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Lysosome enlargement enhanced photochemotherapy using a multifunctional nanogel Weiqi Zhang, and Ching-Hsuan Tung ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b16575 • Publication Date (Web): 22 Jan 2018 Downloaded from http://pubs.acs.org on January 23, 2018

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ACS Applied Materials & Interfaces

Lysosome Enlargement Enhanced Photochemotherapy Using a Multifunctional Nanogel Weiqi Zhang and Ching-Hsuan Tung* Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, USA *To whom correspondence should be addressed. 413 East 69th Street, Box 290, New York, NY 10021, USA. E-mail: [email protected].

ABSTRACT: Large lysosomes are susceptible towards rupture due to an increased membrane tension. Here we report a strategy to first enlarge and weaken the lysosome and then destroy it to boost the efficiency of photochemotherapy using a hyaluronan nanogel, carrying chloroquine as a lysosomal expander, rhodamine B as a photosensitive lysosomal destroyer, and cisplatin as a chemotherapeutic. This allin-one nanogel provides a facile approach and new insight to improve the photochemotherapy, by making use of lysosome’s size, as a risk factor in lysosomal destabilization.

KEYWORDS: photochemotherapy, hyaluronan, nanogel, chloroquine, lysosomal destablization

The sequestration of macromolecules and nanoparticles in lysosomes is one of the major barriers towards an efficient intracellular drug delivery,1-4 because 1) the physical barrier of the lysosomal membrane prevents its trapped drugs access their molecular target;2 2) the digestive environment within the lysosome deteriorates the drug’s efficiency;3-4 and 3) the storage of drug’s within the

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lysosomes reduce the effective drug concentration and favor the drug resistance.5 Thus facilitating the drug’s lysosomal escape could greatly improve its therapeutic performance especially for those agents delivered by nanocarriers prone to accumulation in the endo-lysosomal system. It is noted that the lysosomal escape of the drug may also be accompanied by the release of its contents, eg. cathepsins, which could trigger the cell’s death cascade.6-8 To date, various lysosome-destabilizing agents with the ability to either induce osmotic swelling, membrane penetration, pore formation, or physical disruption of lysosomes have been reported.3-4 Chloroquine (CQ), an antimalarial drug, is a typical lysosomal destabilization mediator due to its known pharmacodynamics and clinical tolerability.9 The most notorious example of how CQ promotes lyosomal escape is its application in gene delivery.10-11 The CQ induced osmotic swelling of the lysosome begins with its protonation and is followed by an influx of water molecules,12-13 resulting in an increased chance for plasmid to escape the lysosome and access the nucleus for gene expression. In fact, a larger lysosome has been proposed to be as a risk factor for lysosomal destabilization because of the increased surface tension.8, 14-15 Reactive

oxygen

species

(ROS),

especially

those

generated by

a

photosensitizer (PS) under a light source, are able to oxidize the membrane lipids; thus, providing a facile and tempo-spatially controlled approach to destabilize lysosomes that has been intensively exploited in photo-chemotherapy (PCT).6, 16-18 PCT integrates the advantages of both phototherapy and chemotherapy, but it is challenging to simultaneously deliver PS and chemotherapeutics to the same sites.


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Because of their different chemical properties and pharmacokinetics, PS and chemotherapeutics may possess different distributions once administered.16 To overcome this co-delivery issue, an all-in-one multi-functional nanodrugplex was prepared based on a recently developed hyaluronan (HA) platform that allows multiple payloads to be packaged together.19-20 The HA nanogel, named HA/Cis/CQ/Rb, encapsulates cisplatin (Cis), CQ and rhodamine B (Rb) and specifically targets cells with higher CD44 expressions for lysosomal transportation. It is envisioned that following lysosomal localization, CQ will act as a lysosomal attenuator to enlarge the lysosome and make it susceptible towards membrane disruption. The light irradiated Rb functions as a lysosome destroyer by generating ROS in situ (Figure 1). The resulting lysosomal membrane permeabilization (LMP) is expected to prompt the lysosomal escape of Cis, as well as to promote PCT’s efficiency.

Figure 1. Proposed mechanism for the HA/Cis/CQ/Rb nanogel to boost the PCT efficiency.



