Subscriber access provided by UNIV OF TEXAS DALLAS
Letter
Switchable Liposomes: Targeting Peptides Functionalized and pH-Triggered Cytoplasmic Delivery Qiuju Han, Weizhi Wang, Xiangqian Jia, Yixia Qian, Qian Li, Zihua Wang, Weikai Zhang, Shu Yang, Yunhong Jia, and Zhiyuan Hu ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b05678 • Publication Date (Web): 08 Jul 2016 Downloaded from http://pubs.acs.org on July 9, 2016
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Applied Materials & Interfaces is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 7
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Applied Materials & Interfaces
Switchable Liposomes: Targeting Peptides Functionalized and pHTriggered Cytoplasmic Delivery Qiuju Han† a, b, Weizhi Wang† a*, Xiangqian Jia† a, b, Yixia Qiana, Qian Lid, Zihua Wanga, Weikai Zhanga,e, Shu Yanga, Yunhong Jiac*, Zhiyuan Hua* a. CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China b. Pharmacy College, Jinzhou Medical University, Jinzhou, Liaoning 121001, China c. College of Basic Science, Jinzhou Medical University, Jinzhou, Liaoning 121001, China d. Institute of Chemistry, Chinese Academy of Science, Beijing 100190, China e. Medical College, Henan University of Science and Technology, Luoyang, Henan 471003, China
.
† These authors contributed equally to this work
ABSTRACT: One switchable nano delivery system was constructed. Liposomes were functionalized by novel dual-recognition peptide STP which is pH-responsive as well as the affinity ligand of tumor marker VEGFR2 (angiogenesis marker vascular endothelial growth factor receptor 2). Efficient drug delivery and in vivo therapy could be “turned on” and accelerate only in the condition of VEGFR2 overexpression and mild acidic environment. We envisioned that the successful demonstration of this switchable nanocarrier system would open a new avenue on rapid cytoplasmic delivery for specific cancer diagnostics and therapeutics.
KEYWORDS: Switchable liposomes, pH-responsive peptide, VEGFR2, drug delivery, cancer therapy One of the challenges for cancer chemotherapy is to deliver drugs into tumor sites in a specific way.1-2 Recently, nanoparticle-based targeting drug delivery strategies have been applied in tumor therapy, such as functionalized liposomes,3-4 micelles5 and dendrimers.6 Among them, liposomes mainly consist of phospholipids, which show good biocompatibility and have great potential application in drug delivery.7-8 Generally, nanoparticles accumulate in tumor sites through a passive targeting way by the enhanced permeability and retention (EPR) effect, which is resulted from leaky vasculature and impaired lymphatics.9-10 However, EPR effect is nonspecific. In order to realize high efficient drug delivery, nanoparticles could be functionalized by affinity ligands, for instance, antibodies, peptides and other small molecules, which exhibit good recognition behavior towards special receptors on cellular membrane.11-12 Moreover, recent advances have paid close attention to stimuli-responsive nanoparticles to reach tumor microenvironments.13 The recurrence and metastasis of cancers are related to tumor microenvironment (TME).14-15 Microenvironment of tumors are formed as the occurrence of tumor cells and new tumor vascularity along with acidosis (pH 5.5-6.9).16-17 Therefore, vascular-sensitive or pH-sensitive nanoparticles could deliver the drugs towards tumor sites at TME.18-19 There are different angiogenesis related growth factors secreted as the new formed tumor vessels. Among them, angiogenesis marker vascular endothelial growth factor receptor (VEGFR) is a typical one.20-21 VEGFR on the vascular endothelial cells is mainly regulated by tyrosine kinases receptors. And among their family, VEGFR2 plays a crucial role in mediating the division of endothelial cells.22 Reports from recent years showed that most malignant tumors presented high expression of VEGFR2.23-24 Therefore, the anti-angiogenic therapy has used in the cancer treatments through the target VEGFR2. Above all, a specific drug delivery system owns both VEGFR2-targeting ability and pH-triggered performance is urgently needed while rarely been reported.
