Cisplatin Prodrug Research Articles

A Purposefully Designed pH/GSH-Responsive MnFe-Based Metal-Organic Frameworks as Cascade Nanoreactor for Enhanced Chemo-Chemodynamic-Starvation Synergistic Therapy.

Metal-organic frameworks (MOFs) have emerged as promising novel therapeutics for treating malignancies due to their tunable porosity, biocompatibility, and modularity to functionalize with various chemotherapeutics drugs. However, the design and synthesis of dual-stimuli responsive MOFs for controlled drug release in tumor microenvironments are vitally essential but still challenging. Meanwhile, the catalytic effect of metal ions selection and ratio optimization in MOFs for enhanced chemodynamic therapy (CDT) is relatively unexplored. Herein, a series of MnFe-based MOFs with pH/glutathione (GSH)-sensitivity are synthesized and then combined with gold nanoparticles (Au NPs) and cisplatin prodrugs (DSCP) as a cascade nanoreactor (SMnFeCGH) for chemo-chemodynamic-starvation synergistic therapy. H+ and GSH can specifically activate the optimal SMnFeCGH nanoparticles in cancer cells to release Mn2+/4+ /Fe2+/3+ , Au NPs, and DSCP rapidly. The optimal ratio of Mn/Fe shows excellent H2 O2 decomposition efficiency for accelerating CDT. Au NPs can cut off the energy supply to cancer cells for starvation therapy and strengthen CDT by providing large amounts of H2 O2 . Then H2 O2 is catalyzed by Mn2+ /Fe2+ to generate highly toxic •OH with the depletion of GSH. Meanwhile, the reduced DSCP accelerates cancer cell regression for chemotherapy. The ultrasensitivity cascade nanoreactor can enhance the anticancer therapeutic effect by combining chemotherapy, CDT, and starvation therapy.

Single-Cell ICP-MS in Combination with Fluorescence-Activated Cell Sorting for Investigating the Effects of Nanotransported Cisplatin(IV) Prodrugs.

The combined use of fluorescence-activated cell sorting (FACS) and single-cell inductively coupled plasma mass spectrometry (SC-ICP-MS) is reported, for the first time, in this work. It is applied to evaluate the differences between the cellular uptake of ultrasmall iron oxide nanoparticles (FeNPs) loaded with cisplatin(IV) prodrug (FeNPs-Pt(IV)) and cisplatin regarding cell viability. For this aim, FACS is applied to separate viable, apoptotic, and necrotic A2780 ovarian cancer cells after exposing them to the nanotransported prodrug and cisplatin, respectively. The different sorted cell populations are individually analyzed using quantitative SC-ICP-MS to address the intracellular amount of Pt. The highest Pt intracellular content occurs in the apoptotic cell population (about 2.1 fg Pt/cell) with a narrow intercellular distribution when using FeNPs-Pt(IV) nanoprodrug and containing the largest number of cells (75% of the total). In the case of the cisplatin-treated cells, the highest Pt content (about 1.6 fg Pt/cell) could be determined in the viable sorted cell population. The combined methodology, never explored before, permits a more accurate picture of the effect of the intracellular drug content together with the cell death mechanisms associated with the free drug and the nanotransported prodrug, respectively, and opens the door to many possible single-cell experiments in sorted cell populations.

New Pathway for Cisplatin Prodrug to Utilize Metabolic Substrate Preference to Overcome Cancer Intrinsic Resistance.

Tumor cells adapt to diverse survival strategies defying our pursuit of multimodal cancer therapy. Prostate cancer (PCa) is an example that is resistant to one of the most potent chemotherapeutics, cisplatin. PCa cells survive and proliferate using fatty acid oxidation (FAO), and the dependence on fat utilization increases as the disease progresses toward a resistant form. Using a pool of patient biopsies, we validated the expression of a key enzyme carnitine palmitoyltransferase 1 A (CPT1A) needed for fat metabolism. We then discovered that a cisplatin prodrug, Platin-L, can inhibit the FAO of PCa cells by interacting with CPT1A. Synthesizing additional cisplatin-based prodrugs, we documented that the presence of an available carboxylic acid group near the long chain fatty acid linker on the Pt(IV) center is crucial for CPT1A binding. As a result of fat metabolism disruption by Platin-L, PCa cells transition to an adaptive glucose-dependent chemosensitive state. Potential clinical translation of Platin-L will require a delivery vehicle to direct it to the prostate tumor microenvironment. Thus, we incorporated Platin-L in a biodegradable prostate tumor-targeted orally administrable nanoformulation and demonstrated its safety and efficacy. The distinctive FAO inhibitory property of Platin-L can be of potential clinical relevance as it offers the use of cisplatin for otherwise resistant cancer.

