Article pubs.acs.org/cm
Dual-Stimulus-Responsive Fluorescent Supramolecular Prodrug for Antitumor Drug Delivery Wenyu Cheng,† Hong Cheng,‡ Shuangshuang Wan,‡ Xianzheng Zhang,*,‡ and Meizhen Yin*,† †
State Key Laboratory of Chemical Resource Engineering, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China ‡ Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University, Wuhan 430072, China S Supporting Information *
ABSTRACT: To achieve higher bioavailability by taking advantage of the complex biological environment, the development of drug delivery systems (DDSs) keeps progressing. Through supramolecular technology, building blocks with different properties and functions could be combined in a controlled manner, realizing programmable drug delivery with high efficiency. In this study, we constructed a supramolecular DDS (SDDS) with charge-reversal polyanions and fluorescent polycations with reduction cleavable camptothecin (CPT) attached. During the supramolecular assembly process, the prodrug exhibited a morphological change from cubelike to rodlike and its fluorescence was significantly enhanced. Programmed drug delivery was achieved by a dual response of the extracellular acid and intracellular reductive environment. In vitro studies of the SDDS made it possible to visualize faster cellular uptake at pH 6.8 than at pH 7.4 because of the reexposure of cationic charges and subsequent successful delivery of CPT to the cell nucleus. In the in vivo studies, SDDS treatment through tail vein injection showed enhanced tumor suppression compared with that of the cationic prodrug and free CPT treatment at a low concentration (1.5 mg/kg of CPT equivalents). Altogether, we developed a novel fluorescent supramolecular system as a tumor microenvironment-responsive carrier of hydrophobic drugs for programmed drug delivery, which could be used in future cancer therapy.
■
INTRODUCTION Camptothecin (CPT) can inhibit the activity of topoisomerase I during DNA replication. Drug loading rates of CPT in most reported micellar systems remain low because of its extreme hydrophobicity.1−6 Covalent conjugation of drugs to polymers through the intracellular environment-responsive bond of cancer cells could effectively prevent burst release.7 To control and improve drug conjugation, active coupling groups are needed.8 With covalent conjugation to polymers, CPT exhibits improved and controllable drug loading efficiency.9−11 Various strategies have been designed to inhibit the aggregation of CPT to establish a usable drug delivery system (DDS).12−16 However, researchers barely consider taking advantage of the complex biological environment to improve bioavailability and reduce the drug concentration. A programmed DDS with an asdesigned drug release process takes full consideration of overcoming the biological barriers, leading to improved bioavailability. Synthetic nanostructures have been widely applied in the delivery of therapeutic drugs, especially hydrophobic antitumor ones.17−19 Compared with nanostructures with a single building block, supramolecular self-assemblies consisting of © 2017 American Chemical Society
two or more building blocks could integrate more functions in a programmable manner. On the basis of their electrostatic interaction, hydrophobic interaction, π−π stacking, or hydrogen bonding, different nanoparticle shapes have been obtained.20−22 As building blocks with opposite charges, polyion has been extensively studied in biological fields, such as drug, gene, and protein delivery. 23 With different morphologies, sizes, and surface properties, polyion could significantly change the bioactivity of DDS.24,25 For example, some functionalized polymers with specific sizes possess an enhanced permeability and retention (EPR) effect, which would assist anticancer drugs in bypassing biological barriers and targeting the cell nucleus.26−29 Additionally, fluorophores have been introduced into the DDS to achieve visualization of the drug delivery process. For example, perylenediimide (PDI) is a dye with excellent optical properties. PDI-cored dendrimers30 and star polymers display excellent water solubility and have been applied in bioimaging31 Received: January 5, 2017 Revised: May 2, 2017 Published: May 2, 2017 4218
DOI: 10.1021/acs.chemmater.7b00047 Chem. Mater. 2017, 29, 4218−4226
Article
Chemistry of Materials
Scheme 1. (a) Chemical Structures of P1, P2, and Their P1@P2 Complex and (b) Illustration of the CPT Delivery Process Using the P1@P2 Supramolecular Complex
and gene,32,33 protein,34 and drug35 delivery. Synthetic branched polyelectrolytes have a structure similar to that of biomacromolecules, making them suitable for biology studies.36 Through molecular dynamics simulations, Larson et al. showed that synthesized cationic dendrimer polyelectrolytes have strong interactions with lipid bilayers, resulting in pore formation on the bilayers. On the contrary, linear cationic polyelectrolytes do not have such an effect.37 Therefore, a PDIcored star polymer-based DDS should be very promising in terms of yielding specific architectures and bioimaging functionalities. Although poly(L-lysine) (PLL), as a nuclear drug carrier, is an excellent building block for supramolecular self-assembly, it is toxic to blood because of the cationic charges. After supramolecular self-assembly of polyanions or polyethylene glycol (PEG) with PLL, the shielded carrier exhibits reduced toxicity.38−41 Among all these shielding polymers, chargereversal polymers have emerged as a solution for responsive drug delivery.42−47 Kataoka et al.45 first reported a protein nanocarrier with a citraconic anhydride-modified chargeconversion polymer. The citraconic amides were degraded in acetate buffer (pH 5.5) within 1 h. To further improve the sensitivity of the amide bond to pH, Shen et al. reported 1,2cyclohexanedicarboxylic anhydride28 modified PEI and 2,3dimethylmaleic anhydride23 modified poly(L-lysine), which exhibited enhanced sensitivity to weak acid. Thus, chargereversal polymer-shielded PLL could further respond to the tumor acid microenvironment and re-expose cationic amine groups, which could guarantee both an elongated circulation time in the blood and higher cellular uptake efficiency.