In this work, a switchable and dual-functional nanocarrier system was constructed based on liposomes encapsulating doxorubicin (DOX). The liposomes were functionalized by one type of peptide STP (SKDEEWHKNNFPLSP) (Scheme 1a) with both pH-responsive and VEGFR2-targeting ability. STP was ever reported in our previous work. This novel pentadecapeptide shows high specificity towards VEGFR2 only at mild acidic microenvironment.25 The main mechanism is the formation of α-helix at -Lys-Asp-Glu-Glu- segment in the N-terminal in the presence of protons. The sequence could enhance recognition ability and the α-helix could improve the penetrability. Thus, the liposomes functionalized by the dualrecognition peptide (called STP-LS) would be a promising drug carrier. The nanocarrier was prepared and its efficiency was comprehensively evaluated both in vitro and in vivo. As we envisioned, STP-LS with DOX encapsulated in it (STPLS-DOX) exhibits high efficiency of targeting, release and penetration in TME towards VEGFR2 not only in vitro but also in vivo (Scheme 1b). STP was prepared by solid phase peptide synthesis (SPPS) and during the prolongation, a cysteine was added at Cterminal.26 1, 2-distearoyl-sn-glycero-3-phosphoethanolamineN-[poly(ethylene glycol)2000]-maleimide (DSPE-PEG2000MAL) was used to conjugate STP-Cys (STP-C) through the coupling of the thiol group (-SH) and the maleimide group (Scheme 1a). STP-C and DSPE-PEG2000-MAL (1:1, w/w) dissolved in deionized water at the concentration of 12 mg/mL, stirring continuously at room temperature for 48 h. We used high-performance liquid chromatography (HPLC) to monitor the addition reaction (Figure S2). The peak intensity of STP-C decreased along with the time, indicating the reaction achieved. Then, reaction solution was put into dialysis bag (cut-off M.W. 3,500) to purify the product STP-PEG2000DSPE. After that, matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) analysis showed that the peak was right-shifted (from m/z 3109 to m/z 5040) after conjugation, which indicated that STP-C
ACS Paragon Plus Environment
ACS Applied Materials & Interfaces
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
conjugated to DSPE-PEG2000-MAL successfully (Figure 1a
Page 2 of 7
and b).
Scheme 1. Schematic illustration of the preparation and application of STP-LS-DOX. (a) STP-PEG2000-DSPE was synthesized by coupling of STP-C with the maleimide group of DSPE-PEG2000-MAL. (b) Schematic representation and the application in vivo of STP-LS-DOX. DOX is well-known and widely used as a chemotherapy drug that shows anti-cancer effect by damaging the DNA structure in nucleus.27-28 Meanwhile, DOX could be used for indicator of autofluorescence (ex: 488 nm, em: 560-590 nm). So, DOX was chosen as the drug model which is encapsulated in the cavity of liposomes. VEGFR2-targeting and pHresponsive liposomes with DOX loaded (STP-LS-DOX) and non-targeting liposomes with DOX encapsulated (LS-DOX) were prepared by thin film dispersion method. STP-LS-DOX was prepared by mixing of soy phospholipids (SPC), cholesterol (CHO), STP-PEG2000-DSPE and DOX (SPC: CHO: STP-PEG2000-DSPE: DOX, 8: 2: 2: 1, w/w/w/w). LSDOX was also prepared as control. The average hydrodynamic diameter and surface charge of LS-DOX and STP-LS-DOX were characterized by dynamic light scattering (DLS). The diameter of STP-LS-DOX was 160 nm and the zeta potential was around -19.5 mV (Figure 1c) while the diameter of LSDOX was 151 nm and the zeta potential was around -14.0 mV (Figure 1c). The change in size indicated that the modification might be achieved. Moreover, the absolute values of the zeta potential revealed that both STP-LS-DOX and LS-DOX exhibited good dispersion stability, which was suitable for the subsequent bio-experiment. The morphologies of STP-LSDOX and LS-DOX were observed by transmission electron microscope (TEM) (Figure 1e and f). These results suggested that both STP-LS-DOX and LS-DOX were nanospherical in shape with stable dispersion. The encapsulation efficiency of STP-LS-DOX was calculated as 82.36%. The encapsulation efficiency of LS-DOX was 80.25%. Additionally, the drug release test in vitro was carried out at 37 °C. As shown in Figure S4, for the same formulation liposome, the release rate at pH 5.8 was higher than pH 7.4. It indicated that STP-LS and LS showed pH-dependent release. The release of DOX-sol (free DOX dissolved in phosphate buffer saline) at two pHs
were similar with high rates. Moreover, no matter at pH 5.8 or pH 7.4, the release rate of STP-LS-DOX was lower than LSDOX. Therefore, the residence time of STP-LS-DOX in the tumor site might be extended and the therapeutic effect could be enhanced.