Ferric iron coordinated cisplatin prodrug reprograms the immune-cold tumor microenvironment through tumor hypoxia relief for enhanced cancer photodynamic-immunotherapy

Ferric iron coordinated cisplatin prodrug reprograms the immune-cold tumor microenvironment through tumor hypoxia relief for enhanced cancer photodynamic-immunotherapy

MOF-based nanozyme grafted with cooperative Pt(IV) prodrug for synergistic anticancer therapy

Manipulating Fenton chemistry in tumor microenvironment (TME) for the generation of reactive oxygen species is an effective strategy for chemodynamic therapy. However, this is usually restricted by limited intracellular content of H2O2 and insufficient acidic environment at the tumor site. Herein, a ferric metal–organic framework (MOF) is covalently grafted with a prodrug of cisplatin (Pt(IV) prodrug) and loaded with a biocatalyst glucose oxidase (GOx) to afford a nanozyme MOF-Pt(IV)@GOx for cascade reactions. In this system, the attached Pt(IV) prodrug on MOF plays a significant role in the cooperative enhancement of GOx loading and chemotherapy. The high concentration of glutathione in TME reduces Fe(III) to Fe(II) for Fenton reaction, and converts Pt(IV) prodrug to cisplatin for DNA targeting and H2O2 production. Meanwhile, glucose oxidation catalyzed by GOx not only consumes glucose for starvation therapy, but also promotes the intracellular acidity and H2O2 supply in TME, which are in favor of Fenton reaction. Both in vitro and in vivo studies demonstrate that MOF-Pt(IV)@GOx enables remarkable anticancer efficacy due to the synergistic trimodal therapy consisting of ferroptosis, starvation therapy, and chemotherapy.

Engineering a synergistic antioxidant inhibition nanoplatform to enhance oxidative damage in tumor treatment.

The antioxidant system of tumor cells severely impairs reactive oxygen species (ROS)-mediated tumor therapy. Despite extensive attempts to attenuate the antioxidant capacity by eliminating ROS scavengers such as glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH) over-expressed in the tumor microenvironment can regenerate GSH from glutathione disulfide (GSSG), hence weakening ROS-induced oxidative damage. Therefore, engineering a nanoplatform capable of depleting both NADPH and GSH is extremely significant for improving ROS-mediated tumor treatment. Herein, a synergetic antioxidant inhibition strategy is proposed to attenuate intracellular antioxidant capacity for hypoxic tumor therapy. In this context, both porous Prussian blue nanoparticles (PPB NPs) and cisplatin prodrug [cis-Pt (IV)] in the nanoplatform can oxidize GSH to directly reduce GSH levels, while PPB NPs also enable NADPH depletion by peroxidase-mimicking to impair GSH regeneration. Furthermore, PPB NPs with catalase-mimicking activity catalyze H2O2 decomposition to alleviate tumor hypoxia, thus reducing the generation of GSH and boosting singlet oxygen (1O2) production by Chlorin e6 (Ce6) for enhancing oxidative damage. Experimental results prove that the nanoplatform, denoted as PPB-Ce6-Pt, can induce remarkable tumor cells apoptosis and ferroptosis. Importantly, a simple loading method and the use of Food Drug Administration (FDA)-approved materials make PPB-Ce6-Pt have great potential for practical applications. STATEMENT OF SIGNIFICANCE: The antioxidant system in tumor cells disables ROS-mediated tumor therapy. Besides, extensive attempts aim at depleting GSH without considering their regeneration. Therefore, we developed a synergetic strategy to attenuate intracellular antioxidant capacity for hypoxic tumor therapy. PPB-Ce6-Pt nanoplatform could not only directly reduce GSH levels but also deplete NADPH by peroxidase-mimicking to impair GSH regeneration. In addition, PPB-Ce6-Pt nanoplatform could catalyze H2O2 decomposition to alleviate tumor hypoxia, thus reducing the generation of GSH and boosting 1O2 production by Chlorin e6 (Ce6) for increasing oxidative damage. Then, intracellular ROS boost and redox dyshomeostasis induced remarkable tumor cells apoptosis and ferroptosis. Importantly, a simple loading method and the use of biosafety materials made the nanoplatform have great potential for practical applications.

