Cascade Promoted Photo-Chemotherapy against Resistant Cancers

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Cascade Promoted Photo-Chemotherapy against Resistant Cancers by Enzyme-Responsive Polyprodrug Nanoplatforms Wenhui Wang, Guohai Liang, Wenjia Zhang, Da Xing, and Xianglong Hu Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.8b01149 • Publication Date (Web): 03 May 2018 Downloaded from http://pubs.acs.org on May 3, 2018

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Chemistry of Materials

Cascade Promoted Photo-Chemotherapy against Resistant Cancers by Enzyme-Responsive Polyprodrug Nanoplatforms

Wenhui Wang,†,‡ Guohai Liang,†,‡ Wenjia Zhang,†,‡ Da Xing,*,†,‡ and Xianglong Hu*,†,‡

†

MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, South

China Normal University, Guangzhou 510631, China ‡

College of Biophotonics, South China Normal University, Guangzhou 510631, China

∗

E-mail: [email protected], [email protected].

ABSTRACT: Cisplatin has long been the first line treatment for a variety of solid tumors. However, the poor pharmacokinetics, intrinsic or acquired drug resistance are the main challenge in cancer therapy. Herein, endogenous enzyme-responsive cisplatin polyprodrug nanoplatforms were developed for the cascade promoted photochemotherapy against drug-resistant cancers. The polyprodrug nanoplatforms, ICG/Poly(Pt), were fabricated from indocyanine green (ICG) photosensitizer and cisplatin

polyprodrug

amphiphiles,

PEG-b-P(Pt-co-GFLG)-b-PEG,

consisting

repeated enzyme-degradable GFLG peptides and cisplatin prodrug units in the hydrophobic block and hydrophilic PEG chains, exhibiting ~24.7 wt% cisplatin loading. Upon cellular uptake in lysosomes, cathepsin B could partially degrade the nanoplatforms into cisplatin prodrug, then 808 nm laser irradiation would excite ICG to afford reactive oxygen species (ROS) and local hyperthermia, thus launching the phototherapy. Furthermore, the concurrent photodynamic and photothermal process could damage lysosomes to accelerate the cytosolic delivery of cisplatin prodrug away from lysosomes, which was followed by GSH reduction into active cisplatin to

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initiate cascade chemotherapy. In addition, the polyprodrug nanoplatforms provided dual-model photoacoustic (PA) and fluorescence imaging to guide the therapeutic treatments. In vitro and in vivo explorations proved that ICG/Poly(Pt) could significantly inhibit the cisplatin-resistant A549/DDP cancers. The well-defined polyprodrug nanoplatforms exhibited great potential for imaging-guided cascade treatments of resistant cancers in intelligent biomedicine.

INTRODUCTION: Cisplatin can disrupt DNA structure in cancer cell nuclei, which has been widely used in the treatment of various solid cancers, including testicular, ovarian, bladder, head and neck, breast and lung cancers,1,2 achieving significant improvement of the survival rate and life quality of suffered persons. However, the further application of platinum (Pt) agents is frequently limited by the severe dose-dependent side effects (e.g., nephrotoxicity and neurotoxicity)3 and especially, the emergence of cisplatin resistance in cancers.4-6 Some cancer cells are intrinsically resistant, while others acquire resistance after initial several treatments,7 the initial sensitivity of cancer cells to cisplatin is high, but the majority of cancer patients will eventually relapse with the development of cisplatin-resistant cancers.8 Therefore, it is imperative to address the resistant issues and enhance the therapeutic efficacy.9,10 In view of the severe drug resistance of cisplatin, many strategies have been put forward to improve the therapeutic index of cisplatin. One strategy to combat cisplatin resistance is to develop Pt(IV) prodrug delivery systems,11-17 which could enhance the cancer selectivity and reduce the adverse effects simultaneously. Pt(IV)-based prodrugs could be reduced and activated by endogenous reductive species, such as glutathione (GSH) and ascorbic acid, forming cytotoxic Pt(II) complexes in cancer cells.18-22 Moreover, drug delivery nanocarriers could protect the cargo molecules from metabolic degradation within hepatorenal tract, prolong the blood circulation lifetime and facilitate the lesion accumulation, thus enhancing the therapeutic efficiency with little side effects. Various smart delivery systems with the feature of


