Multifunctional nanoplatforms for subcellular delivery of drugs in cancer therapy

Progress in Materials Science 107 (2020) 100599

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Multifunctional nanoplatforms for subcellular delivery of drugs in cancer therapy Xing Guoa, Xiao Weia, Zi Chenb, Xiaobin Zhanga, Guang Yanga, Shaobing Zhoua,

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a Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China b Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA

A R T IC LE I N F O

ABS TRA CT

Keywords: Nanoparticle Targeted delivery Cancer therapy Organelle-targeting Stimuli-sensitive

To achieve highly effective treatment to diseases, successful delivery of drugs with a carrier into the specific organelles (nucleus, mitochondria, lysosomes, etc.) is of great importance. Targeted delivery based on nanoparticle (NP)-based drug delivery systems (NDDSs) is mainly focused on cell-membrane targeting. In this review we summarize researches on organelle-specific drug delivery with multifunctional NPs. Many effective strategies are introduced for functionalizing these NPs by altering their chemical composition or by grafting functional groups onto their surface for improving organelle-targeting ability. Only when the concentration of released drugs becomes high enough will they interact with molecular targets on specific organelles to induce

Abbreviations: Ab, antibody; ABC, ammonium bicarbonate; Ad, adenoviruses; ANG, angiopep; ApDCs, aptamer-drug conjugates; AR, aspect ratio; ATP, adenosine triphosphate; AuNPs, gold nanoparticles; B55, residues 83-137 of mature bindin; BBB, blood-brain barrier; CME, clathrin-mediated endocytosis; CPPs, cell penetrating peptides; CPT, camptothecin; CvME, caveolae-mediated endocytosis; DLCs, delocalized lipophilic cations; DMMA, dimethylmaleic anhydride; DOPE, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; DOTAP, 1,2-dioleyl-3-trimethylammonium-propane; DOX, doxorubicin; DQA, 1,1′-decamethylene bis (4-aminoquinaldiniumchloride); EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; EGFP, enhanced green fluorescent protein; ELS, endoplasmic reticulum localization sequence; EPR, enhanced permeation and retention; ER, endoplasmic reticulum; ERHNPs, electro-responsive hydrogel nanoparticles; Fab, antigen-binding fragment; FPs, fusogenic peptides; FR, folate receptor; GA, Golgi apparatus; GALA, glutamic acid-alanine-leucine-alanine; Gb3, globotriaosylceramide; GI, gastrointestinal; GILT, gamma interferon-inducible lysosomal thiol; GLS, Golgi localization sequence; GSH, glutathione; HeLa, human cervix adenocarcinoma; HepG2, human hepatoma; HIV, human immunodeficiency virus; HNPs, hexagonal nanoprisms; HPMA, N-(2-hydroxypropyl) methacrylamide; HT, HEAT; IA, imidazoacridinone; ICP, inductively-coupled plasma-atomic emission spectroscopy; IDS, intracellularly detachable subgroups; IMM, inner mitochondrial membrane; IMS, intermembrane space; Ir, iridium; IUSs, intervening interunit spacers; LAMP, lysosomal-associated membrane protein; LCST, lower critical solution temperature; LCVs, large compound vesicles; LIMP, lysosomal integral membrane protein; LMP, lysosomal membrane permeabilization; LRP, lipoprotein receptor-related protein; LSDs, lysosomal storage diseases; M6P, mannose-6-phosphate; MAPK, mitogen-activated protein kinase; MCF-7, human breast cancer; MD, molecular dynamics; MDR, multidrug resistance; MHC, major histocompatibility complex; MSNP, mesoporous silica nanoparticle; mTOR, mammalian target of rapamycin; MTS, mitochondrial targeting signal; N9, murine microglial cell line; NCs, nanoconjugates; NDDSs, nanoparticle-based drug delivery systems; NE, nuclear envelope; NER, nucleotide excision repair; NLSs, nuclear localization signals; NP, nanoparticle; NPCs, nuclear pore complexes; Nups, nucleoporins; OLL, oligolysine; OMM, outer mitochondrial membrane; PI3K, phosphoinositide 3-kinase; PAMAM, poly(amidoamine); PCL, poly(ε-caprolactone); PEG, poly(ethylene glycol); PEI, poly (ethyleneimine); P-gp, p-glycoprotein; Phis, poly-histidine; PLGA, poly(lactide-co-glycolide); PLA, poly(lactic acid); PLL, poly(L-lysine); PS, polystyrene; PSD, poly(methacryloyl sulfadimethoxine); QDs, quantum dots; R8, octaarginine; RAW 264.7, murine macrophage cell line; RGD, arginylglycyl-aspartic acid; ROS, reactive oxygen species; SNAP, synaptosome-associated protein; SNPs, spherical nanoparticles; STxB, Shiga toxin B; SV40, simian virus 40; TAT, HIV transactivator protein; Tf, transferrin; TfR, transferrin receptor; TPP, triphenylphosphonium; UPR, unfolded protein response; VAMP, vesicle-associated membrane protein; VNB, vapor nanobubble ⁎ Corresponding author. E-mail address: [email protected] (S. Zhou). https://doi.org/10.1016/j.pmatsci.2019.100599 Received 15 April 2017; Received in revised form 25 August 2019; Accepted 26 August 2019 Available online 26 August 2019 0079-6425/ © 2019 Elsevier Ltd. All rights reserved.

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tumor cell apoptosis. Organelle-specific delivery will become one of the primary goals for targeted drug delivery research.

1. Introduction The success of traditional cancer treatments such as chemotherapy and radiation therapy are often constrained by drug-associated side effects, because of the lack of targeted delivery techniques for transporting anticancer compounds to the neoplastic tissue and the fact that the drug concentration at the tumor site is typically low. Targeted delivery of anticancer agents is important to overcome these limitations. Recent developments in nanoparticle (NP)-based drug delivery systems (NDDSs) have demonstrated that they can carry drugs to pathological tissues via cell-membrane targeting and release these drugs in the cytoplasm [1,2]. After successful delivery into the targeted cell, a drug should get access to a particular organelle (endo/lysosome, mitochondria, Golgi apparatus, nucleus, etc.) to be effective [3]. Organelle-specific delivery has become one of the primary goals for targeted drug delivery research [4]. Many chemotherapeutics are limited in clinic application due to the poor water solubility, unmanageable toxicities, and low therapeutic efficiency. One elegant strategy to solve these problems is the use of NDDSs [5–9]. NPs templates with tunable composition, size, shape, and surface chemistry can be used as universal platforms in a variety of disease treatments. Most NDDSs researches have focused on cell-membrane targeting; for an excellent review of recent developments in the field we point the reader to reviews here [10]. Relatively few review articles have covered research on organelle-specific drug delivery. In this review, we provided a comprehensive overview on recent research towards multifunctional NPs for organelle-specific drug delivery. When nanomedicines are injected into blood, they can first accumulate in tumor tissues via the well-known enhanced permeation and retention (EPR) effect [2,11]. They will be internalized into tumor cells via different pathways which depend on their size, shape, stiffness [12], and surface chemistry. To increase drug delivery efficiency, both passive and active targeted delivery strategies are used. After these NPs enter the cytoplasm, it is important for the carried cargos to reach specific organelles. An effective method is to functionalize these NPs by altering their chemical composition or by grafting functional groups onto their surface. Only when the concentration of released drugs becomes high enough will they interact with molecular targets on specific organelles to induce tumor cell apoptosis.