Controlled sequential in situ self-assembly and disassembly of a fluorogenic cisplatin prodrug for cancer theranostics

Temporal control of delivery and release of drugs in tumors are important in improving therapeutic outcomes to patients. Here, we report a sequential stimuli-triggered in situ self-assembly and disassembly strategy to direct delivery and release of theranostic drugs in vivo. Using cisplatin as a model anticancer drug, we design a stimuli-responsive small-molecule cisplatin prodrug (P-CyPt), which undergoes extracellular alkaline phosphatase-triggered in situ self-assembly and succeeding intracellular glutathione-triggered disassembly process, allowing to enhance accumulation and elicit burst release of cisplatin in tumor cells. Compared with cisplatin, P-CyPt greatly improves antitumor efficacy while mitigates off-target toxicity in mice with subcutaneous HeLa tumors and orthotopic HepG2 liver tumors after systemic administration. Moreover, P-CyPt also produces activated near-infrared fluorescence (at 710 nm) and dual photoacoustic imaging signals (at 700 and 750 nm), permitting high sensitivity and spatial-resolution delineation of tumor foci and real-time monitoring of drug delivery and release in vivo. This strategy leverages the advantages offered by in situ self-assembly with those of intracellular disassembly, which may act as a general platform for the design of prodrugs capable of improving drug delivery for cancer theranostics.

Nanoporous Silica Nanoparticles Coloaded with Cisplatin Prodrug and l-Buthionine Sulfoximine for Cancer Therapy

Intracellular glutathione (GSH) is critical for cisplatin-resistant cancers by maintaining the redox balance. Amplifying the intracellular oxidative stress by disrupting the redox balance is an effective method for the treatment of cancers. Therefore, we design a mesoporous silica (MS) nanosystem coated by hyaluronic acid (HA) to codeliver l-buthionine sulfoximine (BSO) and cisplatin prodrug (DSCP) (defined as Pt/BSO-MS-HA). The intracellular GSH could react with DSCP in Pt/BSO-MS-HA, which could release free cisplatin for chemotherapy, and the BSO block the synthesis of GSH, leading to GSH depletion and disrupting the redox balance. Moreover, HA provides homotypic binding capacities and superior immune evasion, which significantly enhance the cell uptake of Pt/BSO-MS-HA and tumor accumulation. In in vivo studies, Pt/BSO-MS-HA could efficiently inhibit tumor growth and showed no obvious side effects. Our study provides an effective strategy to develop biocompatible drug delivery nanosystem by disrupting the redox balance in cancer cells, which significantly increase the therapeutic efficiency of cancer chemotherapy.

Nanomedicines with high drug availability and drug sensitivity overcome hypoxia-associated drug resistance

Tumor hypoxia heterogeneity, a hallmark of the tumor microenvironment, confers resistance to conventional chemotherapy due to insufficient drug availability and drug sensitivity in hypoxic regions. To overcome these challenges, we develope a nanomedicine, NPHPaPN, constructed with hyaluronic acid (HA) grafted with cisplatin prodrug and PEG-azobenzene for hypoxia-responsive PEG shell deshielding and loaded with a DNA damage repair inhibitor (NERi). After arriving at the tumor site, NPHPaPN deshields the PEG shell in response to hypoxia due to the enzymolysis of azobenzene and thus exposes HA. The exposed HA binds to the highly expressed CD44 on cisplatin-resistant tumor cells and mediates drug internalization, thus increasing drug availability to hypoxic tumor cells. After intracellular hyaluronidase-mediated cleavage, the HA NPs release the cisplatin prodrug and NERi, and cause enhanced DNA damage and consequent cell death, thus enhancing the drug sensitivity of hypoxic tumor cells. Eventually, NPHPaPN achieves distinct tumor growth suppression with an ∼84.4% inhibition rate.

Platin-C containing nanoparticles: a recipe for the delivery of curcumin-cisplatin combination chemotherapeutics to mitochondria.

