research in this field. These include: (i) for tumor-targeting drug delivery, although certain transporters have been found to be overexpressed on tumor cells, transporters are also of great importance for normal cells, and how to avoid the off-target distribution of nano-DDS in normal cells is still a big challenge; (ii) the underlying transport mechanisms of transporter-mediated endocytosis is still not entirely clear, especially for the endocytosis mechanism and definite intracellular fate of transporters; (iii) transporters have emerged as a new topic for active targeted drug delivery, but it is not known if transporter targeting has distinct advantages over receptor-mediated targeting for drug delivery; (iv) despite significant progress in animal models, how can we bridge the gap between preclinical animal models and clinical trials? Continuous study of the underlying mechanisms will contribute to the rational design of improved transporter-targeted nano-DDS in the future.