2
ACS Paragon Plus Environment
Page 3 of 7
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Applied Materials & Interfaces
Figure 1. (a) MALDI-TOF-MS spectra of DSPE-PEG2000-MAL. (b) MALDI-TOF-MS spectra of STP-PEG2000-DSPE. (c) Size distribution of STP-LS-DOX. (d) Size distribution of LS-DOX. (e) TEM graph of STP-LS-DOX (f) TEM graph of LS-DOX.
To evaluate the targeting delivery efficiency of STP-LSDOX towards VEGFR2 positive cells at different pH environment, human umbilical vein endothelia cell line HUVEC was employed. It was reported that HUVEC have specific binding sites (VEGFR2, with 500 sites/cell) of VEGF and the dissociation constant was reported as low as 9 pM.29 Human embryonic kidney cell line 293T (VEGFR2 nonexpression) was chosen as negative control cell. The above cells were incubated with the nano capsules (STP-LS-DOX or LS-DOX, 30 µg/mL, 200 µL) as well as Hoechst 33342 (nucleus indicator, 10 µg/mL, 200 µL) for 15 min at 37 °C. The DOX autofluorescence was measured by confocal laser scanning microscope (CLSM, 63×, oil-immersion objective) imaging to investigate the delivery behavior of STP-LS-DOX towards the cells at different condition (pH 5.8 or pH 7.4). As shown in Figure 2, bi-channel fluorescence signals were observed at blue channel (Hoechst 33342, ex: 405 nm, em: 488 nm) and red channel (DOX, ex: 488 nm, em: 560-590 nm) in order to trace the interaction between liposomes and cells. In Figure 2a and b, HUVEC cells treated with STP-LS-DOX demonstrated much stronger fluorescent intensity than LSDOX at pH 5.8. DOX was successfully delivered into the cytoplasm. Additionally, at the same condition, very low fluorescence was observed in 293T cells (Figure 2c). On the contrary, at pH 7.4, lower fluorescence signals were observed in both HUVEC cells and 293T cells incubated with STP-LSDOX (Figure 2d and e). This revealed that STP-LS-DOX is inactive at neutral condition. It showed higher uptake efficiency of STP-LS-DOX in HUVEC cell line at pH 5.8 since the overexpression of VEGFR2, which indicated that targeting binding achieved. The nano delivery system could be “switched on” only in the existence of VEGFR2 overexpression in the mild acidic condition, which showed a dual-functionalized behavior.
Figure 2. Confocal microscope images of liposomes towards cells. Blue fluorescence is Hoechst 33342, and red fluorescence represents DOX. (a) HUVEC cells were incubated with STP-LSDOX at pH 5.8. (b) HUVEC cells were incubated with LS-DOX at pH 5.8. (c) 293T cells were incubated with STP-LS-DOX at pH 5.8. (d) HUVEC cells were incubated with STP-LS-DOX at pH 7.4. (e) 293T cells were incubated with STP-LS-DOX at pH 7.4.