2. Internalization strategies 2.1. Internalization mechanisms According to the physicochemical properties of particles and the types of cells, there are two major internalization mechanisms: phagocytosis and pinocytosis. Phagocytosis is the process of cell eating, usually occurs in internalization of large particles; and pinocytosis is also called as cell drinking, which occurs when small particles enter the cell. These internalization pathways are quite important since they determine the NPs fate through various possible subcellular compartments. For instance, NPs internalized through clathrin-mediated endocytosis will locate in lysosomes, while those internalized through caveolin-mediated endocytosis will not [13]. In clathrin-mediated endocytosis internalization, NPs must escape from the lysosomes as soon as possible in order to prevent

Fig. 1. Internalization mechanisms of NPs by cells and respective size limitations. Large particles usually generate a phagocytic response; particles > 1 μm (purple spheres) are internalized through micropinocytosis; while uptake of smaller particles can be assisted by a couple of pathways. According to size variations, 120 nm-NPs (green spheres) are internalized through clathrin-mediated endocytosis (CME), 90 nm-NPs (orange spheres) are internalized through CME- and caveolae-mediated endocytosis (CvME)-independent endocytosis, and 60 nm-NPs (blue spheres) are internalized through CvME. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) 2

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loading degradation. After that, the cargo can be delivered to the desired subcellular compartments including the cytosol, the mitochondria, or the nucleus. The cellular uptake pathway of particles is heavily dependent on particle size (Fig. 1). 2.1.1. Phagocytosis Phagocytosis mostly occurs in professional phagocytes, including polymorphonuclear leucocytes and mononuclear cells such as macrophage and monocytes [14]. In contrast, non-professional phagocytes like epithelial cells and endothelial cells show a much weaker phagocytic activity [15]. Particles smaller than 10 μm can be taken up by macrophage, which is the main obstacle that hinders the drug delivery to the targeted cell. Macrophages can take in particles up to 10 μm in size and are one of the major barriers that limit the effective delivery of vehicles to the desired location. It remains a grand challenge to develop NPs that are capable of evading macrophage clearance and sustaining good bio-distribution. Generally, particles > 1 μm generate a phagocytic response [16,17]. 2.1.2. Pinocytosis Pinocytosis, the non-phagocytic endocytosis, is restricted to specialized cells and occurs in all cell types [18]. For cancer-associated delivery, tumor cells belong to non-phagocytic cells, can take in particles up to 500 nm [19], therefore, pinocytosis is more relevant to the uptake of NPs by tumor cells. There are four main pinocytotic mechanisms, which will be described as following. 2.1.2.1. Clathrin-mediated endocytosis (CME). This is the main pathway for cellular entry. CME happens with the assistance of clathrin, a cytoplasmic protein, which assembles into the coated pits during the process. CME allows for the cellular internalization by decorating NPs with particular ligands, which are capable of recognizing the specific receptors overexpressed on the cell membranes [15]. The coated pits develop into vesicles after endocytosis, followed by entry into the endo/lysosomes to release the NPs [14]. Therefore, NPs have to escape form the endo/lysosomes for further subcellular delivery after being internalized by CME. 2.1.2.2. Caveolae-mediated endocytosis (CvME). Caveolae is small flask-shaped membrane invagination [18], commonly found in many cells, especially the adipocytes [20]. Various proteins are involved in endocytosis and trancytosis through CvME, like cavin, dynamin, synaptosome-associated protein and vesicle-associated membrane protein [21,22]. Unlike the CME, CvME bypasses the endo/lysosomal compartments. Thus, delivery of proteins and DNA into cells through CvME can effectively prevent the therapeutics from degrading by endo/lysosomes [23,24]. Compared to the CME, CvME possesses slower process and forms smaller vesicles [25]. 2.1.2.3. CME- and CvME-independent endocytosis. This pathway refers to the internalization of the particles by the cells without clathrin and caveolin. Vesicles formed by clathrin- and caveolin-independent endocytosis are around 90 nm in diameter. The internalized particles are matured to become early and late endosomes. There are not many NPs reported that can be internalized by the CME- and CvME-independent endocytosis, and understanding of interactions between NPs with cells in such pathway is still in a nascent stage. 2.1.2.4. Macropinocytosis. Macropinocytosis occurs in many cells, especially macrophages [26]. For macropinocytotic pathway, NPs are transferred into the cells by forming an invagination around them at the plasma membrane, termed as a macropinosome [27]. Once inside the cells, these macropinosomes are fused with endo/lysosomal compartments or recycle the content to cell membrane [26]. Macropinocytosis is an actin-driven process like phagocytosis, but the macropinosomes are much larger, commonly several microns. This endocytic pathway is generally nonspecific to take in large particles [28]. 2.2. Targeting A key goal of drug delivery system is to unload their payloads at the desired tissue. Targeting comprises passive and active targeting. The biophysicochemical characteristics of NPs, such as particle size, shape, charge and targeting ligands can influence the interaction of NPs with cells. The following is a brief discussion about the passive and active targeting of NPs-based drug delivery systems. 2.2.1. Passive targeting The blood vessels in tumor tissues are frequently leaky, so NPs can passively target tumors via the EPR effect [29]. The EPR effect has become an effective means for delivery of anticancer drugs to tumors, whether using polymer conjugates, liposomes or micelles. Passive targeting of NPs is mainly affected by the biophysicochemical properties of them, which have an influence on cellular uptake, toxicity, and exocytosis. Thus, studying the relationship between the NPs biophysicochemical characteristics and their interaction with cells provides an elegant method for designing effective nanocarriers. 2.2.1.1. Size. The particle size greatly influences the process of cellular internalization. It may affect the uptake efficiency and kinetics, the internalization mechanism, and the subcellular distribution. NPs larger than 500 nm can be phagocytized by macrophages, while smaller NPs can be endocytized by phagocytic or non-phagocytic cells regardless of the method of administration [19,30,31]. Internalization by non-phagocytic cells like tumor cells is desirable to achieve therapeutic effects, and macrophages usually clears large particles from the body quickly, which is undesirable. Particle size also influences the process of crossing the cell membrane. Kulkarni et al. prepared a couple of commercial 3

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polystyrene NPs with various size (20, 50, 100, 200, and 500 nm), and investigated their ability to transport across the gastrointestinal barrier and the blood-brain barrier [32]. The results showed that the 100 nm and 200 nm polystyrene NPs were able to bypass the two barriers. The size can also affect the subcellular distribution of NPs. For instance, Lovrić et al. proved that smaller quantum dots with a diameter of 2.2 nm could enter the nucleus of murine microglial (N9) cells, while the larger quantum dots approximately 5.2 nm were limited in the nuclear entry with distribution throughout the cytoplasm [33]. In another study, Huang et al. investigated the cellular uptake of gold nanoparticles (AuNPs) with different diameters by human breast cancer (MCF-7) cells. It was found that smaller AuNPs internalized faster. Furthermore, the two AuNPs measuring in 2 nm and 6 nm were located in both the cytoplasm and the nucleus, while the AuNPs measuring in 15 nm were hardly found in nucleus [34]. Tang et al. incubated three CdSe/ZnS quantum dots (3, 4.8 and 8 nm) with human cervix adenocarcinoma (HeLa) cells, the inductively-coupled plasma-atomic emission spectroscopy (ICP) analysis showed that only 3 nm particles were able to accumulate in the nucleus [35]. 2.2.1.2. Shape. Numerous shapes of NPs are able to be constructed due to the rapid development in the technologies. Spheres, rods, cylinders, spherocylinders have been researched to date [36–38]. Non-spherical NPs with various aspect ratios instead of spheres aroused wide interest since the aspect ratio (AR) is a key factor in biological processes, especially the cellular uptake. Gratton et al. reported that the uptake of cylindrical NPs was relevant to their aspect ratios to a large extent [36]. The high-aspect-ratio cylinders (AR = 3) were internalized about four times faster than the low-aspect-ratio cylinders (AR = 1) of similar volumes. In order to study the influence of AR on the cellular internalization, Meng et al. designed a series of mesoporous silica NPs (MSNPs) with different lengths. After incubation with HeLa cells, the extent of internalization was dependent on the variation of AR [39]. MSNPs with AR ranging from 2.1 to 2.5 could deliver more therapeutics to HeLa cells. Vácha et al. reported molecular dynamics (MD) simulations of the cellular uptake of ligand-coated NPs with varying shapes [38]. They showed that the passive endocytosis of spherocylinders is more efficient than that of spheres. Interestingly, study of endocytosis of spherocylinders and cylinders demonstrated that AR has no significant effects on both particles. However, endocytosis is suppressed for cylinders since there are defects at the sharp edges, which prevented the separation of the two membranes. It has shown that shape has a profound impact on the endocytosis of NPs by the macrophages as well as the tumor cells [40]. To design a shape which can avoid uptake by macrophages has garnered considerable attention. Champion et al. demonstrated that a macrophage is more able to internalize a spherical-shape particle, while worm-shaped particles exhibited negligible uptake by macrophages of the same volume [41]. Lin et al. compared the behaviors of spherical NPs (SNPs) and hexagonal nanoprisms (HNPs) in vitro [42]. This study on phagocytosis of HNPs and SNPs showed that HNPs can efficiently decrease phagocytosis more than by SNPs from 91.6 ± 0.8% to 68.1 ± 2.4%. Hu et al. synthesized a polymer-drug conjugate with a reduction-labile linker [43]. A couple of morphologies could be formed by the prodrug. The in vitro cell study indicated that the fastest internalization rate was displayed by the spiky staggered lamellae, and the large compound vesicles (LCVs) showed slower cellular entry while particles with spherical shape internalized slowest compared to the other two. They also investigated the internalization mechanism of the particles with various morphologies. The result indicated that the endocytic pathway of the staggered lamellae and LCVs was mainly by CME- and CvME-independent endocytosis, which was distinct from that of smooth disks and spheres. Interestingly, all other particles apart from the spheres exhibited nuclear drug delivery and more significant cytotoxicity. Furthermore, the in vivo study illustrated that the staggered lamellae and the smooth disks circulated longer in blood compared with LCVs and spheres. 2.2.1.3. Surface charge. The shape and size of NPs contribute markedly to their interaction with cells, however, the surface charge is the dominant factor that influences internalization. It is well-known that positively charged NPs tend to have a higher rate of cell uptake in comparison with the neutral and negatively charged NPs [44]. He et al. studied the relationship between the surface charge of chitosan grafted NPs and the cellular entry rate. Slight surface charge differences remarkably influenced the internalization [31]. It has been shown that the uptake by macrophages increased as the surface charge’s magnitude increased (either positive or negative), however, the NPs with more positive charge and less negative charge were more efficiently internalized by the non-phagocytic cells. In our previous study, we designed a charge-reversal polymer micelle system, which was negatively charged under neutral conditions, but would reverse to carry positive charge triggered by the tumor extracellular pH [45]. We proved that these chargereversal micelles were capable of cancer cell entry quickly at pH 6.8, which is a result of electrostatic interaction, while the cellular uptake of these micelles at pH 7.4 is negligible. This illustrates that the micelles with a positively charged surface, rather than those with a negatively charged surface, can be internalized more by the cells. Most recently, Zhou et al. reported a polymer-drug conjugate that could be triggered by the γ-glutamyl transpeptidase on the cell membrane to generate cationic primary amines. The resulted positively charged conjugate subsequently underwent caveolae-mediated endocytosis and transcytosis, which lead to the fast extravasation and efficient transcytosis of cancer cells [46]. Not just size and surface properties affect the interaction between NPs and cells, it is strongly dependent on cell types as well. Liu et al. investigated the surface charge effect on cell interaction with NPs. AuNPs with both positive charge and negative charge were treated with nonphagocytic human hepatoma (HepG2) cells and murine macrophage (RAW 264.7) cells [47]. There’s no significant difference in uptake by RAW 264.7 cells, whereas HepG2 cells took in much more positively charged AuNPs than AuNPs with negative charge. 2.2.2. Active targeting Although the EPR effect shows an obvious histological difference between normal and tumor tissues, the exploitation of this alone 4