In this study, we constructed a supramolecular DDS (SDDS) of two oppositely charged building blocks. Fluorescent star polycation P1 linked with CPT through a reduction-responsive bond was designed as a step in SDDS (Scheme 1). To overcome the cationic cytotoxicity, P1 was integrated with a charge-reversal anionic copolymer (P2) to obtain P1@P2, which worked as another step in the SDDS. Because of its negatively charged surface, P1@P2 was stable in blood and the complex accumulated at a tumor site through an EPR effect (I). In the tumor extracellular microenvironment, cleavage of the acid-labile amide bond led to charge conversion and disassembly of P1@P2 (II). The exposure of surface cations resulted in enhanced cellular uptake (III). Then, the prodrug was released through a “proton sponge” effect48 (IV). At the end, CPT was cleaved from the cationic prodrug through GSH (V) and entered the cell nucleus (VI) to show its cytotoxity in the apoptosis of cancer cells. Taken together, the tumor acidic and reductive dual-stimulus-responsive fluorescent supramolecular complex with CPT might have great potential in SDDS and cancer therapy.
■
EXPERIMENTAL SECTION
Materials. NCA-Lys was purchased from Chengdu Enlai biological technology Co. Ltd. 4-Dimethylaminopyridine (DMAP), 1-ethyl-3-[3(dimethylamino)propyl]carbodiimide hydrochloride (EDC), propanoic acid, 3-[(triphenylmethyl)thio]-2,2′-dithiodipyridine, N,N′-dicyclohexylcarbodiimide (DCC), N-hydroxysuccinimide (NHS), 3mercaptopropionic acid, and N,N-diisopropylethylamine (DIEA) were purchased from Alfa Aesar. Camptothecin (CPT), triethylsilane, PEG2000-NH2, and dimethylmaleic anhydride were from Aladdin. 4219
DOI: 10.1021/acs.chemmater.7b00047 Chem. Mater. 2017, 29, 4218−4226
Article
Chemistry of Materials Dulbecco’s modified Eagle’s medium (DMEM), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), fetal bovine serum (FBS), penicillin-streptomycin, trypsin, and Dulbecco’s phosphate-buffered saline (PBS) were obtained from GIBCO Invitrogen Corp. Cathepsin B (bovine spleen) was purchased from Biology Institute. Characterization. 1H nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 600 spectrometer at room temperature. Mass spectra were recorded on a XEVO-G2QTOF (ESI) instrument (Waters). Ultraviolet−visible (UV−vis) spectra were recorded on a spectrometer (Cintra 20, GBC). Fluorescence spectroscopic studies were performed on a fluorescence spectrophotometer (Horiba JobinYvon FluoroMax-4 NIR). Scanning electron microscopy (SEM) micrographs were recorded on a HITACHI S-4800 scanning electron microscope under an accelerating voltage of 10 kV. High-performance liquid chromatography (HPLC) was performed on a Shimadzu liquid chromatograph (LC-20AT) with a C18 column (Eclipse XDB-C18, 5 μm, 4.6 mm × 150 mm). Methanol and water were used as the mobile phase for gradient elution (concentration of methanol programmed from 10 to 100% within 1 h) of P1 and P1 after incubation with dithiothreitol (DTT) (10 mM) with a flow rate of 1 mL/min. The detection peak was at 365 nm, which is attributed to CPT. Self-Assembly of P1 and P1@P2. P1 at 0.02 mg/mL and P2 at 0.06 mg/mL were prepared in water. P2 was dropped into P1 and the mixture stirred with a plastic dropper for a few minutes. Then, a drop of the mixture was dripped onto the glass slide and evaporated overnight. P1 (0.01 mg/mL) was prepared in the same way. ζ Potential Measurements. ζ potentials of samples were measured with a Malvern Zetasizer Nano instrument with a compatible disposable capillary cell (DTS 1070 from Malvern). P1 and P1@P2 were diluted instantly before being measured as a 1 mL aqueous solution (0.01 mg/mL). Measurements were taken automatically and repeated three times to obtain the mean values and standard deviations. Isothermal Titration Calorimetry (ITC) Analysis. ITC analysis was performed at 25 °C using a Nano ITC instrument (TA Instruments Waters, LLC) by following a previously reported method.49 After an initial delay of 300 s, a solution of P2 (0.8 mg/ mL in water) was titrated via 25 injections (10 μL per injection) into P1 (0.05 mg/mL in water). The raw data were collected and analyzed by TA Instruments Nano Analyze TM software. The titration curves were fitted using the independent model. Thermodynamic parameters, including the entropy change (ΔS), enthalpy change (ΔH), and affinity constant (Ka), were given by this software. Cell Culture. Human cervical carcinoma (HeLa) and transformed African green monkey SV40-transformed kidney fibroblast (COS7) cells were cultured in complete DMEM with 10% FBS and 1% antibiotic (penicillin-streptomycin, 10000 units/mL). Murine mammary carcinoma (4T1) cells were cultured in complete MEM with 10% FBS and 1% antibiotic. The cell culture was kept at 37 °C in a 5% CO2 humidified atmosphere. All experiments were performed on cells in the logarithmic growth phase. Quantitative Study of Cellular Uptake by Flow Cytometry. HeLa cells were seeded on a six-well plate (105 cells/well) in 1 mL