The above experiments had proven that the STP-LS-DOX could improve the uptake of VEGFR2-overexpressing cells at mild acidic condition. We continued to evaluate the cellular permeability of the nano capsules. Dynamic observation was demonstrated by CLSM at pH 5.8 (acidic condition), pH 6.5 (tumor microenvironment) or pH 7.4 (neutral condition) at 37 °C for 10, 15, 30, 60 or 120 min with the liposomes concentration of 30 µg/mL (200 µL). As shown in Figure 3a, STP-LS-DOX could obviously bind on cell membrane after 10 min incubation at pH 5.8. After 15 min incubation, STP-LSDOX started the cellular entry process (Figure 3b). Along with the time, DOX could been delivered into the cells gradually (Figure 3c and d). After 2 h, DOX distributed all over the cytoplasm and some of them reached nuclear membrane (Figure 3e). At pH 6.5, along with the time, DOX could delivered into the cells gradually (Figure 3f-i). After 2 h, DOX had been into cytoplasm and some of them reached nuclei (Figure 3j). DOX also entered into HUVEC cells at pH 7.4, however, the fluorescence signal was much weaker, which indicated that the binding and delivery efficiency was lower. (Figure 3k-o). As a control, after incubation with LS-DOX for
3
ACS Paragon Plus Environment
ACS Applied Materials & Interfaces
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
30 min, low fluorescence appear on the cell membrane. With a longer time, LS-DOX still showed low fluorescence signal (Figure S5). For LS-DOX, endocytosis is the dominant way for cellular entry. However, for STP-LS-DOX, we estimated that the rapid binding speed is result from the synergy of peptide recognition and pH-triggered penetration. It suggested that once all the conditions have been met, switchable drug delivery could be realized at a satisfactory efficiency. Furthermore, to assess the cellular uptake of the STP-LSDOX, we used the flow cytometry to measure the fluorescence intensity of different nano capsules (Figure S6). HUVEC cells were treated with STP-LS-DOX, LS-DOX or free DOX for 30 min at room temperature at pH 5.8. STP-LS-DOX showed the significant fluorescence signal. However, both LS-DOX and free DOX exhibited lower efficiency. The results brought into correspondence with the image results, which further suggested that STP-LS-DOX was an efficient strategy for drug delivery towards VEGFR2 at mild acidic environment.
Figure 3. Dynamic monitoring cellular uptake of STP-LS-DOX at different conditions. (a-e) Fluorescence confocal images of HUVEC incubated with STP-LS-DOX at pH 5.8. (f-j) Fluorescence confocal images of HUVEC incubated with STPLS-DOX at pH 6.5. (k-o) Fluorescence confocal images of HUVEC incubated with STP-LS-DOX at pH 7.4.