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is often not adequate. Active targeting has been efficiently exploited to increase the cancer cell entry of NPs and improve the therapeutic effects of their cargos. NPs with actively targeted ligands recognize and bind to specific receptors, which are expressed a lot on cancer cells and minimal on normal cells. The ligands usually include folate, transferrin, aptamers, antibodies, and peptides. 2.2.2.1. Folate. Folate has been one of the most extensively utilized small molecule ligands for targeted drug delivery. Folate is small and less prone to degradation than biomolecular ligands. It has a high affinity to folate receptor (FR), which is up-regulated on the surface of many human tumor cells [48]. The binding of folate to FR has a very high affinity (KD ∼ 10-9), thus, the folate conjugates can deliver cargos targeted to the cancer cells instead of being internalized by the normal cells [49]. Our group developed several folate-attached micelle systems, one example being a polymeric prodrug system for tumor targeting and pH-triggered drug release [50]. The anticancer drug, doxorubicin (DOX), is chemically conjugated to the polymer backbone via pH-responsive hydrazone linkages, and folate bared on the surface of the micelles facilitates the endocytosis by the FR over-expressing tumor cells. Another folate-attached micelle system is a star-shaped vehicle connected with folate as the targeting ligand and the disulfide bond between the hydrophilic and hydrophobic segments can be cleaved by glutathione (GSH) in cytoplasm [51]. More recently, we designed a dual-targeting and dual-responsive polymer micelle system, which possesses both passive targeting ability by a charge-reversal induced electrostatic interaction and an active targeting effect by FR-mediated endocytosis [45]. This dual-targeting vehicle can be internalized by the tumor cells more quickly than the single-targeting one. The results indicate that all of these folate conjugates possessed excellent actively targeting efficacy to FR-overexpressed cancer in vitro and the best therapeutic effect in vivo. 2.2.2.2. Transferrin. Transferrin (Tf) is another ligand that selectively binds to specific membrane-bound receptors on cells for targeting via receptor-mediated endocytosis. Transferrin is an 80-kDa glycoprotein, which selectively binds to its receptor TfR [52]. Since TfR is overexpressed in the tumor cells, Tf-decorated NPs show potential application in the target-cell-specific drug delivery [53]. Roy et al. developed a Tf-targeted chemotherapeutic delivery system [54]. In vitro cell study demonstrated that Tf-targeted group obviously induced more HeLa cells death in comparison with those without Tf decoration. In another study, Sarisozen et al. simultaneously loaded paclitaxel and curcumin into the Tf-modified micelles [55]. The in vitro 3D cell culture experiments proved that the targeted micelles penetrated the spheroid more efficiently than the non-targeted micelles, and combining paclitaxel with curcumin yielded better results than either individually. 2.2.2.3. Aptamers. Aptamers are single-stranded oligonucleotides that fold by intramolecular interactions into unique conformations [56]. Aptamers include DNA, RNA or modified oligonucleotides resistant to nuclease degradation [57]. The use of aptamers to decorate NPs remains an attractive targeting strategy given their small size (∼15 kD), lack of immunogenicity, as well as their easy penetration and targeting to tumor cells [58]. Various aptamer-modified NPs have been prepared to successfully deliver cargos to tumor sites [59–61]. However, the development of aptamer-drug conjugates (ApDCs) faces problems such as complicated preparation and low controllability. In order to resolve these problems, Wang et al. developed a therapeutic module that facilitated solid synthesis of ApDCs [62]. By using this module, they synthesized a photo-cleavable phosphoramdite, which could both target tumor cells specifically and release drugs triggered by light. 2.2.2.4. Antibodies. An antibody (Ab) is a large Y-shaped glycoprotein that can target specific antigens present on the cell membrane. The antibody-antigen interactions can induce antitumor effects caused by multiple mechanisms, such as interfering with ligandreceptor binding and suppression of protein expression [63]. The usage of Abs as targeting ligands has been extensively investigated over the last decade and has resulted in multiple successful treatments [64–66]. However, Abs-targeted NPs still encounter many limitations due to the large molecule weight (∼150 kDa) as well as a hydrodynamic radius of 15–20 nm, instability in organic solvents, and rapid NPs clearance caused by the potential immunogenicity of Abs [67]. Current technology has overcome some of these limitations, for example, by using antigen-binding fragment (Fab) of Abs as targeting ligands, but the monomers and dimers of the Fab recognition patterns still result in large molecules with sizes around 50 and 100 kDa, respectively [2,68]. One method to prolong blood circulation is to remove the crystallizable fragment (i.e., using only Fab fragments), however, these Abs-NPs are still cleared faster than undecorated NPs [69]. 2.2.2.5. Peptides. Peptides are smaller than antibodies, and more stable, less immunogenic, and much easier for NPs conjugation [58]. Screening of potential peptides is usually completed by using a combinatorial phage library, which results in ligands with length ranging from 10 to 15 amino acids. They have high affinity with specific tumor targets [70]. The most studied peptide sequence is that of arginyl-glycyl-aspartic acid (RGD) which strongly binds to integrin ανβ3 overexpressed on endothelial and specific cancer cells [71]. The recognition of the RGD sequence to the ανβ3 integrin has the potential to be exploited for cancer therapy. Kim et al. attached RGD to polymer-coated oncolytic adenoviruses (Ad) vectors to ensure Ad can be selectively delivered to tumor cells [72]. Enhanced transduction efficiency and incremental cytotoxicity were displayed in RGD-conjugated group, which also showed significant in vivo antitumor effect against lung orthotropic tumor. Another peptide sequence capable of targeting behavior is angiopep-2 (ANG), which specifically binds to the low-density lipoprotein receptor-related protein. This receptor is overexpressed on the glioma cells and blood-brain barrier (BBB). ANG-NPs can penetrate the BBB to suppress the neuronal discharges and provide an effective therapy for epilepsy. In order to enhance the brain delivery of phenytoin sodium, Ying et al. decorated one electro-sensitive hydrogel NPs with ANG and studied their antiepileptic activity by using an amygdala kindling model [73]. They found that the ANGmodified NPs could cross the BBB and release the phenytoin sodium within the brain during epileptiform abnormalities. 5