of DMEM including 10% FBS and cultured in a 5% CO2 humidified atmosphere for 24 h. The original medium was replaced with DMEM containing P1@P2, at an equivalent CPT concentration of 2 μg/mL at pH 6.8 and 7.4. After incubation for 1 h at 37 °C, HeLa cells were washed three times with PBS and each time for 5 min. Thereafter, cells were harvested with trypsin and washed twice. Then washed cells were suspended in PBS and centrifuged at 4 °C and 1000 rpm for 4 min. The supernatants were discarded, and the cell pellets were washed with PBS to remove the background fluorescence in the medium. After being washed and centrifuged twice, cells were resuspended with 200 μL of PBS. Cellular uptake of P1@P2 was quantitatively studied with a FACS Calibur flow cytometer (BD Biosciences). A minimum of 10000 events per sample was analyzed. The emission was from the fluorophore of P1. Evaluation of Cellular Uptake by Confocal Laser Scanning Microscopy (CLSM). 4T1 cells were seeded in six-well plates,
incubated in 1 mL of DMEM including 10% FBS, and cultured for 24 h at 37 °C. To examine cellular uptake, P1@P2, P1 or P5 was added at an equivalent CPT concentration of 2 μg/mL to cultured cells. The cells were incubated in medium at pH 7.4 or 6.8 for an additional 1 h. The medium was then removed and washed six times with PBS. Fresh medium was added to cells again after they had been washed. Cellular uptake was observed via laser scanning confocal microscopy (Nikon C1-si TE2000). As a control, COS7 cells were incubated with P1@P2 under the same medium and culture conditions. To identify whether CPT can be efficiently released to the cell nucleus, 4T1 cells were incubated with P1@P2 at pH 6.8 for 2, 12, and 24 h. Then the cells were subjected to CLSM examination. Cytotoxicity Assay. The in vitro cytotoxicity of P1@P2 against HeLa, COS7, and 4T1 cells was determined by the MTT assay at pH 7.4 and 6.8. HeLa, COS7, and 4T1 cells were seeded onto 96-well plates (6000 cells/well). The original 100 μL of medium with 10% FBS was replaced with medium containing P1@P2 at pH 7.4 and 6.8 after incubation for 24 h. The cells were further incubated with fresh medium for 4 h at 37 °C. Then the medium with P1@P2 was replaced with 200 μL of fresh medium and incubated for an additional 48 h. Afterward, MTT (5 mg/mL, 20 μL per well) was added during a further 4 h incubation. Subsequently, the supernatant in each well was replaced with 150 μL of dimethyl sulfoxide to dissolve the formazan of MTT. The optical density (OD) of a fresh well was determined by a microplate reader at 570 nm (Bio-Rad, model 550). The relative cell viability was calculated according to the following equation: cell viability (%) = OD(sample) × 100/OD(control). OD(control) and OD(sample) are the optical density in the absence and presence of the sample, respectively. Each value was averaged from eight independent experiments. As the control, the cytotoxicities of CPT and P1 were also determined by the same assay process. In Vivo Toxicity Assessment of P1@P2. P1, CPT, and P1@P2 at a dose of 1.5 mg/kg of CPT equivalents were intravenously injected into BALB/c rats (female, 5 weeks old, n = 4 for each group) through the tail vein. P2 was used at a dose of 45 mg/kg. The rats treatment with PBS were used as the control group. The weights of the rats were recorded every day for 12 days. Animals and the Tumor Xenograft Model. Female BALB/c rats (5 weeks old) were purchased from Cancer Institute & Hospital of the Chinese Academy of Medical Sciences and used under protocols approved by the institute’s Animal Care and Use Committee. To set up the tumor model, 1 × 106 4T1 suspended in 100 μL of PBS were subcutaneously injected into the backsides of the BALB/c rats. The tumor volumes (V) were measured by the length (A) and width (B) of tumors and calculated as V = [(tumor length) × (tumor width)2]/2. The relative tumor volume was defined as V/V0 (where V0 is the tumor volume when the treatment was initiated). Therapeutical Evaluation of P1@P2 for Tumor-Bearing Rats. The BALB/c 4T1 tumor-bearing rats were randomly divided into five groups (n = 4 for each group). After the tumor volumes reached ∼100 mm3, the rats were injected with (1) P1@P2 (equivalent CPT dose of 1.5 mg/kg), (2) P1 (equivalent CPT dose of 1.5 mg/kg), (3) P2 (45 mg/kg), (4) free CPT (1.5 mg/kg), and (5) PBS (100 μL). The tumor volumes were measured and calculated with a Vernier caliper every day. The weights of rats were recorded over the course of the experiments. Then, the rats were sacrificed on the 12th day. The tumors were dissected and weighed. The tumor inhibiting rates were calculated to evaluate the therapeutic efficacy. The dissected tumors of the P1@P2, P1, P2, free CPT, and PBS groups (groups 1−5, respectively) were embedded in paraffin and made as 4 μm slices by cryosection. Furthermore, the frozen slices were stained with H&E to further characterize the therapeutic effects. The slices were imaged under an inverted fluorescence microscope.
