Dual-Targeted Zeolitic Imidazolate Frameworks Drug Delivery System Reversing Cisplatin Resistance to Treat Resistant Ovarian Cancer.

Objective: Ovarian cancer cells are prone to acquire tolerance to chemotherapeutic agents, which seriously affects clinical outcomes. The development of novel strategies to enhance the targeting of chemotherapeutic agents to overcome drug resistance and minimize side effects is significant for improving the clinical outcomes of ovarian cancer patients. Methods: We employed folic acid (FA)-modified ZIF-90 nanomaterials (FA-ZIF-90) to deliver the chemotherapeutic drug, cisplatin (DDP), via dual targeting to improve its targeting to circumvent cisplatin resistance in ovarian cancer cells, especially by targeting mitochondria. FA-ZIF-90/DDP could rapidly release DDP in response to dual stimulation of acidity and ATP in tumor cells. Results: FA-ZIF-90/DDP showed good blood compatibility. It was efficiently taken up by human ovarian cancer cisplatin-resistant cells A2780/DDP and aggregated in the mitochondrial region. FA-ZIF-90/DDP significantly inhibited the mitochondrial activity and metastatic ability of A2780/DDP cells. In addition, it effectively induced apoptosis in A2780/DDP cells and overcame cisplatin resistance. In vivo experiments showed that FA-ZIF-90/DDP increased the accumulation of DDP in tumor tissues and significantly inhibited tumor growth. Conclusion: FA-modified ZIF-90 nanocarriers can improve the tumor targeting and anti-tumor effects of chemotherapeutic drugs, reduce toxic side effects, and are expected to be a novel therapeutic strategy to reverse drug resistance in ovarian cancer.

The therapeutic effect and MR molecular imaging of FA-PEG-FePt/DDP nanoliposomes in AMF on ovarian cancer.

Purpose: This study aimed to construct targeting drug-loading nanocomposites (FA-FePt/DDP nanoliposomes) to explore their potential in ovarian cancer therapy and molecular magnetic resonance imaging (MMRI). Methods: FA-FePt-NPs were prepared by coupling folate (FA) with polyethylene-glycol (PEG)-coated ferroplatinum nanoparticles and characterized. Then cisplatin (DDP) was encapsulated in FA-FePt-NPs to synthesize FA-PEG-FePt/DDP nanoliposomes by thin film-ultrasonic method and high-speed stirring, of which MMRI potential, magnetothermal effect, and the other involved performance were analyzed. The therapeutic effect of FA-FePt/DDP nanoliposomes combined with magnetic fluid hyperthermia (MFH) on ovarian cancer in vitro and in vivo was evaluated. The expression levels of Bax and epithelial-mesenchymal transition related proteins were detected. The biosafety was also preliminarily observed. Results: The average diameter of FA-FePt-NPs was about 30 nm, FA-FePt/DDP nanoliposomes were about 70 nm in hydrated particle size, with drug slow-release and good cell-specific targeted uptake. In an alternating magnetic field (AMF), FA-FePt/DDP nanoliposomes could rapidly reach the ideal tumor hyperthermia temperature (42~44 °C). MRI scan showed that FA-FePt-NPs and FA-FePt/DDP nanoliposomes both could suppress the T2 signal, indicating a good potential for MMRI. The in vitro and in vivo experiments showed that FA-FePt/DDP-NPs in AMF could effectively inhibit the growth of ovarian cancer by inhibiting cancer cell proliferation, invasion, and migration, and inducing cancer cell apoptosis, much better than that of the other individual therapies; molecularly, E-cadherin and Bax proteins in ovarian cancer cells and tissues were significantly increased, while N-cadherin, Vimentin, and Bcl-2 proteins were inhibited, effectively inhibiting the malignant progression of ovarian cancer. In addition, no significant pathological injury and dysfunction was observed in major visceras. Conclusion: We successfully synthesized FA-FePt/DDP nanoliposomes and confirmed their good thermochemotherapeutic effect in AMF and MMRI potential on ovarian cancer, with no obvious side effects, providing a favorable strategy of integrated targeting therapy and diagnosis for ovarian cancer.