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3. Intracellular delivery After NPs pass through the first barrier in blood and arrive in the tumor, they must be internalized by cancer cells. The intracellular specific target of NPs depends on the drug action, for instance, gene and antisense oligonucleotides should be transported to nucleus, proapoptotic drugs and mitochondrial DNA to mitochondria, enzymes for lysosomal storage disease and siRNA for mRNA interference to lysosomes, drugs for neurodegenerative disorders and endoplasmic reticulum (ER) storage stress to the Golgi/endoplasmic reticulum (Fig. 2). However, the intracellular delivery of NPs represents a challenge since the cellular internalization of them is energy-dependent, which is different from the endocytosis of small molecules that cross the membrane by random diffusion. NPs will be trapped in the endo/lysosomes even if they have been successfully internalized, and subsequently, the degradation of the NPs together with drugs takes place in acidic conditions. As a consequence, just a tiny part of the loaded drugs can be delivered once in the cytoplasm. To solve this problem, a variety of strategies have been developed as described below. 3.1. Cell penetrating peptides (CPPs) CPPs are a class of short amphiphilic peptides with up to 30 amino acids, commonly used to facilitate cellular uptake of NPs. CPPs are also known as membrane translocating sequences, protein transduction domains and Trojan peptides [74]. Because of the abundance in lysine or arginine, these peptides are highly cationic. CPPs are divided into three classes based on origin: derived CPPs, chimeric CPPs and synthetic CPPs [75,76]. The TAT peptide (human immunodeficiency virus (HIV) transactivator protein), derived from the transactivator activator of human immunodeficiency virus, is one of the frequently used derived CPPs that gain access to the cells [75,77,78]. Chimeric peptides, for instance transportan (TP), are consisting of regions from the neuropeptide galanin and the wasp venom mastoparan. Polyarginine is the best studied synthetic peptide, the cationic nature of which efficiently promote cell entry [79]. Regardless of in-depth investigation of the cell penetrating activity, the internalization mechanism of CPPs is still controversial. Three main possibilities for CPPs crossing the membranes have been proposed: direct penetration into cells, translocation through forming a transitory structure and translocation through endocytosis-mediated pathway (energy-dependent pathway)

Fig. 2. NPs with various biophysicochemical characteristics for subcellular targeting. The orange box represents organelle-related diseases, the purple box represents drugs that act on organelles, and the blue box represents the motifs for subcellular targeting. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) 6

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[80–82]. The pathway of CPPs-mediated delivery mainly depends on the concentration of CPPs, the type of cell, and the lipid composition of membrane [83,84]. The endocytosis-mediated pathway is the main internalization mechanism for CPPs according to many studies. CPPs-mediated delivery possesses significant advantages, such as quick internalization, ease of synthesis, and lack of toxicity. CPPs have been conjugated to a variety of NPs to facilitate their cellular uptake, including gold NPs, quantum dots (QDs), magnetic QDs, polymeric micelles, and liposomes. 3.1.1. TAt TAT, derived from the 86-mer trans-activating transactivator activator of human immunodeficiency virus, is one of the most thoroughly studied and extensively used CPPs for intracellular delivery [85,86]. TAT is comprised of 13 amino acids containing two lysine and six arginine residues (GRKKRRQRRRPPQ), which contribute to its basicity and hydrophilicity. In 1999, Josephson et al. fabricated dextran coated superparamagnetic iron oxide NPs derivatized with TAT [87], which is the first report of internalizing NPs using TAT. In another study, TAT-derivatized magnetic NPs displayed a 100-fold higher lymphocytes accumulation over the TAT-free group [88]. TAT-mediated delivery involves multiple mechanisms. Torchilin et al. prepared an intracellular delivery system of TATfunctionalized liposomes, which exhibited efficient cellular uptake even at low temperature and in the presence of metabolic inhibitors, indicating a non-energy dependent process of internalization [89]. Nevertheless, another study showed that TAT-decorated liposomes entered the ovarian carcinoma cells via clathrin-coated pits or caveolin-dependent endocytosis instead of direct cytosolic delivery by plasma membrane translocation [90]. Even if these researchers proved that the TAT-mediated cellular entry is governed by various pathways, whether the energy-dependent and energy-independent modes of transport would occur concurrently still remains unknown. The cell internalization efficiency of TAT-conjugated NPs can be determined by many properties of NPs, including particle size, shape and surface property as described in Section 2.2.1. To promote the cell entry of TAT-conjugated NPs, the TAT concentration and surface arrangement in solution should be considered as well. Todorova et al. simultaneously carried out computational simulations and experiments to study the influence of the two factors on cell permeation (Fig. 3) [91]. By altering the TAT concentrations from 0 to 9%, the higher concentration made the NPs unstable and reduced cell entry, the lower concentration lead to the decrease of the bare NPs exposure; and 5.4% TAT displayed the optimal cell internalization. Moreover, they found that the arrangement of TAT also affected the cell penetration with a relatively even distribution resulting in effective membrane interaction while the high TAT density would lead to the conformational collapse because of the repulsive interactions, in turn hinder the membrane penetration. Recently, Ming et al. studied the relationship between TAT coating density of PEG-PCL micelles and the cell internalization behavior. They found that the increase of TAT density resulted in the increase of membrane-anchoring and internalization rate, and also accelerated the energy-independent pathway [92]. 3.1.2. Penetratin Penetratin, another frequently used CPP, is derived from the homeodomain (residues 43-58) of Drosophila antennapedia [93]. This 16-amino-acid peptide with a N-terminal can be synthesized and facilitate cell entry [93]. In contrast, the same peptide without N-terminal or C-terminal have a limited access to the cells, indicating a necessity of this sequence for efficient internalization. Penetratin internalizes cells either by endocytosis [94–96] or endocytosis along with direct membrane translocation [97,98]. Penetratin possesses the ability to bind heparin sulfates [99] or chondroitin sulfates [100] with high-affinity, offering assistance to endocytosis as a unique internalization pathway for penetratin. In the condition of ionic detergents, penetratin is able to form multimers [93], followed by electrostatically interaction with anionic phospholipids and penetration into the cell membrane [101]. The penetratin/lipid interaction is a function of the vesicle lipid compositions. A high lipid/peptide ratio (325/1) resulted in the αhelical conformation of penetratin, while a low lipid/peptide ratio (10/1) gave the antiparallel β-sheets [102]. Simultaneously, the lipid bilayer organization and the lipid acyl chain direction can be changed by penetratin upon deep insertion into membrane bicelles [103]. Penetratin has been chemically conjugated to a variety of drugs or NPs to facilitate their cellular entry. Penetratin was reported to be functionalized to polymer NPs and the resulting penetratin-NPs displayed increased cell entry [104]. Furthermore, the in vivo biodistribution test indicated obvious brain accumulation enhancement with minimal uptake by non-target sites.

Fig. 3. Illustration of the influence of TAT concentration and distribution in solution on cellular internalization efficiency [91]. 7

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3.1.3. Octaarginine (R8) Peptides consisting of merely arginine residues, namely oligoarginines, have been widely used for membrane penetration [105]. Although both arginine and lysine are representative basic amino acids, oligoarginines usually promote cellular uptake more efficiently than oligolysines with the same number of residues, mainly due to the fact that more hydrogen bonds form in arginine [106–108]. Among the oligoarginines, R8 with 8 arginine residues exhibits maximized internalization, while others with more or fewer arginine residues were less effective [105]. R8 has been successfully utilized for intracellular transport of several NPs, including multifunctional envelope-type NPs [109] and lipid NPs [110] for gene delivery, as well as PEGylated liposomes for DOX delivery [111]. The use of transporter conjugates can not only gain the cellular uptake but has also been considered as a promising strategy to overcome the drug resistance. The conjugation of R8 to a representative small-molecule therapeutic agent (Taxol) through a bioactivatable disulfide linker results in significantly improved therapeutic effect against malignant cells that are resistant to Taxol alone [112]. The mechanism of this transporter-drug conjugate for overcoming multidrug resistance (MDR) mainly result from a different mode of entry and physical properties of it in comparison with free drug. El-Sayed et al. studied the effect of R8 decoration on endo/lysosomal escape of liposomes and the escape modes of them [113]. They found that the liposomes with R8 modification were capable of endo/lysosomal escape through liposomes-endo/lysosomal membrane fusion at either neutral condition (pH 7.4) or acidic condition (pH 5.5). As a control, the fusion of octalysine (K8) modified liposomes only took place at pH 7.4.