The success story of cisplatin spans over six decades now and yet it continues to be the key player in most chemotherapeutic regimens. Numerous efforts have been made to improve its efficacy, address its shortcomings, and overcome drug resistance. One such strategy is to develop new platinum(IV)-based prodrugs with functionally active ligands to deliver combination therapeutics. This strategy not only enables the drug candidate to access multiple drug targets but also enhances the kinetic inertness of platinum complexes and thereby ensures greater accumulation of active drugs at the target site. We report the synthesis of Platin-C, a platinum(IV)-based cisplatin prodrug tethered to the active component of ancient herbal medicine, curcumin, as one of the axial ligands. This combination complex showed improved chemotherapeutic efficacy in cisplatin resistant A2780/CP70 cell lines compared with the individual components. An amine-terminated biodegradable polymer was suitably functionalized with the triphenylphosphonium (TPP) cation to obtain a mitochondria-directed drug delivery platform. Quantification of Platin-C loading into these NPs using complementary techniques employing curcumin optical properties in high-performance liquid chromatography and platinum-based inductively coupled plasma mass spectrometry evidenced efficacious payload incorporation resulting in functional activities of both the components. Stability studies for a period of one week indicated that the NPs remain stable, enabling substantial loading and controlled release of the prodrug. The targeting nanoparticle (NP) platform was utilized to deliver Platin-C primarily in the mitochondrial network of cancer cells as monitored using confocal microscopy employing the green fluorescence of the curcumin pendant. Our studies showed that amine terminated NPs were relatively less efficient in their ability to target mitochondria despite being positively charged. This re-validated the importance of lipophilic positively charged TPP surface functionalities to successfully target cellular mitochondria. We validated the capabilities of Platin-C and its mitochondria-targeting nanoparticles towards inflicting mitochondria-directed activity in cisplatin-sensitive and cisplatin-resistant cell lines. Furthermore, our studies also demonstrated the effectiveness of Platin-C incorporated targeting NPs in attenuating cellular inflammatory markers by utilizing the curcumin component. This study advances our understanding of the cisplatin prodrug approach to combine chemotherapeutic and inflammatory effects in accessing combinatory pathways.

Cancer cell membrane biomimetic mesoporous silica nanotheranostics for enhanced Ferroptosis-mediated immuogenic cell death on Gastric cancer

Selective induction of ferroptosis of cancer cells would be a promising approach to trigger immunogenic cell death (ICD) and sequentially potentiate immunotherapy. Actually, the efficiency to produce toxic lipid peroxides (LPO) and deplete glutathione (GSH) at the tumor site plays a key role in inducing ferroptosis. Herein, a cancer targeted cascade nanosystem (CCM@Mn@MSN-Pt(IV), CMnMPt) was constructed for synergistic chemo-dynamic and chemotherapy by conjugating Mn ions-doped mesoporous silica nanoparticles (Mn@MSN) and cisplatin prodrug (Pt(IV)), with cancer cell membrane cloaking. Owing to the bio-mimetic surface functionalization, the immune escape and homologous targeting behaviors of CMnMPt would dramatically enhance its cancer targeting and retention abilities. Once internalized by cancer cells, intracellular GSH would be depleted attributed to the bio-degradation of Mn@MSN and reduced of Pt(IV), resulting in Mn2+ release and cisplatin transform (from Pt(IV) to Pt(II)). Subsequently, generated Pt(II)) could damage nuclear DNA, and further activate nicotinamide adenine dinucleotide phosphate oxidases (NOXs) to enhance downstream H2O2 levels. Additionally, Mn2+ ions could catalyze H2O2 into highly reactive hydroxyl radical (OH), which results in a further increase in LPO content. In summary, CMnMPt could induce ferroptosis-mediated ICD, and recruit cytotoxic T lymphocytes cells, offering potential clinical applications to facilitate anti-tumor immunotherapy.