■
RESULTS AND DISCUSSION
Preparation and Characterization of P1 and P1@P2. P1 is PDI-cored four-armed cationic polylysine with CPT attached. P2 is a linear polyanion with dangling charge-reversal groups. Syntheses of P1 and P2 are presented in Scheme S1. 4220
DOI: 10.1021/acs.chemmater.7b00047 Chem. Mater. 2017, 29, 4218−4226
Article
Chemistry of Materials The four-armed initiator with four amine groups,50 SPDP [Nsuccinimidyl-3-(2-pyridyldithiol) propionate],23 CPT-SPDP,23 and P227 were synthesized as previously reported. The precursor of P1 was synthesized through ring-opening polymerization of S-carbobenzoxy-L-lysine N-carboxyanhydride (NCA-Lys) with a molecular weight distribution of 1.09 (Figure S1). CPT was covalently linked to the star polymer through SPDP51 to give rise to P1. As shown in (Figures S2− S8), important intermediates were identified by 1H NMR and mass spectra. P2 was mixed with cationic P1 at a weight ratio of 3:1 to make sure that the P1@P2 complex was negatively charged. The concentration−absorbance equation of CPT (Figure S9a) is Y = 54.75X + 5 × 10−4, where Y is the absorbance of CPT and X is the concentration of CPT (milligrams per milliliter). According to Figure S13, the calculated CPT loading capacity was 11.6%, which is a medium rate compared with those from other studies.1,15,23 The drug loading capacity (percent) was calculated as (mass of CPT in micelles)/(mass of polymer). HPLC was conducted to verify whether CPT was covalently linked to the cationic polymer. The peak at 32 min in the HPLC data was attributed to P1 (Figure S10a), and the peak at 39 min was attributed to CPTSH (Figure S10a−d). The integration of the peak area determined that >90% of CPT was covalently linked to the cationic polymer (Figure S10a,b). When P2 was added to P1, the P1@P2 complex was stable in solution. In such a way, water-soluble fluorescent prodrug P1@P2 was successfully prepared with a tumor acidic and reductive stimulus-responsive bond as well as CPT loading. Supramolecular Self-Assembly. To evaluate the selfassembly ability of the prodrug, P1 and P1@P2 in an aqueous solution were investigated by SEM. Figure 1a shows that
larger than the sizes of the hard core measured by SEM. The planar structure of CPT endowed it with strong π−π interaction, which provided the driving force for prodrug assembly. During the self-assembly process of positively charged P1 and negatively charged P2, both the strong π−π interaction of CPT and the electrostatic interaction might contribute to the formation of supramolecular nanostructures. As previously reported, 5 μg/mL). At pH 6.8 and relatively high concentrations, P1@P2 exhibited the highest inhibition efficiency in cellular proliferation, which was mostly attributed to enhanced cellular uptake because of the reexposure of positive charges in P1 and subsequent release of CPT in a reductive environment in tumor cells (Figure S10b). These results confirmed that the P1@P2 supramolecular 4223
DOI: 10.1021/acs.chemmater.7b00047 Chem. Mater. 2017, 29, 4218−4226
Article
Chemistry of Materials
This further verified the effectiveness of the cationic shielding charge-reversal methodology in cancer therapy.