Fig. 4. Schematic illustration of tumor tissue penetration and cellular internalization of NDDSs [125]. 8

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3.2. Endosomal escape Endosomes usually are the first intracellular compartments encountered by NPs. The endosomes are acidic (pH 5–6) compared to extracellular environment and late evolve into more acidic lysosomes (pH 4–5). Besides, the lysosomal enzymes perhaps lead to the degradation of the carriers and the cargos [114]. Therefore, NPs have to escape from the endo/lysosomes as quickly as possible to get access to the intended subcellular target. There are a variety of approaches that have been successfully applied in endosomal escape, mainly through adopting fusogenic peptides and cationic materials [115]. 3.2.1. Fusogenic peptides (FPs) FPs are acid-responsive amphiphilic peptides, usually utilized to assist NPs in escaping from the endo/lysosomes due to their membrane destabilizing activity. The majority amino acid sequences of FPs are derived as viral fusion protein segments that come from such sources as influenza and HIV. These peptides exist as random coils under the physiological pH condition attributing to the electrostatic repulsion between anionic carboxyls. Once triggered by a lower pH in the environment of late endosomes or lysosomes, the carboxyls become protonated, followed by the formation of an α-helix secondary structure of the peptides. Finally, the structured peptides would merge with the endo/lysosomal membrane and thus escape from the endo/lysosomes successfully [116–118]. A synthetic 30-amino-acid peptide GALA with a glutamic acid- alanine-leucine-alanine repeat produced a membrane permeabilization effect at endo/lysosomal pH, endowing NPs with an efficient cytosolic delivery of loaded cargos [119,120]. In a recent work by Niikura et al., a sea urchin fertilization protein derived peptide, B55 (residues 83-137 of mature bindin), could simultaneously facilitate endo/lysosomal escape of various macromolecules and in turn promote cytosolic delivery [121]. 3.2.2. Cationic materials Another approach for endosomal escape is achieved by using cationic materials as carriers. Extensively studied cationic materials are usually cationic polymers and cationic lipids, most of which are rich in amine groups, making them positively charged [122]. Polyethyleneimine (PEI) has been one of the most representative and frequently used materials that exhibit endosomal escape. The capability of PEI to escape is driven by two mechanisms. PEI interacts with the endosomal membrane to make it porous, thus allowing the cargos to leak out into the cytosol. The other mechanism is the proton sponge effect of PEI [123]. The buffering action of PEI obtained by capturing hydrogen protons in the endo/lysosomes causes the osmotic swelling of this organelle, followed by endosome bursting and cargo release. Many cationic materials are able to interact with negatively charged genes or proteins to generate nanocomplexes, which inhibits their hydrolysis by lysosomal enzymes [124]. These nanocomplexes are usually positively charged, enhancing penetration into cells as a result of electronic interaction [115]. 3.3. Stimuli-sensitive NDDSs NDDSs that respond to environmental stimuli followed by intracellular delivery of therapeutics have been extensively explored. The stimuli can be external like the application of a magnetic field, ultrasound, heat, and light, or internal like changes in pH values, reduction conditions, and enzyme activity (Fig. 4) [125]. By allowing NDDSs to respond to stimulus, they are capable of delivering the cargos intracellularly, making further subcellular targeting possible. 3.3.1. Temperature sensitive Temperature is a widely studied stimulus. Compared with normal tissues, the temperature of tumor tissue is abnormal [126,127]. Tumor cells can be effectively killed by hyperthermia in the range of 40–43 °C due to the activation of apoptotic mechanism [128]. Additionally, the tumor can be heated artificially to increase the pore size of the perivascular site and quicken the blood flow, resulting in enhanced NPs accumulation in tumor. A commonly used temperature-sensitive material is poly(N-isopropylacrylamide), which possesses a lower critical solution temperature (LCST) in solution. Barhoumi et al. developed a photothermally targeted thermosensitive polymer-masked NPs based on poly(N-isopropylacrylamide)-co-polyacrylamide copolymer [129]. By conjugating this copolymer to the silica core-gold shell NPs, the peptide ligand decorated on the NPs surface can be masked at the physiological temperature. Upon NIR light trigger, the gold NPs convert it into heat, which causes the collapse of the polymer chain, followed by the exposure of the peptide ligand and binding the corresponding receptor integrin β1 on the cell surface. A relatively novel thermoresponsive carrier for intracellular delivery is fabricated by encapsulating ammonium bicarbonate (ABC) into liposomes [130–132]. Once triggered by hyperthermia (42 °C), ABC would decompose to generate CO2 bubbles, which destroyed the liposomal membrane and released the cargo. This bubble-generating liposomal system has the potential to observe the thermo-triggered drug release process as well, because ultrasound imaging could be enhanced as the generated CO2 bubbles are hyperechogenic. 3.3.2. pH sensitive The physiological pH in normal tissues is ∼7.4 while in tumors it ranges from 6 to 7 [133]. Lysosomes usually possess a pH of 4 to 5. Study on pH sensitive drug delivery systems dates back to the 1970s. The initial research was focused on liposomes that contain pH sensitive phospholipid components such as phosphatidylethanolamine, which induced destabilization of the vehicle upon acid trigger, followed by the release of the cargo [134]. Similar materials which are intrinsically sensitive to lower pH include PEI, poly(Llysine) (PLL), poly(amidoamine) (PAMAM) chitosan, etc., as discussed in Section 3.2.2. In addition to these lysosomal pH responsive materials, NPs prepared by polymers that respond to weak acid within tumor tissues have been successfully developed as well, such as poly-histidine (PHis) [135,136] and poly(methacryloyl sulfadimethoxine) (PSD) [137]. Another strategy for endowing a carrier 9

10

ER-Golgi network

Endo/lysosomes

Mitochondria

DOX

Nucleus

STxB-SN-38 prodrug

TPP-STxB conjugate

Porphyrin

Liposomes

MNPs

KLA peptide-modified liposomes DQAsomes TPCL NPs Mito-CIO Fe3O4 NPs

FA-PLL/amide-CPT conjugate FPAMAM/amide-CPT conjugate TAT-MSNs

PELEss-DA micelles

TAT-MSNs

Formulation

SN-38

IA

NH4HCO3

DOX

PTX

Ce6

CPT

Agent

Organelle

Table 1 Methods that are targeted to organelles for cancer therapy.

STxB binds to the glycolipid Gb3 receptor, then transported via endosomes and the GA to the ER by retrograde route; the disulfide bond can be broken triggered by GSH, and SN-38 would be released from the conjugate By conjugating STxB to the photocytotoxic porphyrin compound TPP(p-O-β-D-GluOH)3, the resulted TPP-STxB exhibited a high photocytotoxic activity against Gb3-expressing HeLa cells

MNPs targeted to EGFR-overexpressing cancer cells induce LMP when an AMF was applied, subsequently cathepsin B released from lysosomes can activate caspase-dependent death pathways and further induce cancer cell death Upon heating, NH4HCO3 in liposomes creates cavitation with CO2, which disrupted lysosomal membranes to release proteolytic enzymes into the cytosol By illuminating the MDR cancer cells that are preloading IA in the lysosomes, the cells would be eradicated based on photodestruction of lysosomes by IA and tumor cell lysis via formation of ROS

Mito-CIO quickly elevated the intracellular temperature of HeLa cells upon NIR irradiation due to their mitochondrial localization, enhancing the cytotoxicity in HeLa cells

DLCs and DQAsomes show high affinity with mitochondrial membranes; drugs delivered into mitochondria induces apoptosis of MDR cancer cells through mitochondrial signaling pathways by release of cytochrome c and activation of caspase-9 and −3

The intranuclear-accumulated Ce6 can generate ROS upon irradiation right inside nuclei to destroy DNA instantaneously

HeLa cells

TAT peptide binds importin α and β and subsequently targets the NPCs of cancer cells to facilitate intranuclear entry; DOX delivered into the nucleus causes DNA damage and/or inhibit topoisomerase to induce cell death PELEss-DA micelles with size-changeable ability can deshield PEI shell triggered by GSH to become PELA micelles that are smaller than nuclear pores, which directly delivers DOX into nucleus to overcome MDR Targeted charge-reversal conjugates carry CPT to the nucleus to cause cell death

[168] [169]

HeLa cells

[167] HT-29 cells

MDR A549/K1.5 and 2008/ MRP1 cells

[130,131]

[166]

MDA-MB-231 cells

HT1080 cells

[163] [164] [165]

[162]

PTX-resistant A549 cells MCF-7/ADR cells HeLa and HepG2 cells HeLa cells

[161]

[160]

[149]

[159]

[157,158]

Refs.