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responding to external stimulations (such as light, magnetic field, ultrasound, and hyperthermia) or internal stimulations (such as reduction/oxidation, pH, and enzyme), showed even better performances.23-26 However, conventional strategies based on similar anti-cancer mechanism with cisplatin often suffered other limitations, including low drug loading, high risk of multi-drug resistance, and the final compromised anticancer activities,27 resulting in limited success in the circumvention of platinum resistance. Recently, synergistic therapy has attracted much attention to potentially overcome drug resistance in cancer cells.28,29 The integration of alternative therapeutic approaches with different drugs or diverse working mechanisms provided opportunities to overcome the drug resistance of cancer cells.30-32 Additionally, a well-demonstrated polyprodrug strategy exhibited distinct properties, featured by repeating prodrug units, high drug loading, responsive prodrug cleavage and concurrent active drug release, which demonstrated great potency in the hierarchical self-assembly,33 microstructure modulated theranostic application,34 and membrane modulation of polyprodrug-gated vesicles.35 Polyprodrug strategy has been also investigated to develop polymeric platforms with diverse morphologies, drug types, and responsive signals in biomedicine.36-47 Inspired by this, the rational design of cisplatin polyprodrug with other therapeutic modalities is potential to combat the drug resistance in the treatment of persistent cancers. In this work, endogenous enzyme-responsive cisplatin polyprodrug nanoplatforms, ICG@Poly(Pt), were developed from the co-assembly of ICG and cisplatin polyprodrug amphiphiles, PEG-b-P(Pt-co-GFLG)-b-PEG, composed by repeating cathepsin B-degradable GFLG peptides and cisplatin prodrug units in the middle block and hydrophilic PEG block. Upon cellular uptake, cathepsin B in lysosomes partially degrade the nanoparticles to release free ICG and cisplatin prodrugs. Then 808 nm laser irradiation affords ROS and heat to launch phototherapy based on the light-absorbing ICG, which can damage lysosome and promote the cytosolic delivery of cisplatin prodrugs into reductive cytosolic milieu, followed by reduction into



cisplatin parent drug to activate cascade chemotherapy. For in vivo theranostics, photoacoustic (PA) and fluorescence dual-model imaging was performed for the guided therapy (Scheme 1).

Scheme 1. Schematic illustration for ICG-loaded enzyme-responsive polyprodrug nanoplatforms. ICG@Poly(Pt) was composed by ICG and cisplatin polyprodrug amphiphiles tethered with repeating degradable GFLG peptides, PEG-b-P(Pt-coGFLG)-b-PEG. Upon cellular uptake, cathepsin B in the lysosomes partially degrade ICG@Poly(Pt) into free ICG and the cisplatin prodrugs. Then 808 nm laser irradiation affords ROS and heat for phototherapy based on light-absorbing ICG, which can promote the lysosome damage and escape of cisplatin prodrugs into reductive cytosol, followed by reduction into cisplatin parent drug to activate cascade chemotherapy. For in vivo theranostics, photoacoustic (PA) and fluorescence (FL) dual-model imaging was performed for the guided therapy.

RESULTS AND DISCUSSION

Fabrication and Characterization of Cisplatin Polyprodrug Nanoplatforms.


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Enzyme-responsive polyprodrug amphiphiles, PEG-b-P(Pt-co-GFLG)-b-PEG, were synthesized from condensation polymerization of diamine-tethered GFLG peptides and dicarboxyl-functionalized cisplatin prodrugs, and subsequent PEG decoration (Scheme S1). PEG-b-P(Pt-co-GFLG)-b-PEG was characterized by 1H-NMR spectrum, which exhibited a relatively high cisplatin loading content, up to ~24.7 wt%. The aqueous

self-assembly

of

PEG-b-P(Pt-co-GFLG)-b-PEG

afforded

cisplatin

polyprodrug micelles, noted as Poly(Pt), exhibiting spherical morphology by TEM analysis, and a diameter of ~200 nm determined by DLS (Figure 1A). Furthermore, PEG-b-P(Pt-co-GFLG)-b-PEG could encapsulate ICG to afford ICG-loaded polyprodrug micelles, ICG/Poly(Pt), with an ICG loading of ~16.2 wt%. The formed ICG/Poly(Pt) had a uniform spherical morphology with a diameter of ∼170 nm (Figure 1B). The TEM image of ICG/Poly(Pt) appeared to be darker than that of Poly(Pt), which could be ascribed to the presence of ICG with high electron density. The zeta potential values of Poly(Pt) and ICG/Poly(Pt) were demonstrated to be slightly negative, specially, -10.6 mV and -6.2 mV, respectively, which was in favor of minimizing non-specific protein absorption in blood circulation. Moreover, upon storing at room temperature for up to four weeks, the almost constant diameters of ICG/Poly(Pt) and Poly(Pt) were observed, indicating the excellent stability of cisplatin polyprodrug micelles (Figure S2). On the other hand, compared with free ICG, the absorption of ICG/Poly(Pt) red-shifted obviously and became wider due to probable stacking effect of ICG in the hydrophobic core (Figure 1C). The absorbance intensity at 808 nm was around the maximum absorption peak, while the absorption of water and tissue was limited at 808 nm, making ICG/Poly(Pt) potentially superior for deep-penetrating light treatment. In addition, the stability of ICG/Poly(Pt) and free ICG in the dark was evaluated by their UV-vis absorption (Figure 1D). The absorbance intensity of ICG/Poly(Pt) remained ~90% of initial value at one week, and ~80% at four weeks, while that of free ICG decreased to ~33% and ~13%, respectively. The solution color of ICG solution disappeared almost completely at four weeks, suggesting severe ICG