Berplatin: A Conjugate of Berberine and Cisplatin Serving as a Potent Antitumor Agent with Distinctive Tumor Cell Uptake and Minimal Side Effects

AbstractDesign of Pt(IV) prodrugs with biologically active axial ligands is an excellent approach to overcome the disadvantages (nonspecific killing, side effects, and drug resistance) of conventional first‐line Pt(II)‐based chemotherapeutic drugs, such as cisplatin, carboplatin and oxaliplatin. The selection of ideal axial ligands is essential for the success of Pt(IV) drugs. Previously, that berberine exhibits great superiority in tumor selectivity is found with uncovered mechanisms. In this study, that berberine is specifically internalized and accumulated in tumors but not normal cells through endocytosis pathways is first disclosed. Therefore a new Pt(IV) prodrug of cisplatin bearing berberine as an axial ligand, named berplatin, is designed and synthesized. Different from cisplatin, berplatin can be effectively and selectively internalized into cancer cells, through macropinocytosis and caveolin‐1 (CAV‐1)‐dependent active endocytosis, and cleaved in intracellular reductive environments to generate cisplatin and berberine, which synergistically induces substantial DNA breaking, apoptosis and cell cycle arrest in both cisplatin‐sensitive and ‐resistant cancer cells. In vivo, berplatin manifests much higher antitumor activity and undetectable side effects compared to cisplatin. This study demonstrates that berplatin can serve as a potent Pt(IV) prodrug for the treatment of cisplatin‐sensitive and ‐resistant cancers with active uptake, excellent specificity, and minimal side effects.

A Pt(IV)-conjugated brain penetrant macrocyclic peptide shows pre-clinical efficacy in glioblastoma.

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, with a median survival of approximately 15months. Treatment is limited by the blood-brain barrier (BBB) which restricts the passage of most drugs to the brain. We previously reported the design and synthesis of a BBB-penetrant macrocyclic cell-penetrating peptide conjugate (M13) covalently linked at the axial position of a Pt(IV) cisplatin prodrug. Here we show the Pt(IV)-M13 conjugate releases active cisplatin upon intracellular reduction and effects potent in vitro GBM cell killing. Pt(IV)-M13 significantly increased platinum uptake in an in vitro BBB spheroid model and intravenous administration of Pt(IV)-M13 in GBM tumor-bearing mice led to higher platinum levels in brain tissue and intratumorally compared with cisplatin. Pt(IV)-M13 administration was tolerated in naïve nude mice at higher dosage regimes than cisplatin and significantly extended survival above controls in a murine GBM xenograft model (median survival 33days for Pt(IV)-M13 vs 24days for Pt(IV) prodrug, 22.5days for cisplatin and 22days for control). Increased numbers of γH2AX nuclear foci, biomarkers of DNA damage, were observed in tumors of Pt(IV)-M13-treated mice, consistent with elevated platinum levels. The present work provides the first demonstration that systemic injection of a Pt(IV) complex conjugated to a brain-penetrant macrocyclic peptide can lead to increased platinum levels in the brain and extend survival in mouse GBM models, supporting further development of this approach and the utility of brain-penetrating macrocyclic peptide conjugates for delivering non-BBB penetrant drugs to the central nervous system.

Specific disruption of glutathione-defense system with activatable single molecule-assembled nanoprodrug for boosted photodynamic/chemotherapy eradication of drug-resistant tumors

Developing single molecule-assembled nanoprodrugs that can reverse the glutathione (GSH)–mediated drug resistance of tumors provides promising potentials for precision and effective cancer theranostics. Herein, we developed a novel single molecule-assembled nanoprodrug for effective photodynamic/chemotherapeutic eradication of drug-resistant tumors via the multistage GSH-depletion. The nanoprodrug MSSP-NP could be fancily fabricated by self-assembly of an amphiphilic activatable molecular MSSP, which is synthesized by covalently conjugating the photosensitizer methylene blue (MB) with a GSH-sensitive cisplatin prodrug via a tumor targeting thiolated polypeptide. Upon the nanoprodrug MSSP-NP systematic administrated, its photoactivities and pharmacological effects can be thoroughly switched on by intracellular GSH to produce the photosensitizer MB and chemotherapeutic drug cisplatin, along with the multi-step consumption of GSH, which could remarkably boost oxidative stress and reverse the drug resistance. As a result, the nanoprodrug could effectively disrupt the tumor GSH-defense system to afford high-efficiency photodynamic/chemotherapeutic inhibition of drug resistance tumors (96.4%) with minimum side effects.

Conquering Cancer Multi-Drug Resistance Using Curcumin and Cisplatin Prodrug-Encapsulated Mesoporous Silica Nanoparticles for Synergistic Chemo- and Photodynamic Therapies.