HeLa cells

SKOV-3 and MCF-7 cells

MCF-7/ADR cells

Cancer

Mechanisms

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with a pH response is introducing via an acid-labile linkage. The linkages that respond to the tumor microenvironment include benzoic-imine [138] and 2,3-dimethylmaleic anhydride (DMMA) [139], and those that respond to the lysosomal pH include hydrazine [140,141], β-thiopropionate [142], imine [143,144], ortho ester [145,146], and ketal [147]. pH-sensitive NPs that react to the tumor acidic environment can be applied in tumor targeting by decorating DMMA on the amino groups of PEI [148] or PLL [149] to form charge-reversal carriers, while those responding to a lower pH have been widely used in endosomal escape as mentioned in Section 3.2.2 or subcellular targeted delivery, which will be further discussed in Section 4. 3.3.3. Reduction sensitive Redox potential differs in normal organs and tumors, as well as in intracellular and extracellular environments; this unique feature can also be introduced in intracellular drug delivery system. The reductive GSH concentration in tumor cells is 100–1000 times higher than that in blood due to the rapid plasmic enzymatic degradation; GSH in tumor tissue is also 100 times higher than in normal tissues [150]. In addition to the high concentration of GSH in cytosol, the endo/lysosomes also possess a reductive environment, which has the potential to assist NPs in endo/lysosomal escape [151]. In particular, the reductive environment in endo/ lysosomes is induced by a specific gene, γ-interferon-inducible lysosomal thiol reductase (GILT), which resembles cysteine rather than GSH [152]. Indeed, the lysosomal redox potential is modulated by cysteine such as thiols, which can be converted to disulfide bonds under oxidative condition. Similarly, disulfide bonds convert to thiols in the presence of reductants; this inter-conversion plays a key role in biological process maintaining the cellular native protein structure [153]. According to this mechanism, the reduction sensitive NPs that possess disulfide linkages can keep stable in physiological condition, while rapid thiol-disulfide exchange occurs triggered by reducing agents, promoting an intracellular drug delivery. Disulfide linkages can be introduced in the polymer structure, or between polymer and drugs to form conjugates [51,154,155]. Besides, other linkages including thioether bond, selenoether bond, diselenide bond, carbon bond and carbon-carbon bond can also be used for designing redox-responsive drug delivery systems [156]. 4. Organelle-specific targeting Certain organelles are associated with various diseases (Fig. 2), but therapeutic molecules often fail to reach their subcellular target after being internalized by the cell. Recent research has focused on organelle targeting as a new vector for drug-delivery. (Table 1). The necessity and strategies to target each organelle are addressed in this section. 4.1. Nuclear targeting The nucleus is usually the final target of a therapeutic after crossing a series of biological barriers. This important organelle regulates gene expression and exchange proteins with cytosol to control cellular process [170]. Fig. 5 shows the structure of a typical nucleus. The nuclear envelope with bilayer membrane is perforated by nuclear pore complexes (NPCs), and separates the nucleus from the cytosol. The nucleoporins (Nups), constituent proteins of NPCs, determine the NPCs' structural and functional aspects. The human nuclear genome possesses 3.2 × 109 base pairs, of which 2% codes for around 30,000 [171–173]. A variety of gene-associated diseases may occur if the 30,000 genes mutate. Therefore, the nucleus is the most significant subcellular organelle target in nanomedicine. There exist various therapeutic targets in the nucleus, including proteins, nuclear receptors, and DNA. Most anticancer drugs are DNA toxins, working on nuclear DNA to interfere with replication or inhibit topoisomerase to cause cell death. Thus, they must enter the nucleus to work. Even though NPs are internalized by the desired cells, it is still difficult to get access into the nucleus. It is reported that DNA less than 0.1% from cytoplasm were capable of nuclear entry [174]. Furthermore, multidrug resistance (MDR) has become an increasingly serious problem in cancer treatment. The P-glycoprotein (P-gp) overexpressed on MDR cell membrane can actively efflux various anticancer drugs outside of the cell. Therefore, it is an urgent task to design a vehicle that directly and

Fig. 5. Schematic representation of nuclear entry of the drug-loaded NPs through the nuclear pore complexes. 11

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effectively transports the drugs into the nucleus to elicit their pharmacological responses and bypass P-gp. Drugs or NPs can move across the NPCs via both passive and active delivery. Passive delivery of cytoplasm to nucleus occurs by using ions, small molecules, and NPs of up to 9 nm [175]. Macromolecules larger than 39 nm (40 KDa) are not capable of nuclear entry either upon the occurrence of mitosis, which makes the nuclear membrane break down, or through active delivery. It has been reported that the nucleolin in the cytoplasm of breast cancer cells could actively and continuously migrated into the nucleus, endowing the nucleolin with natural nuclear targeting function [176]. Besides, nuclear entry of larger particles can rely on nuclear transport receptor-mediated delivery, resulting from the specific binding of the oligopeptide sequences to the receptors. These receptors are called nuclear localization signals (NLSs) [177], and they can ferry the vehicles via the NPCs. A series of functional NPs, including MSNPs [156,157,161], micelles [178–181], gold NPs [182–184], QDs [35,185,186], drug conjugates [187], peptide assemblies [188,189], etc., have been reported to be capable of nucleus targeting through conjugation of NLSs to the surface of the NPs. Among all the NLSs, the TAT peptide has been proved to be an efficient moiety for delivering NPs to cell nuclei through binding import receptors importin α and β [190,191]. The nuclear transport kinetics are highly dependent on the surface density of NLS. Maity et al. proved that QDs decorated with 83, 246, and 265 NLS peptides could effectively accumulate in the nucleus of HeLa cells with an average amount of 30.4%, 43.3%, and 49.0% of the intracellular QDs, respectively [186]. In contrast, less than 30% of the QDs entered the nucleus decorating with 63, 231, and 308 peptides. An alternative nuclear transport receptor-mediated delivery relies on the interaction between epidermal growth factor receptor (EGFR) and the karyopherin family of nuclear transport proteins [192–195]. EGFR that are particularly pronounced in cancer cells has a key role in nuclear delivery of NPs [196–199]. For instance, the nuclear EGFR is related to an increased resistance to chemotherapy [200] and inversely associated with survival in a couple of tumor [201,202]. Thus, nuclear delivery of genotoxic NPs through EGFR/karyopherin-mediated translocation has the potential to be applied for malignant tumor therapy. Methods of nuclear delivery of EGFR has been to modify with targeting moieties and exposure to stresses, for instance, through irradiation [203,204]. Yuan et al. developed EGFR-targeted NPs composed of a Fe3O4 core and a TiO2 shell (Fe3O4@TiO2) to facilitate cellular uptake and translocation into nucleus (Fig. 6) [205]. The Fe3O4@TiO2 NPs were modified with a couple of peptides to form peptide nanoconjugates (NCs). To select the NCs with the most affinity to EGFR and karyopherin-β, their EGFR-binding affinity as well as the NCs-EGFR/karyopherin-β interaction were investigated. The result indicated that an 11-amino-acid peptide bound with EGFR best, they called it B-loop peptide. By using X-ray fluorescence microscopy to image and quantify intracellular NCs directly, they confirmed the increased nuclear delivery of the EGFR-targeted B-loop NCs. They also showed that light activation of targeted NCs in cell nuclei significantly destroyed the double helix of DNA, probably due to the successful EGFR nuclear accumulation. An alternative strategy for nuclear delivery of NPs larger than nuclear pores is to destroy the integrity of nuclear membranes. For instance, Zhu et al. fabricated a nanoplatform for direct nuclear delivery via disrupting the nuclear membrane upon light irradiation [206]. The NPs consisting of PEG, polyamine-containing polyhedral oligomeric silsesquioxane and photosensitizer rose bengal could effectively disrupt the lysosomal structures through light-triggered singlet oxygen oxidation, followed by accumulating in the perinuclear region and augmenting the permeability of the nuclear membrane via inducing lipid peroxidation, allowing the influx of NPs. In another work, Houthaeve et al. provided a method based on vapor nanobubble (VNB)-mediated photoporation, which allows for temporarily perturbing the integrity of nuclear envelope (NE) [207]. Upon wide-field laser illumination, the gold NPs around the nucleus after endocytic uptake or electroporation-mediated delivery produced short-lived VNB, resulting in minute mechanical damage to the NE, subsequently creating small pores, which promoted nuclear entry of macromolecules that are too large to pass the NE. In this case, nuclear photoporation provides prospective potential for boosting nuclear delivery. In addition to endowing the NPs with an actively targeted ligand and disrupting the nuclear membrane, another promising strategy is to shrink the NPs on demand [208–212]. Limited by the diameter of nucleopores, NPs should be small enough for nuclear entry. However, NPs with such a small size of diameter usually have a short blood half-life as well as low tumor accumulation. To

Fig. 6. Interactions of EGFR-targeted NCs and non-targeted NCs with EGFR extracellularly (a) and intracellularly (b) [205]. 12