complex with CPT functioned through acid-triggered charge conversion and reductive environment-sensitive drug release, which finally delivered CPT into tumor cells to exert its antitumor capability. In Vivo Tumor Inhibition Ability of P1@P2. The in vivo tumor inhibition efficiency was evaluated in 4T1 tumor-bearing mice. The mice were divided into five groups and treated with P1@P2, P1, P2, CPT, or PBS. Animals were treated each of the first 4 days and then every other day. As shown in Figure 6a, body weights of the mice in the P1@P2, P1, CPT, and PBS
■
CONCLUSIONS In summary, we successfully developed a charge-reversal fluorescent supramolecular complex (P1@P2) with CPT built inside for programmed SDDS. Enhanced drug loading efficiency was achieved through chemical conjugation of CPT to a PDI-cored fluorescent star polymer. Hydrophobic interaction dominated the complexation of P1 and P2, leading to fluorescence enhancement and morphological transition. Beyond that, P1@P2 was responsive to the tumor extracellular and intracellular microenvironment, which was favorable for programmed cellular uptake and drug release. An in vivo study demonstrated that P1@P2 induced more potent control of tumor than free CPT and cationic prodrug P1 did. In short, a new strategy was established to develop smart drug nanocarriers in programmed SDDS and cancer therapy with enhanced therapeutic efficiency via the design of chargereversal supramolecular complex P1@P2, by which certain biological barriers could be avoided.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemmater.7b00047. Synthetic procedures of all the compounds, including P1 and P2, 1H NMR spectra and mass spectra of important intermediates, HPLC of P1 and P1 after incubation with DTT, spectra of P1 with surfactants, the possible solubilizing mechanism of P1@P2, and CLSM images of 4T1 cells incubated with P1@P2 for 2, 12, and 24 h (PDF)
Figure 6. (a) Body weights of tumors with different treatments. (b) Relative tumor volumes of 4T1 xenograft tumor-bearing mice treated with P1@P2, P1, P2, CPT, and PBS within 12 days. These results are presented as the arithmetic mean and standard deviation of tumor volumes in each group (n = 4). (c) Photographs of tumors after different treatments on the 12th day. (d) H&E staining of tumor sections harvested from mice receiving P1@P2 (d1), P1 (d2), P2 (d3), CPT (d4), and PBS (d5). The results are expressed as means ± the standard deviation. As determined by a t test, **p < 0.01 and *p < 0.05.
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected].
groups remained stable, while P2 causes the weights to decrease during the first 4 days probably because the strong negative charges disrupted the internal environment. The tumor volume of the group treated by intravenous injection of P1@P2 was more effectively inhibited than those of P1, P2, and free CPT groups were (Figure 6b). The result demonstrated the successful cancer therapy via charge reversal. Figure 6c shows photographs of the respective tumor tissues after treatment for 12 days. Histological examination of tumor slices stained with hematoxylin and eosin (H&E) in each group was qualitatively performed on the basis of optical microscopy. The typical characteristics for chemotherapy-induced loss of nuclei, cell shrinkage, and coagulation of tumor tissues35 treated with P1@ P2, P1, and free CPT could be observed. The necrotic rate in the P1@P2-treated tumor was explicitly the highest of all tested groups. As shown in Figure 6d, the large area of the necrotic region could be observed in the P1@P2-treated tumor. In contrast, the P1-, P2-, CPT-, or PBS-treated tumors displayed a lower necrotic level with a large amount of living cells. These results confirmed the powerful treatment efficiency of P1@P2 for in vivo control of tumors. Although cationic prodrug P1 had an excellent in vitro cell inhibitory effect (Figure 5a,c), its in vivo tumor control ability was not sufficient (Figure 6b). This is probably because of the intrinsic positive charge and fast clearance of P1 from blood.
ORCID
Xianzheng Zhang: 0000-0001-6242-6005 Meizhen Yin: 0000-0001-8519-8578 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (21574009, 51521062, and 21174012), the Beijing Natural Science Foundation (2142026), the Beijing collaborative innovative research center for cardiovascular diseases, and the Higher Education and High-quality and World-class Universities (PY201605).
■
REFERENCES
(1) Cai, K.; He, X.; Song, Z.; Yin, Q.; Zhang, Y.; Uckun, F. M.; Jiang, C.; Cheng, J. Dimeric Drug Polymeric Nanoparticles with Exceptionally High Drug Loading and Quantitative Loading Efficiency. J. Am. Chem. Soc. 2015, 137, 3458−3461. (2) Liu, Y. Q.; Li, W. Q.; Morris-Natschke, S. L.; Qian, K.; Yang, L.; Zhu, G. X.; Wu, X. B.; Chen, A. L.; Zhang, S. Y.; Nan, X.; Lee, K.-H. Perspectives on Biologically Active Camptothecin Derivatives. Med. Res. Rev. 2015, 35, 753−789.