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degradation, whereas the color change of ICG/Poly(Pt) was inconspicuous. The polymeric envelope significantly isolated ICG from the surrounding robust environment, thus the stability of ICG was improved greatly upon being encapsulated by

the

cisplatin

polyprodrug

amphiphiles,

PEG-b-P(Pt-co-GFLG)-b-PEG.

Additionally, the strong near infrared (NIR) absorption of ICG/Poly(Pt) implied that the polyprodrug nanoplatforms could potentially be employed as a novel PA agent.48 In vitro PA analysis was performed to evaluate this potency. ICG/Poly(Pt) and free ICG at various mass concentrations were embedded in agar gel cylinders to produce PA imaging phantoms on a multispectral optical tomography (MSOT) imaging system. As presented in Figure 1E, ICG/Poly(Pt) and free ICG both exhibit mass concentration-dependent PA signals, and the sample of ICG/Poly(Pt) was much brighter than free ICG at the same ICG content, exhibiting much stronger PA intensity. These results verified that ICG/Poly(Pt) would be an ideal contrast agent for PA imaging, exhibiting higher PA signals than free ICG counterpart due to the potential photothermal-enhanced PA signals and relatively high stability of ICG in ICG/Poly(Pt) (Figure 1F).49

Figure 1. Physicochemical characterization of the ICG-loaded polyprodrug nanoplatforms, ICG@Poly(Pt). As a control, ICG-free Poly(Pt) aqueous dispersions


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were fabricated from the self-assembly of PEG-b-P(Pt-co-GFLG)-b-PEG. TEM images and hydrodynamic diameter distribution recorded for (A) Poly(Pt) and (B) ICG@Poly(Pt). (C) UV absorption spectra of free ICG, Poly(Pt), and ICG/Poly(Pt), respectively. (D) Relative absorbance intensities recorded at 785 nm for the water dispersion of free ICG and ICG/Poly(Pt) at room temperature for different durations. Inset photograph (left) and right one indicated for the samples at 0 week and 4 weeks, respectively. (E) In vitro PA images of ICG/Poly(Pt) at different contents. (F) Linear relationship between PA signal intensity and the content of ICG/Poly(Pt).

Endogenous Enzyme-Responsive Degradation of Polyprodrug Nanoplatforms. Cathepsin B is a cysteine protease that displays increased levels in the cytoplasm of various cancer cells, such as colorectal cancer, malignant glioma, breast cancer, lung cancer, prostate cancer, and melanoma,50 which was well-demonstrated to degrade GFLG sequence efficiently.51-56 The presence of repeating GFLG peptide sequence and cisplatin prodrugs in the backbone of PEG-b-P(Pt-co-GFLG)-b-PEG allowed the enzyme and redox dual-responsive degradation as well as controlled release profile of cisplatin prodrugs (Scheme 1). To check whether ICG/Poly(Pt) could respond to enzyme and reductive stimuli, the morphology and size changes of ICG/Poly(Pt) were examined upon incubation with or without papain and GSH by TEM and DLS analysis. Papain has similar activity as lysosomal cathepsin B, which can degrade GFLG peptide efficiently.57 No detectable aggregation or significant morphology and size change was observed upon incubating at pH 7.4 without papain (Figure 2A), whereas the polyprodrug nanoplatforms could degrade into small fragments after incubation at pH 5.5 with papain (Figure 2B). If the inhibitor of papain was present, the degradation was inhibited remarkably (Figure 2C). To mimic the endocytosis and intracellular trafficking pathway (Scheme 1), undergoing lysosomal trapping (acidic and enzymatic milieu) and subsequent lysosomal escape into reductive cytosolic milieu (high GSH content), the dispersion of ICG/Poly(Pt) was firstly treated with papain at pH 5.5, followed by incubation with GSH at pH 7.4, almost no residue was observed by the TEM analysis (Figure 2D), indicating that the GFLG cleavable sites and ester bonds linked with cisplatin were ACS Paragon Plus Environment