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solve this dilemma, Fan et al. developed size-changeable NPs composed of oligolysine/iridium (III) (OLL-Ir) compound, which are sized 128 nm in physiological condition but dissociate into ∼18 nm complexes in a lysosomal environment [213]. After lysosomal escape, the OLL-Ir NPs can enter the nucleus freely due to their small size and the active targeting moiety of oligolysine segments. In our previous work, a size changeable polymeric micelle system with a dual-shell composed of mPEG-PLA-ss-PEI-DMMA (PELEss-DA) was developed for nuclear targeting (Fig. 7) [158]. These micelles could enter the cancer cells via electrostatic interaction resulting from the surface negative charge reversing to a positive charge in acidic tumor tissues. After cellular uptake and lysosomal location, the micelles become larger triggered by the excess H+ in the lysosomes and can easily escape through the proton sponge effect. PEI shells are deshielded by the cleavage of disulfide bond between poly(lactic acid) (PLA) and PEI under a high concentration of glutathione in the cytoplasm to generate new micelles that are smaller than nucleopores. Consequently, they can enter the nucleus and release cargo to cause cancer cell death. Li et al. developed a similar delivery system with size changeable and charge reversal capabilities [214]. A nuclear-targeting peptide, R8NLS, was conjugated to DOX to generate DoxR8NLS, which was further grafted to the N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer backbone via a hydrazone linkage to form P-DoxR8NLS. This cationic prodrug was then cross-linked with the anionic DMMA-modified HPMA to form a complex, PNV [214]. This nanosystem underwent a stepwise size reduction from ∼55 nm to ∼10 nm in tumor extracellular conditions with DOX release triggered by an acidic endo/ lysosomal environment. 4.2. Mitochondrial targeting Mitochondria are power-generated organelles with bilayer membrane, transforming oxygen and nutrients into adenosine triphosphate (ATP) and distribute energy throughout the cell [215]. This process is necessary for sustaining life and supporting organ function. Apart from ATP production, mitochondria participate in many other biological activities like management of reactive oxygen species (ROS) and biosynthesis of amino acid [216,217]. The abnormalities in the mitochondrial functions have been implicated in a series of neurodegenerative diseases. In addition, mitochondrial dysfunction is related to characteristics of tumor cells, such as impaired apoptosis [218,219]. Mutations in apoptotic-related genes usually lead to the MDR of tumor cells [220]. Hence, mitochondria are important action site for cancer therapy [221]. However, the highly complex structure of this organelle makes mitochondrial delivery a difficult task (Fig. 8). The inner mitochondrial membrane (IMM) is dense with a 3-fold higher protein/lipid ratio and membrane potential than those of cell membrane [222]. These properties assist mitochondria in sequestering various materials, making them difficult to penetrate [223]. A series of chemotherapeutics including paclitaxel [224], etoposide [225], betulinic acid [226], and ceramide [220] act on mitochondria to trigger apoptosis; delivering these drugs directly to mitochondria is a promising concept for cancer therapy. There have been several methods to achieve mitochondrial targeting. The first approach is implemented by using delocalized lipophilic cations (DLCs), which can reduce the activation energy related to deionization that must take place before its uptake through the hydrophobic IMM [227,228]. To increase the ionic radius, the cations are spread over a large surface area, resulting in an effective reduction in the interaction with surrounding water molecules [229]. These cations move across the IMM driven by their large negative potential, leading to a higher concentration of mitochondria-targeted conjugates in the matrix. Triphenylphosphonium (TPP) is the most common example of DLCs for mitochondrial targeting, and has a single positive charge stabilized over three phenyl groups [230]. Besides the delocalized positive charge, TPP possesses a large hydrophobic surface area, facilitating the interaction with IMM and subsequently permitting uptake into the mitochondrial matrix [231]. TPP can be conjugated to small molecules including natural/synthetic antioxidants [232–238], spin-traps [239] and superoxide probes [240,241] as well as hydrophilic polymers/amphiphilic copolymers for mitochondrial targeting [242–248]. A series of TPP-decorated NPs have been extensively studied for mitochondria-specific bio-imaging, diagnosis and therapy, such as Fe3O4 NPs [165], nanoprobe [249,250], carbon dots

Fig. 7. Illustration of size changeable polymeric micelles for cancer therapy by direct nuclear drug delivery [159]. 13

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Fig. 8. Schematic description of mitochondrion structure and antitumor mechanism of mitochondrial targeted NPs. The therapeutics cause mitochondrial membrane damage and subsequently induces ROS (reactive oxygen species) generation, inhibits the production of ATP (adenosine triphosphate), and finally induces cancer cell death.

Fig. 9. (A) Illustration of occurrence of hyperthermia induced by NIR-triggered Mito-CIO. (B) CLSM images showing HeLa cells after incubation with different agents [165]. 14

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[251,252], gold NPs [253,254], MSNPs [255], and polymer NPs [164,256,257]. Cho et al. developed a synergistic anticancer drug delivery nanocarrier based on TPP-conjugated poly(ε-caprolactone) (TPCL) [164]. Different morphologies of TPCL NPs including nanovesicles, nanofibers, and nanosheets have been formed depending on the preparation method. After simultaneous encapsulation of DOX and its hydrochloride, TPCL NPs exhibit enhanced mitochondrial uptake over free cargo, showing an improved tumor-killing activity. Jung et al. reported a TPP-modified and NIR-triggered system, Mito-CIO, loading with coumarin for fluorescence observation (Fig. 9) [165]. In vitro cell test showed that Mito-CIO entered the mitochondria while the non-targeted CIO were accumulated in the ER. Besides, a higher cytotoxicity was displayed by Mito-CIO over CIO under NIR irradiation. For the in vivo study, the NIR-triggered Mito-CIO significantly inhibited tumor growth compared to other groups. Both the in vitro and in vivo test indicated that hyperthermia in mitochondria were more efficient to induce tumor death than in ER. Mitochondrial targeted liposomes made of positively charged amphiphilic molecules can also be used as potential mitochondrial transporters. The most intensively investigated examples are DQAsomes, which are formed by dicationic mitochondriotropic compounds dequalinium [258]. DQAsomes can transport drugs and DNA to mitochondria due to their high mitochondrial affinity [259,260]. A novel liposome carrier for mitochondrial targeting is R8 moieties bearing MITO-Porter that fuse with mitochondrial membrane to get access [261–263]. The endocytic mechanism of this carrier was dependent on R8 density with high density resulting in micropinocytosis, while low density gave a CME-mediated uptake [264]. More recently, Bae et al. reported that DQA80s nanosomes consisting of dequalinium/1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/ 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), showed increased cellular uptake and more cytotoxicity than DQAsomes [265]. The potential anticancer effect of DQA80s was probably due to the production of ROS via mitogen-activated protein kinase (MAPK) signaling pathways, loss of mitochondrial membrane potential, and the caspase-3 activation [265]. The third strategy for mitochondrial targeting is to use the mitochondrial targeting signal (MTS) peptide [223]. Although the Nterminal of MTS peptide are nonspecific, they still possess parallel characteristics to some extent [266]. MTS exhibited significant mitochondrial targeting ability by successfully delivering various therapeutics into this organelle [267–270]. However, due to the limitation of the polypeptide sequence length and requirement for cell penetrating vehicle like positively charged polymers or liposomes, using this strategy for mitochondrial targeting is uncommon [271]. In addition to the above-mentioned methods, it has