4224
DOI: 10.1021/acs.chemmater.7b00047 Chem. Mater. 2017, 29, 4218−4226
Article
Chemistry of Materials (3) Tang, L.; Fan, T. M.; Borst, L. B.; Cheng, J. Synthesis and Biological Response of Size-Specific, Monodisperse Drug-Silica Nanoconjugates. ACS Nano 2012, 6, 3954−3966. (4) Palanikumar, L.; Kim, H. Y.; Oh, J. Y.; Thomas, A. P.; Choi, E. S.; Jeena, M.; Joo, S. H.; Ryu, J.-H. Noncovalent Surface Locking of Mesoporous Silica Nanoparticles for Exceptionally High Hydrophobic Drug Loading and Enhanced Colloidal Stability. Biomacromolecules 2015, 16, 2701−2714. (5) Choi, K. Y.; Yoon, H. Y.; Kim, J.-H.; Bae, S. M.; Park, R.-W.; Kang, Y. M.; Kim, I.-S.; Kwon, I. C.; Choi, K.; Jeong, S. Y.; Kim, K.; Park, J. H. Smart Nanocarrier Based on PEGylated Hyaluronic Acid for Cancer Therapy. ACS Nano 2011, 5, 8591−8599. (6) Wu, X.; Sun, X.; Guo, Z.; Tang, J.; Shen, Y.; James, T. D.; Tian, H.; Zhu, W. In Vivo and In Situ Tracking Cancer Chemotherapy by Highly Photostable NIR Fluorescent Theranostic Prodrug. J. Am. Chem. Soc. 2014, 136, 3579−3588. (7) Mura, A.; Nicolas, J.; Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 2013, 12, 991−1003. (8) Lu, Y.; Aimetti, A. A.; Langer, R.; Gu, Z. Bioresponsive materials. Nat. Rev. Mater. 2016, 2, 16075−16091. (9) Assali, M.; Cid, J.-J.; Pernía-Leal, M.; Muñoz-Bravo, M.; Fernández, I.; Wellinger, R. E.; Khiar, N. Glyconanosomes: DiskShaped Nanomaterials for the Water Solubilization and Delivery of Hydrophobic Molecules. ACS Nano 2013, 7, 2145−2153. (10) Guo, X.; Shi, C.; Yang, G.; Wang, J.; Cai, Z.; Zhou, S. DualResponsive Polymer Micelles for Target-Cell-Specific Anticancer Drug Delivery. Chem. Mater. 2014, 26, 4405−4418. (11) Lee, M. H.; Kim, J. Y.; Han, J. H.; Bhuniya, S.; Sessler, J. L.; Kang, C.; Kim, J. S. Direct Fluorescence Monitoring of the Delivery and Cellular Uptake of a Cancer-Targeted RGD Peptide-Appended Naphthalimide Theragnostic Prodrug. J. Am. Chem. Soc. 2012, 134, 12668−12674. (12) Tang, Q.; Cao, B.; Cheng, G. Co-delivery of Small Interfering RNA Using a Camptothecin Prodrug as the Carrier. Chem. Commun. 2014, 50, 1323−1325. (13) Wang, J.; Sun, X.; Mao, W.; Sun, W.; Tang, J.; Sui, M.; Shen, Y.; Gu, Z. Tumor Redox Heterogeneit-Responsive Prodrug Nanocapsules for Cancer Chemotherapy. Adv. Mater. 2013, 25, 3670−3676. (14) Bhuniya, S.; Maiti, S.; Kim, E. J.; Lee, H.; Sessler, J. L.; Hong, K. S.; Kim, J. S. An Activatable Theranostic for Targeted Cancer Therapy and Imaging. Angew. Chem., Int. Ed. 2014, 53, 4469−4474. (15) Liao, L.; Liu, J.; Dreaden, E. C.; Morton, S. W.; Shopsowitz, K. E.; Hammond, P. T.; Johnson, J. A. A Convergent Synthetic Platform for Single-Nanoparticle Combination Cancer Therapy: Ratiometric Loading and Controlled Release of Cisplatin, Doxorubicin, and Camptothecin. J. Am. Chem. Soc. 2014, 136, 5896−5899. (16) Soukasene, S.; Toft, D. J.; Moyer, T. J.; Lu, H.; Lee, H.-K.; Standley, S. M.; Cryns, V. L.; Stupp, S. I. Antitumor Activity of Peptide Amphiphile Nanofiber-Encapsulated Camptothecin. ACS Nano 2011, 5, 9113−9121. (17) Cheetham, A. G.; Zhang, P.; Lin, Y.-a.; Lock, L. L.; Cui, H. Supramolecular Nanostructures Formed by Anticancer Drug Assembly. J. Am. Chem. Soc. 2013, 135, 2907−2910. (18) Lock, L. L.; Reyes, C. D.; Zhang, P.; Cui, H. Tuning Cellular Uptake of Molecular Probes by Rational Design of Their Assembly into Supramolecular Nanoprobes. J. Am. Chem. Soc. 2016, 138, 3533− 3540. (19) Wexselblatt, E.; Esko, J. D.; Tor, Y. On Guanidinium and Cellular Uptake. J. Org. Chem. 2014, 79, 6766−6774. (20) Lu, J.; Liu, C.; Wang, P.; Ghazwani, M.; Xu, J.; Huang, Y.; Ma, X.; Zhang, P.; Li, S. The Self-Assembling Camptothecin-Tocopherol Prodrug: An Effective Approach for Formulating Camptothecin. Biomaterials 2015, 62, 176−187. (21) Martinez, J. O.; Brown, B. S.; Quattrocchi, N.; Evangelopoulos, M.; Ferrari, M.; Tasciotti, E. Multifunctional to multistage delivery systems: The evolution of nanoparticles for biomedical applications. Chin. Sci. Bull. 2012, 57, 3961−3971.