Page 4 of 7
were detected by Infinite M200 microplate reader. Under pH 5.8 (Figure S7a), at lower concentration of DOX (0.001 mg/mL), the difference of cell inhibition was significant among the three groups. With the concentration of DOX increasing, enhanced inhibition effects were performed for all the nano capsules. However, compared with the others, cells incubated with STP-LS-DOX showed higher inhibition effects. At pH 6.5 (Figure S7b), STP-LS-DOX showed higher inhibition effects than the other groups with corresponding to pH 5.8. These results suggested the potential of efficient in vivo therapy. In order to test the delivery efficiency in real tumor system, in vivo imaging assays were carried out. Near-infrared fluorescent dye 1,1-dioctadecyl-3,3,3,3tetramethylindotricarbonyaineiodide (DiR, ex: 748 nm, em: 780 nm) took the place of DOX and was encapsulated in the liposomes. STP-LS-DiR and LS-DiR were prepared for the trace of nanocapsules in vivo. Delivery efficiencies were evaluated by mice bearing xenograft tumors derived from human colonic adenocarcinoma cells (HT-29). It is reported that more than 90% of the VEGFR2 is retained on the blood vessels of the HT-29 tumor xenografts model.30 STP-LS-DiR and LS-DiR were intravenously injected into the mice at concentration of 1 µg/mL DiR (200 µL) while phosphate buffered saline (PBS) was injected as control. Fluorescence intensity and distribution were measured at different times by Maestro in vivo spectrum imaging system. As shown in Figure 4a-d, after 4 h, STP-LS-DiR began to accumulate at tumor site while LS-DiR had not been achieved. Along with the time, the tumor accumulation of STP-LS-DiR increased obviously while the LS-DiR still showed relative lower signal. Almost none fluorescence could be observed in PBS injection group. Therefore, the accumulative efficacy is much higher of STP-LS-DiR than LS-DiR at tumor site because the dualfunctional acceleration. At last, the mice were sacrificed and tumors as well as major organs were isolated. Their fluorescence images were also recorded. The ex vivo fluorescent detection (Figure 4e-f) showed that the tumor treated with STP-LS-DiR exhibited high fluorescence signal. These results illustrated that STP-LS nanocarrier system could achieve high drug delivery efficiency towards VEGFR2 overexpression tumors. To further evaluate the vasculaturetargeting efficacy of STP-LS at mild acidic condition, the histological examinations about paraffin section of HT-29 tumor tissues were carried out. We labeled the tumor vessels with fluorescein isothiocyanate (FITC) tagged anti-CD31 (a vessel indicator). Nucleus were counterstained with 4’, 6-diamidino-2-phenylindole (DAPI). The results were obtained by CLSM. As illustrated in Figure 4g-i, tumors with STP-LSDOX treatment had much higher fluorescence signal intensity than that LS-DOX and PBS treated ones, which provided direct evidence for high vasculature-targeting efficacy at tumor acidic microenvironment of our switchable liposomes.
The inhibitory activity of nano capsules were assessed in vitro. HUVEC was still chosen as model. The cell viabilities were assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. After 48 h treatment with various formulations of DOX (STP-LS-DOX, LS-DOX or DOX) at different pHs (pH 5.8 or pH 6.5) with DOX concentration 0.001, 0.01, 0.1, 0.4, 0.8 mg/mL (100 µL), cells
4
ACS Paragon Plus Environment
Page 5 of 7
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Applied Materials & Interfaces DOX group exhibited a serious damage of the tumor issues. Additionally, the apoptosis of tumor cells was detected by terminal deoxynucleotidyl transferased dUTP Nick-End labeling (TUNEL) assay (Figure 5d). The assay illustrated that cell apoptosis of STP-LS-DOX group was obvious while other groups remained unchanged. Additionally, organs were also analyzed by H&E staining from the three groups. There is no apparent morphological difference among the therapeutic groups in heart, liver, spleen, lung or kidney (Figure S8). It implied that STP-LS-DOX could achieve at the targeted sites with high efficiency and would not cause serious hurt to other non-targeted sites, which expressed satisfactory therapeutic effect.
Figure 4. In vivo and ex vivo imaging of tumor targeting delivery by STP-LS and LS. (a-d) Real-time biodistribution and tumor accumulation of STP-LS-DiR, LS-DiR and PBS treatment after 4 h, 8h, 12h and 24h. (e) Ex vivo fluorescence imaging of tumor and organ accumulation. (f) Quantitative fluorescence intensity ex vivo. Fluorescence intensity was measured in counts/energy/area and presented as average (n=3). (g-i) Paraffin sections of tumors treated in different conditions.