Recently, the development of anti-cancer approaches using different physical or chemical pathways has shifted from monotherapy to synergistic therapy, which can enhance therapeutic effects. As a result, enormous efforts have been devoted to developing various delivery systems encapsulated with dual agents for synergistic effects and to combat cancer cells acquired drug resistance. In this study, we show how to make Institute of Bioengineering and Nanotechnology (IBN)-1-based mesoporous silica nanoparticles (MSNs) for multifunctional drug delivery to overcome drug resistance cancer therapy. Initially, curcumin (Cur)-embedded IBN-1 nanocomposites (IBN-1-Cur) are synthesized in a simple one-pot co-condensation and then immobilized with the prodrug of Cisplatin (CP) on the carboxylate-modified surface (IBN-1-Cur-CP) to achieve photodynamic therapy (PDT) and chemotherapy in one platform, respectively, in the fight against multidrug resistance (MDR) of MES-SA/DX5 cancer cells. The Pluronic F127 triblock copolymer, as the structure-directing agent, in nanoparticles acts as a p-glycoprotein (p-gp) inhibitor. These designed hybrid nanocomposites with excellent structural properties are efficiently internalized by the endocytosis and successfully deliver Cur and CP molecules into the cytosol. Furthermore, the presence of Cur photosensitizer in the nanochannels of MSNs resulted in increased levels of cellular reactive oxygen species (ROS) under light irradiation. Thus, IBN-1-Cur-CP showed excellent anti-cancer therapy in the face of MES-SA/DX5 resistance cancer cells, owing to the synergistic effects of chemo- and photodynamic treatment.

The induction of PANoptosis in KRAS-mutant pancreatic ductal adenocarcinoma cells by a multispecific platinum complex

Oncogenic KRAS reprograms pancreatic ductal adenocarcinoma (PDAC) cells to a state that is awfully resistant to apoptosis. An alternative coping strategy is to trigger a nonapoptotic cell death. Herein, a multi specific platinum complex SEP was constructed by conjugating a quinone derivative seratrodast to a prodrug of cisplatin. Interestingly, SEP-treated KRAS-mutant PDAC cells showed the characteristics of pyroptosis, apoptosis and necroptosis, similar to PANoptosis (a newfound inflammatory cell death). Mechanistically, SEP could enter cancer cells effectively, then damage nuclear DNA, boost mitochondrial superoxide anion radicals and affect various signaling pathways related to redox homeostasis and tumor metabolism. To our best knowledge, SEP is the first metal complex, even small molecule, to elicit PANoptosis (pyroptosis, apoptosis and necroptosis) in cancer cells, providing a new strategy to overcome apoptotic resistance of KRAS-mutant PDAC.

Preparation of cisplatin delivery calcium phosphate nanoparticles using poly(Pt(IV) prodrug) as the payload

Directly encapsulating cisplatin in calcium phosphate nanoparticles (CPNPs) is a challenge because of the low water-solubility and weak binding affinity with calcium phosphate (CaP) of the cisplatin. In this work, we present a unique strategy using a polymer (poly(Pt(IV) prodrug)) bearing numerous carboxyl side groups and incorporating redox-sensitive cisplatin Pt(IV) prodrugs in its backbone as the payload for encapsulation in CPNPs. The poly(Pt(IV) prodrug) was efficiently encapsulated in CPNPs (>90 %), attributing to its improved solubility in alkaline water and strong binding affinity with CaP deriving from the plenty of carboxyl side groups. The CPNPs were stable and almost entirely inhibited the premature release of platinum drugs in the medium mimicking the pH condition of the bloodstream, whether there were reduction agents or not. While in an acidic condition with reduction agents, they released platinum drugs rapidly due to simultaneous reduction and hydrolysis of the poly(Pt(IV) prodrug). Further bioactivity experiments demonstrated the poly(Pt(IV) prodrug) encapsulated CPNPs were of higher efficacy against cancerous cells than free cisplatin and poly(Pt(IV) prodrug) owing to the enhanced platinum drugs uptake by cancerous cells via the CPNPs.