(22) Fu, J.; Schlenoff, J. B. Driving Forces for Oppositely Charged Polyion Association in Aqueous Solutions: Enthalpic, Entropic, but Not Electrostatic. J. Am. Chem. Soc. 2016, 138, 980−990. (23) Zhou, Z.; Shen, Y.; Tang, J.; Fan, M.; Van Kirk, E. A.; Murdoch, W. J.; Radosz, M. Charge-Reversal Drug Conjugate for Targeted Cancer Cell Nuclear Drug Delivery. Adv. Funct. Mater. 2009, 19, 3580−3589. (24) Feng, T.; Ai, X.; An, G.; Yang, P.; Zhao, Y. Charge-Convertible Carbon Dots for Imaging-Guided Drug Delivery with Enhanced In Vivo Cancer Therapeutic Efficiency. ACS Nano 2016, 10, 4410−4420. (25) Zhou, Z.; Ma, X.; Jin, E.; Tang, J.; Sui, M.; Shen, Y.; Van Kirk, E. A.; Murdoch, W. J.; Radosz, M. Linear-dendritic Drug Conjugates Forming Long-Circulating Nanorods for Cancer-Drug Delivery. Biomaterials 2013, 34, 5722−5735. (26) Zhou, T.; Zhou, X.; Xing, D. Controlled Release of Doxorubicin from Graphene Oxide Based Charge-Reversal Nanocarrier. Biomaterials 2014, 35, 4185−4194. (27) Du, J. Z.; Sun, T. M.; Song, W. J.; Wu, J.; Wang, J. A TumorAcidity-Activated Charge-Conversional Nanogel as an Intelligent Vehicle for Promoted Tumoral-Cell Uptake and Drug Delivery. Angew. Chem., Int. Ed. 2010, 49, 3621−3626. (28) Xu, P.; Van Kirk, E. A.; Zhan, Y.; Murdoch, W. J.; Radosz, M.; Shen, Y. Targeted Charge-Reversal Nanoparticles for Nuclear Drug Delivery. Angew. Chem., Int. Ed. 2007, 46, 4999−5002. (29) Yuan, Y. Y.; Mao, C. Q.; Du, X. J.; Du, J. Z.; Wang, F.; Wang, J. Surface Charge Switchable Nanoparticles Based on Zwitterionic Polymer for Enhanced Drug Delivery to Tumor. Adv. Mater. 2012, 24, 5476−5480. (30) Sun, M.; Müllen, K.; Yin, M. Water-Soluble Perylenediimides: Design Concepts and Biological Applications. Chem. Soc. Rev. 2016, 45, 1513−1528. (31) Yin, M.; Shen, J.; Pflugfelder, G. O.; Müllen, K. A Fluorescent Core-Shell Dendritic Macromolecule Specifically Stains The Extracellular Matrix. J. Am. Chem. Soc. 2008, 130, 7806−7807. (32) Xu, Z.; He, B.; Shen, J.; Yang, W.; Yin, M. Fluorescent WaterSoluble Perylenediimide-Cored Cationic Dendrimers: Synthesis, Optical Properties, and Cell Uptake. Chem. Commun. 2013, 49, 3646−3648. (33) He, B.; Chu, Y.; Yin, M.; Müllen, K.; An, C.; Shen, J. Fluorescent Nanoparticle Delivered dsRNA Toward Genetic Control of Insect Pests. Adv. Mater. 2013, 25, 4580−4584. (34) Zheng, Y.; You, S.; Ji, C.; Yin, M.; Yang, W.; Shen, J. Development of an Amino Acid-Functionalized Fluorescent Nanocarrier to Deliver a Toxin to Kill Insect Pests. Adv. Mater. 2016, 28, 1375−1380. (35) Sun, M.; Yin, W.; Dong, X.; Yang, W.; Zhao, Y.; Yin, M. Fluorescent Supramolecular Micelles for Imaging-Guided Cancer Therapy. Nanoscale 2016, 8, 5302−5312. (36) Xu, W.; Ledin, P. A.; Shevchenko, V. V.; Tsukruk, V. V. Architecture, Assembly, and Emerging Applications of Branched Functional Polyelectrolytes and Poly (ionic liquid)s. ACS Appl. Mater. Interfaces 2015, 7, 12570−12596. (37) Lee, H.; Larson, R. G. Multiscale Modeling of Dendrimers and Their Interactions with Bilayers and Polyelectrolytes. Molecules 2009, 14, 423−438. (38) Chiang, Y.; Cheng, Y.; Lu, C.; Yen, Y.-W.; Yu, Lu-Yi.; Yu, K.; Lyu, S.; Yang, C.; Lo, C. Polymer−Liposome Complexes with a Functional Hydrogen-Bond Cross-Linker for Preventing Protein Adsorption and Improving Tumor Accumulation. Chem. Mater. 2013, 25, 4364−4372. (39) Han, L.; Zhao, J.; Zhang, X.; Cao, W.; Hu, X.; Zou, G.; Duan, X.; Liang, X.-J. Enhanced siRNA Delivery and Silencing Gold-Chitosan Nanosystem with Surface Charge-Reversal Polymer Assembly and Good Biocompatibility. ACS Nano 2012, 6, 7340−7351. (40) Yang, X. Z.; Du, X. J.; Liu, Y.; Zhu, Y. H.; Liu, Y. Z.; Li, Y. P.; Wang, J. Rational Design of Polyion Complex Nanoparticles to Overcome Cisplatin Resistance in Cancer Therapy. Adv. Mater. 2014, 26, 931−936. 4225