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Taking advantage of the facile synthesis of HA nanogels, several controls were synthesized in addition to HA/Cis/CQ/Rb, including nanogels containing only chemotherapeutics

(HA/Cis),

chemotherapeutics

plus

lysosomal

expander

(HA/Cis/CQ) and chemotherapeutics plus lysosomal destroyer (HA/Cis/Rb) (Figure 2 and Table S1). The cationic-aromatic structure of CQ and Rb make them aggregated in the HA nanogel,19 that was evidenced by the red-shifted and broadened absorption spectra, (Figure S1a) as well as the quenched Rb fluorescence in comparison to its free form (Figure S1b). In comparison to the near complete quenched fluorescence observed in HA/Cis/Rb, the residual Rb fluorescence in HA/Cis/CQ/Rb was presumably due to loose Rb aggregates caused by the perturbation of CQ in the nanogel.

Figure 2. Characterization of nanogels. a) The structure of the key component in the nanogel. b) Hydrodynamic size and PDI of nanogels in water. c) Zeta potential. d) TEM images of nanogels. The inserted cartoon shows the assumed structure of


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corresponding nanogel. e) The dark and light toxicity of nanogels towards MDA-MB231 cells. Light irradiation: 35 mW/cm2 at 544 nm, 3 min. From the dynamic light scattering (DLS) analysis (Figure 2b-c), the acquired HA/Cis, HA/Cis/CQ, HA/Cis/Rb and HA/Cis/CQ/Rb, in water, carried a negative charge with a hydrodynamic size of 107.4, 160.4, 110.9 and 210.2 nm, respectively. When more payloads were withheld during synthesis, the nanogel presented a gradually improved size distribution, supported by a narrowed polydispersity index (PDI) (Figure 2b and Figure S2). The morphology and population of HA/Cis/CQ/Rb was clearly verified by transmission electron microscopy (TEM) in Figure 2d, while irregular shapes and uneven populations were observed in the rest of the nanogels especially for HA/Cis. Table S2 and S3 summarized the loading efficiency of Cis, CQ and Rb, varying at 14.4-20.3%, 11.4-13.8% and 5.4-7.1% respectively in all nanogels. The final molar ratio of HA to Cis, CQ, and Rb within the different nanogels was maintained at a close range (Table S2) to facilitate the subsequent systematic comparison in cells. The payload release profiles including Cis, CQ and Rb of all nanogels were checked in PBS at 37 °C (Figure S3). A slow release of payloads was observed, and reached plateaus after 24 hours of incubation. The release curves for a specific drug in all formulations were similar within 4 days, indicating a similar encapsulation environment for the drugs within different nanogels. Prior studies with similar nanogels have also confirmed that these nanogels are relatively stable in PBS over a 2-day study period, as minimal size change was observed.19-20 To check the PCT efficiency of the nanogels, MDA-MB-231 was selected as a model cell due to its high levels of CD44 expression,19-21 a membrane receptor for



HA. MDA-MB-231 is a type of triple negative breast cancer (TNBC) that lacks effective therapeutics. Recently, Cis, an atypical drug for the treatment of breast cancer, has shown an improved response rate towards TNBC in clinical trials.22 The MDA-MB-231 cells were treated by HA/Cis, HA/Cis/CQ, HA/Cis/Rb and HA/Cis/CQ/Rb with Cis ranged from 6.25 to 100 μM for 1 day, and were exposed to an LED light (35 mW/cm2 at 544 nm) for 3 minutes. The cells were then subjected to a cell viability assay 1 day post-irradiation. Without light irradiation, all formulations demonstrated a dose-dependent, but limited toxicity, due to the therapeutic effects of the encapsulated drugs (Figure 2e). As expected, the light treatment showed no added benefit to the groups with HA/Cis, HA/Cis/CQ and HA/Cis/Rb. Conversely, a significant photo-enhanced toxicity in the HA/Cis/CQ/Rb group was observed (Figure 2e). The IC50 value of cisplatin in the HA/Cis/CQ/Rb group, under the light (35 mW/cm2, 3 min), was around 11.6 µM, which was over 2-fold lower than that of free cisplatin (24.9 µM, Figure S4), supporting the advantage of this all-in-one nanogel’s phototoxicity. Furthermore, this added PCT effect in the HA/Cis/CQ/Rb treated group is light dose-dependent as evidenced by live-dead cell staining (Figure S5a) and cell viability assays (Figure S5b). For example, an 8-minute light irradiation killed all of the HA/Cis/CQ/Rb treated cells, while no difference was found between the irradiated and non-irradiated cells in the HA/Cis, HA/Cis/CQ and HA/Cis/Rb treated groups (Figure S5b). This light-responsiveness unique to HA/Cis/CQ/Rb highlighted the essential coexistence of CQ and Rb in the nanogel to mediate the PCT effect.