Fig. 10. Schematic illustration of the lysosomal targeted conjugate [288]. 15

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been reported that the temperature of mitochondria was approximately 10 ℃ higher than other organelles [272], such a temperature difference can be exploited for thermo-responsive drug delivery to mitochondria [273]. By sequestering the therapeutics within the mitochondria, it is potentially to bypass the MDR, such as the membrane-associated Pgp pump [274–276]. This is because P-gp only pumps the drugs in the cytosol out of the cells [277]. The commonly used chemotherapeutics including DOX and platinum usually face the problem of P-gp even if delivered intracellular. The DOX-MITO-Porter fabricated by loading DOX into a MITO-Porter, could effectively deliver DOX to mitochondria of human DOX-resistant renal (OS-RC2) cells, consequently bypassed the P-gp and killed the cells [261]. In addition to P-gp, another protein that resist to platinum is nucleotide excision repair (NER) [278]. Mitochondria delivery of platinum to bypass NER is an effective strategy to kill platinumresistant cells [279–281]. Leukemia resistant to chlorambucil is mainly due to the overexpression of antiapoptotic proteins in Bcl2 family, which in turn inactivates apoptosis [282]. By activation of apoptosis, a mitochondrial targeted chlorambucil, mtCbl, successfully overcame the chlorambucil resistance of leukemic cells [283]. 4.3. Endo/lysosomal targeting Lysosomes are membrane-bound subcellular organelles found in nearly all animal-like eukaryotic cells. The hydrolytic enzymes in lysosomes can digest a couple of cellular materials, including proteins, nucleic acids and carbohydrates. Various pH-dependent NDDSs were designed to inhibit degradation in these compartments. The lysosomal-associated diseases like lysosomal storage diseases (LSDs) limit cell transport [284]. Enzyme replacement therapy is still the best treatment for LSDs [285,286]. Mannose6phosphate receptors (MPRs) can bind with the Golgi apparatus and then transported to the endo/lysosomal system [287], increase macrophage delivery of the enzyme in Gaucher’s disease (one LSD). Considering the overexpression in the endo/lysosomal compartments of a variety of cell types, MPRs are prospective targets for endo/lysosomal delivery. Hoogendoorn et al. described a strategy to develop an MPR ligand [288], and attached it to a cathepsin probe to generate a conjugate (Fig. 10). The MPR ligandmodified conjugate displayed an enhanced targeting activity; while the non-targeted control showed minimal lysosomal accumulation. In addition to MPRs, another receptor overexpressed on lysosomes is integral membrane protein LIMP-2, which has an affinity with β-glucocerebrosidase (β-GCase). This process depends on lysosomal pH that LIMP-2 binds to β-GCase in early endosomes while releasing it in more acidic late lysosomes [289]. Zhao et al. investigated the mechanism of pH-triggered combination and separation between LIMP-2 and β-GCase by using structural simulation [290]. The results indicated that a higher pH at both pH 5.5 and 6.5 lead to the transformation of Histidine 150 to threonine, which in turn locked LIMP-2, followed by binding to β-GCase. In contrast, a lower pH in late lysosomal compartment made Histidine 150 protonated, resulting in the change in conformation and separation between βGCase and LIMP-2. The major functions of lysosomes are degradation of macromolecules and release of enzymes intracellularly. The lysosomal protease cathepsin B that assists in maintaining the homeostasis of cells has been proved to take part in cell death pathways [291]. Upon particular trigger, the lysosomal membrane becomes permeable, followed by release of cathepsin B [292–294], which in turn activate the lysosomal pathway of apoptosis and further induce cell death [295]. Therefore, lysosomes are thought to be related to cancer cell progression. Magnetic nanoparticles (MNPs) can be used to selectively permeabilize cancer lysosomes. By applying an alternating magnetic field, Domenech et al. demonstrated that the EGFR-targeting MNPs effectively made the lysosomal membrane permeable after treatment with EGFR-expressed tumor cells [166]. Lysosomes are highly associated with drug resistance in cancer resulting from the sequestration of anticancer drugs in their acidic environment. For instance, Gotink et al. reported that the expression of lysosomal-associated membrane protein 1 (LAMP-1) and LAMP-2 in the resistant cells increased after being treated with sunitinib, an antiangiogenic tyrosine kinase inhibitor [296]. This finding proved that lysosomal sequestration could be a novel mechanism of sunitinib resistance. A series of therapeutic approaches for lysosomal targeting have attempted to overcome MDR. One approach has been to treat lysosomes with photosensitizers, which

Fig. 11. Illustration of Gb3-mediated retrograde delivery of drug-conjugated Shiga toxins for Golgi-ER network targeting. 16

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can be triggered under irradiation and oxidize the lysosomal membrane, and finally release the therapeutics to avoid sequestration in lysosomes [297]. Adar et al. developed a novel light activating strategy to overcome MDR. By illuminating the imidazoacridinoneloaded cancer cells, lysosomes are destroyed and cells become sensitive to drugs. Therefore, lysosomal photodestruction is a promising approach to overcome MDR [167]. 4.4. Golgi apparatus (GA)/endoplasmic reticulum (ER) targeting GA and ER are closely associated organelles and they have similar structures. The membranes of ER form sacs, also called cisternae, where proteins are folded and transferred to GA [298]. GA and ER play a key role in the retrograde trafficking pathway, which bypasses the acidic pH and degrading enzymes in the endo/lysosomes [299]. There’s more than one mechanism involved in retrograde transport from GA to ER, such as coatomer protein complex-I (COPI)-dependent and COPI-independent pathways [300,301]. Overexpression of Golgi-associated proteins, pharmacological agents, and certain pathological changes can lead to profound alterations in the GA, which causes various neurodegenerative disorders [302–304]. In addition, ER dysfunction causes an unfolded protein response, which inhibits protein synthesis and protein folding. Both GA and ER are relevant to tumor and potentially targets for anticancer therapeutics [305]. Targeting of therapeutic agents to the ER-Golgi network has been applied in cancer diagnosis and therapy [299,306]. The therapeutics delivered to these intracellular compartments should enter the cells by CME-independent endocytosis for purpose of avoiding sequestration within endo/lysosomes. A series of strategies have been demonstrated for ER-Golgi targeting. One effective approach is to aim at the mammalian (or mechanistic) target of rapamycin (mTOR). mTOR is a phosphatidylinositol 3-kinase (PI3K) -related kinase that responds to the surrounding and cellular nutrition and energy conditions. mTOR signal can be activated via diverse stimuli, including nutrients, ATP and stress signals [307]. mTOR is highly correlated with cancer. For instance, activation of mTOR in certain tumor cells leads to PI3K inhibition. In contrast, inactivation of mTOR results in an increase in PI3K activity and the subsequent decrease of the antiproliferative effect of mTOR inhibition, killing the tumor [308]. It is worth mentioning that ER-Golgi network is main place where mTOR exists [309]. Hence, mTOR is an appealing therapeutic target in the ER-Golgi network. Another targeting strategy with significant potential is to conjugate a therapeutic moiety to protein toxins (Shiga or cholera toxins) that are capable of targeting the ER [306]. This approach takes advantage of retrograde transport [309], which is illustrated in Fig. 11. The Shiga toxin receptor, globotriaosylceramide (Gb3 or CD77), is highly expressed in most common tumors [310,311]. By conjugating to Shiga toxin subunit, topoisomerase inhibitors and imino sugar Nbutyldeoxynojiromycin have been successfully delivered to the ER [168,312]. 5. Conclusion and outlook The goal of nanoparticle-based drug delivery is to selectively deliver drugs to a target, which decreases side effects and increases therapeutic efficiency. It can accelerate the development of personalized and precision medicine. To fabricate nanocarriers with potential applications in clinical practices, an in-depth understanding of internalization mechanisms is important. NPs enter cells via different routes, which in turn determine where the NPs end up within the cell. The therapeutic outcome can be influenced by controlling the uptake route of NPs. In this review, several targeting strategies have been discussed, such as optimizing the physicochemical properties of NPs, decorating actively targeted ligands, or using cell penetrating peptides. Subcellular targeting remains a blooming research area. To achieve the goal of transporting drugs directly into organelles, new NPs requires a higher level of complexity. Despite this challenge, some efforts have been made in recent years to target organelles. Endosomes are the first type of intracellular compartment encountered by NPs, which they must escape in order to avoid destruction. Fusogenic peptides and cationic materials have been proven to successfully promote endosomal escape. To deliver the nanomedicines to the site of drug action (genes to nucleus, proapoptotic drugs to the mitochondria, enzymes for LSDs to the lysosomes, etc.), various approaches have been successfully developed. A detailed understanding of the intracellular trafficking of subcellular targeted nanomedicines, as well as their time-dependent fate and drug release profile inside the organelles still remains lacking. Although the task is challenging, sequential multistage targeting is the next step in NP design, and it is hopeful that this new paradigm will be successfully applied in clinic in the upcoming years. Acknowledgements This work was partially supported by the China National Funds for Distinguished Young Scientists (51725303), National Natural Science Foundation of China (Nos. 51373138, 21574105, 51603172), and Sichuan Province Youth Science and Technology Innovation Team (Grant No. 2016TD0026). Z.C. acknowledge the support from Society in Science, the Branco Weiss Fellowship, administered by ETH Zürich. References [1] [2] [3] [4]

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Shaobing Zhou received his B.S. degree in polymer chemistry from Sichuan University (1996) and his Ph.D. in organic chemistry from Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences (2003). He was promoted in 2005 to Full Professor in the School of Materials Science and Engineering, Southwest Jiaotong University. His research interests include the synthesis and characterization of biodegradable polymers, drug-delivery systems, shape-memory polymer composites, and electrospun biodegradable polymer fibers as a tissue engineering scaffold. He is the author or coauthor of more than 120 refereed articles and 15 Chinese patents/patent applications. He has been cited over 5000 times and has an h-index of 45.

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