The ultimate purpose of developing the switchable liposome delivery system is to realize efficient diagnosis and therapy. Tumor inhibition study in vivo was performed to investigate the chemotherapy efficacy. The HT-29 tumor-bearing mice (tumor size: 60-80 mm3) were randomly divided into three groups (n=5). One group was treated intravenously with STPLS-DOX and the other two groups were treated with LS-DOX and PBS, respectively. Both of the nanocarriers were injected at a DOX dosage of 5 mg/kg. The cure progress was terminated after 14 days. Administration was carried out on the 1st, 2nd, 4th, 5th, 7th and 8th day. Successive observation was performed in the next 6 days. After the whole assay, tumors were excised (Figure 5a). We observed that tumor growths of STP-LS-DOX treating group were inhibited obviously while LS-DOX group tumors growth were inhibited only little. As a control, tumors of mice treated with PBS grew rapidly. It means that the both acidic tumor environment and the tumor vessel marker VEGFR2 have “switched on” the liposome delivery system. The weights and tumor sizes were recorded daily during the therapeutic process (Figure 5b and c). Tumors and main organs were exteriorized from mice. As shown in Figure 5d, the histological examination of tumors were evaluated by hematoxylin-eosin (H&E) staining with optical microscopy. The results demonstrated that STP-LS-
Figure 5. (a) Excised tumor photograph after cure process. (b) The tumor size changing curves during the cure process. (c) The mice weight changing curves during the cure process. (d) Analysis of tumor slices with different treatments with H&E staining and TUNEL immunofluorescence staining, respectively.
This study systematically demonstrated a switchable liposomes drug delivery system which functionalized by pHtriggered and VEGFR2-targeting peptides STP. The nano capsules could enhance the anti-tumor effect at acidic tumor microenvironment and are expected to be potential candidates for cancer therapy. Our further work may pay more attention to the stability, specificity and targeting affinity of the peptides in order to develop the enhanced synergy functional nano carrier system which could be prospectively applied in cancer therapy.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Additional figures and some experimental details were included in the Supporting Information, including monitoring of STP-PEG2000-DSPE synthesis; preparation and characterization of liposomes; cellular uptake and
5
ACS Paragon Plus Environment
ACS Applied Materials & Interfaces
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
inhibition tests of liposomes; the evaluation of organic necrosis levels after treatment.
AUTHOR INFORMATION Corresponding Author * E-mail:
[email protected]. * E-mail:
[email protected]. * E-mail:
[email protected].
Author Contributions †Q.H., W.W. and X. J. contributed equally to this work.
Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT We acknowledge funding from the National Natural Science Foundation of China (21305023, 31270875, 31400702), Program for the Top Young Talents of Beijing (2015000021223ZK36), Beijing Municipal Natural Science Foundation (2144058).