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To verify the hypothesis that CQ functions as a lysosomal expander, the lysosome of all nanogel treated cells were stained and the lysosomal size (diameter) was counted based on the fluorescent images (Figure 3). Cells with no treatment, or treated by free CQ, free Rb and free CQ plus Rb were included as controls (Figure S6). The Rb signal from cells treated by both HA/Cis/Rb and HA/Cis/CQ/Rb was finely co-localized with lysosomes (Figure 3), while the free Rb either used alone or together with CQ bound to the mitochondria, presenting as a different staining pattern with lysosomes (Figure S6). As shown, the Rb packed within the nanogel was directed to the lysosome, the common destination site for targeted nanoparticles in cells.2, 19-20 Without the assistance of the nanogel, free CQ, Rb or CQ plus Rb would be unable to show any photo-induced cytotoxicities (Figure S7). This therefore evidenced that the localization of Rb within the lysosome was a key factor in the phototoxicity of the HA/Cis/CQ/Rb group. It was clearly noticed, assisted by the lysoTracker staining, that the presence of CQ either in the form of a free drug or nanogel swelled the lysosomes, which also appeared as intracellular vacuoles under the phase contrast images (Figure 3 and Figure S6). The lysosomal size distribution was about ~2-fold larger in the CQ treated cells than in the cells that had no contact with CQ. For example, HA/Cis/Rb and HA/Cis/CQ/Rb treated cells had a lysosomal size raised from 1.09 ± 0.41 to 2.02 ± 0.92 μm (Figure 3). Nevertheless, the lysosomal size acquired here was consistent with the literature values determined by both the lysoTracker staining and TEM in CQ treated kidney epithelial cells.23



Figure 3. Co-localization with lysosomes. Cells were treated by HA/Cis (a), HA/Cis/CQ (b), HA/Cis/Rb (c) and HA/Cis/CQ/Rb (d). The arrowheads point the typical vacuoles in cells. The related Cis, CQ or Rb concentration was kept at 25, 12 and 6 µM in different groups.

To verify the importance of this lysosomal dilatation, the cells were first pulsed by HA/Cis/CQ/Rb and then incubated with bafilomycin A1 (Baf A1), an inhibitor for v-ATPase that is essential in CQ’s induction of lysosomal swelling.13 In line with other’s reports, the Baf A1 eliminated expanded vacuoles in both free CQ and HA/Cis/CQ/Rb pulsed cells (Figure S8), suggesting the successful inhibition of lysosomal swelling.12, 23 The following live-dead cell staining showed that the Baf A1 treatment clearly alleviated the HA/Cis/CQ/Rb induced light toxicity (Figure S9), supporting that the enlarged lysosome is a key factor for HA/Cis/CQ/Rb’s phototoxicity. To probe the underlying mechanism for the HA/Cis/CQ/Rb’s unique phototoxicity, the intracellular ROS generation under light irradiation was evaluated using DCFDA staining (Figure 4a and Figure S10). In darkness, cells treated by the four nanogels all demonstrated a background level of ROS similar to the control cells,


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while only the cells treated by HA/Cis/CQ/Rb plus light showed a dramatic surge of ROS (Figure 4a). It is obvious that those nanogels without a photosensitizer (Rb) were unable to generate ROS under light irradiation. The densely packed HA/Cis/Rb, whose fluorescence property is near completely quenched, is not photosensitive, resulting in a compromised singlet oxygen generation

24-26.