possibly cleaved sequentially by papain in simulated acidic lysosomal condition and reductive cytosolic milieu. This result was further confirmed by DLS test (Figure 2E). The cascade treatment with enzyme and GSH could degrade the nano-sized aggregates of ICG/Poly(Pt) into almost molecularly dispersed species. Moreover, elevated GSH levels have been found in cisplatin-resistant cell lines,58 and high levels of GSH provide favorable conditions for sufficient degradation of cisplatin prodrugs.59 Based on these, Poly(Pt) was expected to release cytotoxic parent cisplatin much faster in cancer cells than in normal cells. Furthermore, In vitro enzyme-responsive controlled release of Pt from ICG/Poly(Pt) was investigated at comparable conditions. As shown in Figure 2F, there was limited Pt leakage from ICG/Poly(Pt) in the absence of papain at pH 7.4. Whereas in the presence of papain, obvious Pt release could be observed under prolonged enzyme treatment at pH 5.5, which was attributed to the high activity of papain in acidic environment. As a control, when the enzyme was pretreated with antipain hydrochloride, an efficient inhibitor of papain,60 there was much less Pt release under either acidic or neutral conditions. The combined pretreatment with papain and subsequent treatment with GSH could also exhibit obvious drug release. These results suggested that the cisplatin polyprodrug could specifically respond to papain to mediate controlled release of cisplatin prodrugs. Additionally, the high stability of the polyprodrug nanoplatforms in PBS (pH = 7.4, 37 °C) suggested that the prepared drug-delivering vehicles would be stable in physiological blood circulation with reduced drug leakage and potential side effects.57


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Figure 2. Cascade enzymatic and reductive degradation as well as in vitro drug release property of ICG/Poly(Pt). (A-D) TEM images recorded for ICG/Poly(Pt) after different treatments. (A) pH 7.4 without papain, which is like the physiological condition. (B) ICG/Poly(Pt) treated at pH 5.5 and papain, simulating the acidic and enzymatic condition of lysosomes. (C) ICG/Poly(Pt) treated at pH 5.5 with papain and the presence of papain inhibitor, (D) Sample B followed by GSH treating at pH 7.4, mimicking the lysosomal escape into reductive cytosolic environment. (E) Hydrodynamic diameter distribution of ICG/Poly(Pt) after different treatments. (F) In vitro Pt release under different treating conditions.

Cellular Uptake and Intracellular Trafficking. The cellular uptake and intracellular localization of ICG/Poly(Pt) against A549 lung cancer cells were observed at diverse incubation duration by confocal laser scanning microscopy (CLSM) imaging. Representative images suggested that ICG/Poly(Pt) were quickly internalized by A549 cells upon incubation for 4 h (Figure 3). The merged fluorescence images from ICG and Lysotracker green channels further demonstrated that the nanoparticles were mainly located in lysosomes at 4 h, exhibiting a co-localization ratio to be >85%. Further extending the incubation time to 12 h, the value was still to be >70%. It suggested the long-term trapping of nanoparticles in lysosomes, which was favorable for the enzymatic degradation of polyprodrug



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nanoplatforms into cisplatin prodrug species and free ICG release in lysosomes. Notably, the presence of ICG in the polyprodrug nanoplatforms allowed for 808 nm laser irradiation to examine the effect of NIR laser irradiation (Figure 1C). The laser irradiation based on ICG/Poly(Pt) obviously facilitated the out-diffusion of fluorescent pixels of Lysotracker and ICG, even entered the cell nucleus. Whereas only laser irradiation did not destroy the lysosomes of cancers cells in the absence of ICG/Poly(Pt) (Figure S4) We envisaged that the laser-induced hyperthermia and ROS based on light-absorbing ICG could disrupt ICG/Poly(Pt) into Pt(IV) prodrug fragments, which would be further reduced into cisplatin by GSH in cytoplasm, and further increased the drug accumulation inside cancer cells for the enhanced intracellular permeability and fluidity (Scheme 1).61 Then a great deal of Pt(II) complex would enter into the cell nuclei and destroyed the DNA structure, resulting in cell apoptosis eventually. Moreover, the hyperthermia itself could cause severe cell damage, including loss of nucleus, cell shrinkages, and coagulation. Taking these factors into consideration, it was not surprising that laser irradiation significantly increased the uptake of ICG/Poly(Pt) by A549 cells.