REFERENCES (1) Luk, B. T.; Zhang, L. Cell Membrane-Camouflaged Nanoparticles for Drug Delivery. J. Controlled Release 2015, 220, Part B, 600-607. (2) Li, J.; Wang, Y.; Zhu, Y.; Oupický, D. Recent Advances in Delivery of Drug-Nucleic Acid Combinations for Cancer Treatment. J. Controlled Release 2013, 172, 2, 589-600. (3) Alomrani, A. H.; Shazly, G. A.; Amara, A. A.; Badran, M. M. Itraconazole-Hydroxypropyl-Β-Cyclodextrin Loaded Deformable Liposomes: In Vitro Skin Penetration Studies and Antifungal Efficacy Using Candida Albicans as Model. Colloids Surf., B 2014, 121, 74-81. (4) Wibroe, P. P.; Ahmadvand, D.; Oghabian, M. A.; Yaghmur, A.; Moghimi, S. M. An Integrated Assessment of Morphology, Size, and Complement Activation of the PEGylated Liposomal Doxorubicin Products Doxil®, Caelyx®, Doxorubicin, and SinaDoxosome. J. Controlled Release 2016, 221, 1-8. (5) Nasongkla, N.; Shuai, X.; Ai, H.; Weinberg, B. D.; Pink, J.; Boothman, D. A.; Gao, J. cRGD-Functionalized Polymer Micelles for Targeted Doxorubicin Delivery. Angew. Chem., Int. Ed. 2004, 116, 46, 6483-6487. (6) Dobrovolskaia, M. A.; Patri, A. K.; Simak, J.; Hall, J. B.; Semberova, J.; De Paoli Lacerda, S. H.; McNeil, S. E. Nanoparticle Size and Surface Charge Determine Effects of PAMAM Dendrimers on Human Platelets in Vitro. Mol. Pharmaceutics 2012, 9, 3, 382-393. (7) Wang, Z.; Yu, Y.; Dai, W.; Lu, J.; Cui, J.; Wu, H.; Yuan, L.; Zhang, H.; Wang, X.; Wang, J.; Zhang, X.; Zhang, Q. The Use of a Tumor Metastasis Targeting Peptide to Deliver Doxorubicin-Containing Liposomes to Highly Metastatic Cancer. Biomaterials 2012, 33, 33, 84518460. (8) Allen, T. M.; Cullis, P. R. Liposomal Drug Delivery Systems: From Concept to Clinical Applications. Adv. Drug Delivery Rev. 2013, 65, 1, 36-48. (9) Chauhan, V. P.; Jain, R. K. Strategies for Advancing Cancer Nanomedicine. Nat. Mater. 2013, 12, 11, 958-962. (10) Bertholon, I.; Hommel, H.; Labarre, D.; Vauthier, C. Properties of Polysaccharides Grafted on Nanoparticles Investigated by EPR. Langmuir 2006, 22, 12, 5485-5490. (11) Zheng, J.; Kontoveros, D.; Lin, F.; Hua, G.; Reneker, D. H.; Becker, M. L.; Willits, R. K. Enhanced Schwann Cell Attachment and Alignment Using One-Pot "Dual Click" GRGDS and YIGSR Derivatized Nanofibers. Biomacromolecules 2015, 16, 1, 357-363. (12) Pastorino, F.; Brignole, C.; Di Paolo, D.; Nico, B.; Pezzolo, A.; Marimpietri, D.; Pagnan, G.; Piccardi, F.; Cilli, M.; Longhi, R.; Ribatti, D.; Corti, A.; Allen, T. M.; Ponzoni, M. Targeting Liposomal
Page 6 of 7
Chemotherapy Via Both Tumor Cell-Specific and Tumor VasculatureSpecific Ligands Potentiates Therapeutic Efficacy. Cancer Res. 2006, 66, 20, 10073-10082. (13) Chandrasekaran, S.; King, M. R. Microenvironment of TumorDraining Lymph Nodes: Opportunities for Liposome-Based Targeted Therapy. Int. J. Mol. Sci. 2014, 15, 11, 20209-20239. (14) Wood, S. L.; Pernemalm, M.; Crosbie, P. A.; Whetton, A. D. The Role of the Tumor-Microenvironment in Lung Cancer-Metastasis and Its Relationship to Potential Therapeutic Targets. Cancer Treat. Rev. 2014, 40, 4, 558-566. (15) Ji, R.