Conversely, the Rb was

less quenched/aggregated in HA/Cis/CQ/Rb; therefore. the ROS generation property was retained. This photosensitivity variation between HA/Cis/CQ/Rb and HA/Cis/Rb was further verified using the singlet oxygen generation sensor green (SOSG) assay in a test tube (Figure S11).

Figure 4. a) Intracellular ROS generation. b-c) Colocalization of Rb with lysosomes (Qtracker) in HA/Cis/Rb (b) and HA/Cis/CQ/Rb (c) treated cells before and after the light irradiation. The involved Cis, CQ and Rb concentration was set at 25, 12 and 6 µM, respectively. *: p < 0.05, and ***: p < 0.001. ROS is a common factor in the destabilization of the lipid membrane; however, this destabilization requires direct contact between ROS and membrane because of the limited lifetime and action distance of singlet oxygen.6,

27

The

confinement of Rb within the lysosomes provided a probable chance for the generated ROS to interact with the lysosomal membrane in situ. The enlarged



lysosomes possess an increased surface tension,14, 28 which sensitizes the lysosomal membrane towards photo damage. The enclosed contents within the lysosomes may leak out upon the LMP.7-8 To confirm the occurrence of LMP, the Rb signals in cells with no nanogel treatment (Figure S12), HA/Cis/Rb (Figure 4b) and HA/Cis/CQ/Rb (Figure 4c) were tracked before and after light irradiation. Meanwhile the cells were co-loaded with Qtracker, a quantum dot-based lysosomal probe with strong anti-photobleaching ability, to highlight the lysosome.29 After light irradiation, only the Rb in the HA/Cis/CQ/Rb treated cells diffused out of the lysosome, strongly suggesting the occurrence of the light-triggered LMP in this case. The LMP process within the cells was further monitored in real time on a fluorescent microscope with the excitation light continuously on for 3 min. As seen in Movie S1, the Rb fluorescence of HA/Cis/Rb in cells stayed constant over the irradiation period. In contrast, the Rb signal of the HA/Cis/CQ/Rb treated cells increased and diffused throughout the whole cell within 3 minutes of light irradiation, which corroborated the observation in Figure 4c. The release of Rb was together with both CQ and Cis in HA/Cis/CQ/Rb. The leakage of Rb from the lysosome would be accompanied by the lysosomal escape of Cis, thus promoting Cis’s intracellular delivery. Other than the delivered cargoes, the occurrence of LMP could also release its enclosed enzymes eg. cathepsins, which further trigger the cytotoxic cascade.8 As a result, these multiple cytotoxic actions induced by light could collaboratively boost the PCT effect that is unique to HA/Cis/CQ/Rb among all the prepared nanogels.


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In summary, a new strategy to enlarge/weaken and then break lysosome to boost PCT’s efficiency has been demonstrated by using an all-in-one nanogel containing CQ as a lysosomal expander, Rb as a lysosomal destroyer and Cis as a chemotherapeutic. The lysosome targeted HA/Cis/CQ/Rb nanogel directed the mitochondrial dye, Rb, to lysosome for an enriched focal ROS generation, resulting in promoted LMP process and enhanced PCT toxicity. This light triggered release approach provides an alternative to overcome the lysosomal entrapment of therapeutic agents with spatiotemporal control; furthermore, it has demonstrated that, upon the lysosome weakening, even a weak PS like Rb could effectively damage the lysosome. Our design significantly improves the efficiency of the photodynamic reaction and broadens the selection of PS for clinical PCT. Considering the biocompatibility and versatility in encapsulating various cargoes, the current HA nanogel system could advance the photo-chemotherapy by enabling more effective PS and drugs combinations.

ASSOCIATED CONTENT Supporting information The Supporting Information is available free of charge on the ACS Publications website. Experiment details of nanogel synthesis, characterization, cell culture, phototoxicity assay and fluorescent microscopy. Data of spectra analysis, DLS measurements, drug release, live-dead staining, lysosomal imaging of cells treated by free CQ, Rb or CQ and Rb, Baf A1 post-treatment experiments, DCFDA fluorescence in cells and singlet oxygen generation analysis.



Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENT This study was financially supported in part by NIH GM094880.

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