DOI: 10.1021/acs.chemmater.7b00047 Chem. Mater. 2017, 29, 4218−4226
Article
Chemistry of Materials (41) Zhang, W.; Lin, W.; Pei, Q.; Hu, X.; Xie, Z.; Jing, X. RedoxHypersensitive Organic Nanoparticles for Selective Treatment of Cancer Cells. Chem. Mater. 2016, 28, 4440−4446. (42) Lee, Y.; Miyata, K.; Oba, M.; Ishii, T.; Fukushima, S.; Han, M.; Koyama, H.; Nishiyama, N.; Kataoka, K. Charge-Conversion Ternary Polyplex with Endosome Disruption Moiety: A Technique for Efficient and Safe Gene Delivery. Angew. Chem. 2008, 120, 5241− 5244. (43) Huang, Y.; Tang, Z.; Zhang, X.; Yu, H.; Sun, H.; Pang, X.; Chen, X. pH-Triggered Charge-Reversal Polypeptide Nanoparticles for Cisplatin Delivery: Preparation and In Vitro Evaluation. Biomacromolecules 2013, 14, 2023−2032. (44) Li, Q.; Sun, Y.; Sun, Y.; Wen, J.; Zhou, Y.; Bing, Q.; Isaacs, L.; Jin, Y.; Gao, H.; Yang, Y. Mesoporous Silica Nanoparticles Coated by Layer-by-Layer Selfassembly Using Cucurbit[7]uril for in Vitro and in Vivo Anticancer Drug Release. Chem. Mater. 2014, 26, 6418−6431. (45) Lee, Y.; Fukushima, S.; Bae, Y.; Hiki, S.; Ishii, T.; Kataoka, K. A Protein Nanocarrier from Charge-Conversion Polymer in Response to Endosomal pH. J. Am. Chem. Soc. 2007, 129, 5362−5363. (46) Li, L.; Yang, Q.; Zhou, Z.; Zhong, J.; Huang, Y. DoxorubicinLoaded, Charge Reversible, Folate Modified HPMA Copolymer Conjugates for Active Cancer Cell Targeting. Biomaterials 2014, 35, 5171−5187. (47) Peppicelli, S.; Bianchini, F.; Calorini, L. Extracellular acidity, a “reappreciated” trait of tumor environment driving malignancy: perspectives in diagnosis and therapy. Cancer Metastasis Rev. 2014, 33, 823−832. (48) Storrie, H.; Mooney, D. Sustained delivery of plasmid DNA from polymeric scaffolds for tissue engineering. Adv. Drug Delivery Rev. 2006, 58, 500−514. (49) Ji, C.; Zheng, Y.; Li, J.; Shen, J.; Yang, W.; Yin, M. Amphiphilic Squarylium Indocyanine Dye for Long-Term Tracking of Lysosomes. J. Mater. Chem. B 2015, 3, 7494−7498. (50) Klok, H. A.; Hernández, J. R.; Becker, S.; Müllen, K. Star-Shaped Fluorescent Polypeptides. J. Polym. Sci., Part A: Polym. Chem. 2001, 39, 1572−1583. (51) Navath, R. S.; Kurtoglu, Y. E.; Wang, B.; Kannan, S.; Romero, R.; Kannan, R. M. Dendrimer-Drug Conjugates for Tailored Intracellular Drug Release Based on Glutathione Levels. Bioconjugate Chem. 2008, 19, 2446−2455. (52) Boyer, C.; Whittaker, M. R.; Bulmus, V.; Liu, J.; Davis, T. P. The Design and Utility of Polymer-Stabilized Iron-Oxide Nanoparticles for Nanomedicine Applications. NPG Asia Mater. 2010, 2, 23−30. (53) Kolhar, P.; Anselmo, A. C.; Gupta, V.; Pant, K.; Prabhakarpandian, B.; Ruoslahti, E.; Mitragotri, S. Using Shape Effects to Target Antibody-Coated Nanoparticles to Lung and Brain Endothelium. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 10753−10758. (54) Liang, R.; You, S.; Ma, L.; Li, C.; Tian, R.; Wei, M.; Yan, D.; Yin, M.; Yang, W.; Evans, D. G.; Duan, X. A Supramolecular Nanovehicle Toward Systematic, Targeted Cancer and Tumor Therapy. Chem. Sci. 2015, 6, 5511−5518. (55) Yin, M.; Shen, J.; Gropeanu, R.; Pflugfelder, G. O.; Weil, T.; Müllen, K. Fluorescent Core/Shell Nanoparticles for Specific CellNucleus Staining. Small 2008, 4, 894−898.
4226
DOI: 10.1021/acs.chemmater.7b00047 Chem. Mater. 2017, 29, 4218−4226