-C. Hypoxia and Lymphangiogenesis in Tumor Microenvironment and Metastasis. Cancer Lett. 2014, 346, 1, 6-16. (16) Du, J.; Lane, L. A.; Nie, S. Stimuli-Responsive Nanoparticles for Targeting the Tumor Microenvironment. J. Controlled Release 2015, 219, 205-214. (17) Tavakol, S. Acidic pH Derived from Cancer Cells May Induce Failed Reprogramming of Normal Differentiated Cells Adjacent Tumor Cells and Turn Them into Cancer Cells. Med. Hypotheses 2014, 83, 6, 668-672. (18) Zhao, Y.; Ji, T.; Wang, H.; Li, S.; Zhao, Y.; Nie, G. Self-Assembled Peptide Nanoparticles as Tumor Microenvironment Activatable Probes for Tumor Targeting and Imaging. J. Controlled Release 2014, 177, 11-19. (19) Ku, S. H.; Kim, K.; Choi, K.; Kim, S. H.; Kwon, I. C. TumorTargeting Multifunctional Nanoparticles for siRNA Delivery: Recent Advances in Cancer Therapy. Adv. Healthc. Mater. 2014, 3, 8, 1182-1193. (20) Finley, S. D.; Popel, A. S. Effect of Tumor Microenvironment on Tumor VEGF During Anti-VEGF Treatment: Systems Biology Predictions. J. Natl. Cancer Inst. 2013, 105, 11, 802-811. (21) Eng, L.; Azad, A. K.; Habbous, S.; Pang, V.; Xu, W.; Maitland-van der Zee, A. H.; Savas, S.; Mackay, H. J.; Amir, E.; Liu, G. Vascular Endothelial Growth Factor Pathway Polymorphisms as Prognostic and Pharmacogenetic Factors in Cancer: A Systematic Review and MetaAnalysis. Clin. Cancer Res. 2012, 18, 17, 4526-4537. (22) Bruns, A. F.; Herbert, S. P.; Odell, A. F.; Jopling, H. M.; Hooper, N. M.; Zachary, I. C.; Walker, J. H.; Ponnambalam, S. Ligand-Stimulated VEGFR2 Signaling Is Regulated by Co-Ordinated Trafficking and Proteolysis. Traffic 2010, 11, 1, 161-174. (23) Tong, Q.; Qing, Y.; Wu, Y.; Hu, X.; Jiang, L.; Wu, X. Dioscin Inhibits Colon Tumor Growth and Tumor Angiogenesis through Regulating VEGFR2 and AKT/MAPK Signaling Pathways. Toxicol. Appl. Pharmacol. 2014, 281, 2, 166-173. (24) Song, H.; Wang, W.; Zhao, P.; Qi, Z.; Zhao, S. Cuprous Oxide Nanoparticles Inhibit Angiogenesis Via Down Regulation of VEGFR2 Expression. Nanoscale 2014, 6, 6, 3206-3216. (25) Qian, Y.; Wang, W.; Wang, Z.; Han, Q.; Jia, X.; Yang, S.; Hu, Z. Switchable Probes: pH-Triggered and VEGFR2 Targeted Peptides Screening through Imprinting Microarray. Chem. Commun. 2016, 52, 33, 5690-5693. (26) Coin, I.; Beyermann, M.; Bienert, M. Solid-Phase Peptide Synthesis: From Standard Procedures to the Synthesis of Difficult Sequences. Nat. Protoc. 2007, 2, 12, 3247-3256. (27) Wang, Y.; Bansal, V.; Zelikin, A. N.; Caruso, F. Templated Synthesis of Single-Component Polymer Capsules and Their Application in Drug Delivery. Nano Lett. 2008, 8, 6, 1741-1745. (28) Zhang, F.; Braun, G. B.; Pallaoro, A.; Zhang, Y.; Shi, Y.; Cui, D.; Moskovits, M.; Zhao, D.; Stucky, G. D. Mesoporous Multifunctional Upconversion Luminescent and Magnetic "Nanorattle" Materials for Targeted Chemotherapy. Nano Lett. 2012, 12, 1, 61-67. (29) Hagigit, T.; Abdulrazik, M.; Orucov, F.; Valamanesh, F.; Hagedorn, M.; Lambert, G.; Behar-Cohen, F.; Benita, S. Topical and Intravitreous Administration of Cationic Nanoemulsions to Deliver Antisense Oligonucleotides Directed Towards VEGF KDR Receptors to the Eye. J. Controlled Release 2010, 145, 3, 297-305. (30) Ma, T.; Liu, H.; Sun, X.; Gao, L.; Shi, J.; Zhao, H.; Jia, B.; Wang, F.; Liu, Z. Serial in vivo Imaging Using a Fluorescence Probe Allows Identification of Tumor Early Response to Cetuximab Immunotherapy. Mol. Pharmaceutics 2015, 12, 1, 10-17.
6
ACS Paragon Plus Environment
Page 7 of 7
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Applied Materials & Interfaces
TOC Graphic
7
ACS Paragon Plus Environment