Targeted chemo-photodynamic therapy toward esophageal cancer by GSH-sensitive theranostic nanoplatform

As the sixth leading cause of cancer death, esophageal cancer is threatening the life of people worldwide. Traditional treatments, such as surgery, chemotherapy, radiotherapy, are facing always augmented challenges including invasion, multidrug resistance (MDR), off-target toxicity. Chemo & Photodynamic synergistic therapy represents one promising strategy for improved treatment efficiency. But it is still hindered by the lack of tumor targeting, deleterious side effects, and unfavorable microenvironment for photodynamic therapy (PDT). To overcome those obstacles, one theranostic nano-assambly drug, GCDs-Ce6/Pt-EGF, was designed and fabricated. Green fluorescence carbon dots (GCDs) with the excellent optical properties, modifiability and low toxicity were prepared as drug carrier. Epidermal growth factor (EGF) was conjugated to the nano-assembly to realize tumor specific targeting. Chlorin e6 (Ce6) in the presence of laser irradiation achieved PDT by generating proapoptosis reactive oxygen species (ROS). Moreover, Ce6 incorporated into GCDs endowed the nano-assambly imaging ability and facilitate image-guided therapy. Pt(IV), cisplatin prodrug, in the nano-assambly depleted the glutathione (GSH) of tumor microenvironment when it was reduced to cytotoxicity Pt(II). Compared with single treatment, GCDs-Ce6/Pt-EGF exhibited enhanced tumor cell killing capacity and better biosafety in vitro and in vivo, especially for EGFR bearing tumor. It paved ways for developing novel theranostic agent to be potentially applied in clinic.

CuS Nanoparticles-Loaded and Cisplatin Prodrug Conjugated Fe(III)-MOFs for MRI-Guided Combination of Chemotherapy and NIR-II Photothermal Therapy.

Ovarian cancer has become an urgent threat to global female healthcare. Cisplatin, as the traditional chemotherapeutic agent against ovarian cancer, retains several limitations, such as drug resistance and dose-limiting toxicity. In order to solve the above problems and promote the therapeutic effect of chemotherapy, combining chemotherapy and phototherapy has aroused wide interest. In this study, we constructed a versatile cisplatin prodrug-conjugated therapeutic platform based on ultrasmall CuS-modified Fe(III)-metal-organic frameworks (MIL-88) (named M-Pt/PEG-CuS) for tumor-specific enhanced synergistic chemo-/phototherapy. After intravenous injection, M-Pt/PEG-CuS presented obvious accumulation in tumor and Fe(III)-MOFs possessed magnetic resonance imaging (MRI) to guide synergy therapy. Both in vitro and in vivo experimental results showed that M-Pt/PEG-CuS could not only successfully inhibit tumor growth by combining chemotherapy and NIR-II PTT but also avoid the generation of liver damage by the direct treatment of cisplatin(II). Our work presented the development of the nanoplatform as a novel NIR-II photothermal agent, as well as gave a unique combined chemo-photothermal therapy strategy, which might provide new ways of ovarian cancer therapy for clinical translation.

Ferrous ions doped calcium carbonate nanoparticles potentiate chemotherapy by inducing ferroptosis.

Ferroptosis is a recently identified regulated cell death pathway featured in iron prompted lipid peroxidation inside cells and found to be an effective approach to suppress tumor growth. Motived by the high efficacy of ferrous ions (Fe2+) in initiating intracellular lipid peroxidation via the Fenton reaction, this study herein prepares a pH-responsive Fe2+ delivery nanocarrier by coating calcium carbonate (CaCO3) nanoparticles with a metal-polyphenol coordination polymer composed of gallic acid (GA) and Fe2+. Together with simultaneous encapsulation of succinic acid conjugated cisplatin prodrugs (Pt(IV)-SA) and Fe2+, the yielded nanoparticles, coined as PGFCaCO3, are synthesized and exhibit uniform hollow structure. After PEGylation, the resulted PGFCaCO3-PEG shows increased physiological stability and pH-dependent decomposition, drug release and catalytic capability in initiating lipid peroxidation. After being endocytosed, PGFCaCO3-PEG effectively promoted intracellular generation of cytotoxic reactive oxygen species including lipid peroxide, thereby exhibited superior inhibition effect towards both murine 4T1 and CT26 cancer cells over Pt(IV)-SA and GFCaCO3-PEG. As a result, treatment with systemic administration of PGFCaCO3-PEG effectively suppressed 4T1 tumor growth via combined Fe2+ initiated ferroptosis and Pt(IV)-SA mediated chemotherapy. This work highlights that intracellular delivery of Fe2+ is a robust approach to enhance tumor chemotherapy by inducing ferroptosis.