Figure 3. Cellular uptake and intracellular trafficking of ICG/Poly(Pt). CLSM images of A549 cells upon incubation with ICG/Poly(Pt) in the dark (left) or under 808 nm laser irradiation (right, 5 min, 1.0 W cm−2), scale bar: 20 µm.

Photothermal

and

Photodynamic-Induced

Lysosomal


Disruption.

The

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production potency of hyperthermia and ROS for ICG/Poly(Pt) was interrogated in detail. The aqueous dispersions of Poly(Pt), ICG/Poly(Pt) and free ICG were exposed to laser irradiation for different durations (808 nm, 1 W/cm2), respectively, and the dispersion temperature was monitored concurrently (Figure 4A). After a total of 10 min irradiation, the absolute temperature rising of ICG/Poly(Pt) and free ICG was observed to be ~17.8 °C and ~15.5 °C, respectively, while the control sample (PBS) only increased ~ 2.6 °C. Notably, ICG/Poly(Pt) showed higher temperature increasing than free ICG under laser irradiation, similar to the case of previously reported ICG-loaded lipid nanoparticles.62 The ICG encapsulated in Poly(Pt) had higher condensed concentration than free ICG, and the excitation thermal radiation was also entrapped in the enclosure of nanoplatforms,61 resulting in higher photothermal conversion efficiency and lower heat dissipation upon laser irradiation.63 Notably, the photothermal effect of ICG-loaded nanoparticles was demonstrated to damage lysosomes to remarkably promote cytosolic delivery of cargoes.64 Upon irradiation, photosensitizers can transmit the absorbed energy to surrounding oxygen molecules, resulting in ROS generation, primarily singlet oxygen (1O2),65 which can cause serious damage to subcellular organelles.66-69 To validate the potential generation of ROS from ICG for photodynamic therapy, the dispersion of ICG/Poly(Pt) was irradiated by an 808 nm laser light. The ROS state was monitored by non-fluorescent 2,7-dichlorodihydrofluorescein (DCFH), which can be oxidized by ROS to generate fluorescent 2,7-dichlorofluorescein (DCF), and it was employed as a standard probe to detect ROS.70 Moreover, the presence of cellular peroxidases is favorable for the oxidation of DCFH to DCF. The fluorogenic intensity of DCF in the group of ICG/Poly(Pt) significantly increased, much higher than free ICG and other control groups along with the extended irradiation time (Figure 4B). This result indicated that ICG/Poly(Pt) had a higher ROS yield than free ICG,23,71 implying that it was highly preferable to damage lysosomal membranes via well-accepted photochemical internalization effect of ROS.67 Encouraged by above results, we further explored the disruption ability of



ICG/Poly(Pt) on lysosomes under 808 nm laser irradiation by acridine orange (AO) staining. AO is a metachromatic fluorophore that can emit green fluorescence in the cytoplasm, while the green fluorescence transformed into red fluorescence upon trapping in lysosomes.72 In the absence of 808 nm laser irradiation, CLSM images showed that the acidic lysosomes in A549 cells treated with PBS for 8 hours displayed remarkable red fluorescence for both PBS and ICG/Poly(Pt), which agreed well with above lysosome co-localization analysis (Figure 4C). It demonstrated that the lysosomes remained intact and laser irradiation itself is inoffensive to lysosomes. However, upon laser irradiation, the red fluorescence from AO decreased remarkably in the presence of ICG/Poly(Pt) for 4 h, and almost vanished at 8 h, indicating irreversible disruption of the lysosomal membrane. Thus the hyperthermia and ROS produced by ICG/Poly(Pt) could destruct the lysosomes dramatically, which was in favor for the translocation of released Pt(IV) prodrug fragments into cytoplasm for reduction-activated cascade chemotherapy to maximize the therapeutic efficiency (Scheme 1).72,73

Figure 4. Photo-induced hyperthermia and ROS formation to disrupt lysosomes. (A) Temperature elevation and (B) singlet oxygen generation induced by ICG/Poly(Pt) upon laser irradiation. (C) Observation of lysosomal disruption for A549 cells after treating with ICG/Poly(Pt) at various incubation time after laser irradiation (808 nm, 5 min, 1.0 W cm−2) using AO staining, (p

Cascade Promoted Photo-Chemotherapy against Resistant Cancers

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