Dual encapsulation and sequential release of cisplatin and vitamin E from soy polysaccharides and ß-cyclodextrin bioadhesive hydrogel nanoparticles.

Chemically cross-linked hydrogel nanoparticles (HGNPs) offer enhanced properties over their physical counterparts, particularly in drug delivery and cell encapsulation. This study applied pH-thermal dual responsive bio-adhesive HGNPs for dual complexation and enhanced the controlled release and bioavailability of cisplatin (CDDP) and Vitamin E (VE) drugs. The CDDP was loaded into the HGNPs via chemical conjugation with the carboxyl groups in the HGNPs surface by soy polysaccharides (SSPS). At the same time, the host-guest interaction complexed the VE through the ß-cyclodextrin (ß-CD). The HGNPs showed a uniform HGNPs size distribution of 90.77 ± 14.77 nm and 81.425 ± 13.21 nm before and after complexation, respectively. The FTIR, XRD, XPS, and zeta potential confirmed the conjugation. The cumulative release percent of CDDP reached 98 % at pH 1.2, while <45 % was released at pH 7.4. Our HGNPs enhance the incorporation of CDDP by substituting its chlorides with carboxyl groups of the SSPS; the loading of CDDP and VE was 15 ± 0.33 and 11.32 ± 0.25 wt%, respectively. Moreover, the CDDP and VE also released slower from the HGNPs at 25 °C than at 37 °C and 42 °C. The (VE/CDDP)-loaded HGNPs exhibited longer circulation time in vivo than free CDDP and free VE suspension.

pH-Triggered Transformable Peptide Nanocarriers Extend Drug Retention for Breast Cancer Combination Therapy.

Increasing the penetration and accumulation of antitumor drugs at the tumor site are crucial in chemotherapy. Smaller drug-loaded nanoparticles (NPs) typically exhibit increased tumor penetration and more effective permeation through the nuclear membrane, whereas larger drug-loaded NPs show extended retention at the tumor site. In addition, cancer stem cells (CSCs) have unlimited proliferative potential and are crucial for the onset, progression, and metastasis of cancer. Therefore, a drug-loaded amphiphilic peptide, DDP- and ATRA-loaded Pep1 (DA/Pep1), is designed that self-assembles into spherical NPs upon the encapsulation of cis-diamminedichloroplatinum (DDP) and all-trans retinoic acid (ATRA). In an acidic environment, DA/Pep1 transforms into aggregates containing sheet-like structures, which significantly increases drug accumulation at the tumor site, thereby increasing antitumor effects and inhibiting metastasis. Moreover, although DDP treatment can increase the number of CSCs present, ATRA can induce the differentiation of CSCs in breast cancer to increase the therapeutic effect of DDP. In conclusion, this peptide nanodelivery system that transforms in response to the acidic tumor microenvironment is an extremely promising nanoplatform that suggests a new idea for the combined treatment of tumors.

Use of Sodium Thiosulfate as an Otoprotectant in Patients With Cancer Treated With Platinum Compounds: A Review of the Literature.

PURPOSE: Hearing loss occurs in 50%-70% of children treated with cisplatin. Scientific efforts have led to the recent approval of a pediatric formula of intravenous sodium thiosulfate (STS) for otoprotection by the US Food and Drug Administration, the European Medicines Agency, and the Medicines and Health Regulatory Authority in the United Kingdom. To inform stakeholders regarding the clinical utility of STS, the current review summarizes available literature on the efficacy, pharmacokinetics (PK), and safety of systemic STS to minimize cisplatin-induced hearing loss (CIHL). DESIGN: A comprehensive narrative review is presented. RESULTS: Thirty-one articles were summarized. Overall, systemic STS effectively reduces CIHL in the preclinical and controlled clinical study settings, in both adults and children with cancer. The extent of CIHL reduction depends on the timing and dosing of STS in relation to cisplatin. Both preclinical and clinical data suggest that systemic STS may affect plasma platinum levels, but studies are inconclusive. Delayed systemic administration of STS, at 6 hours after the cisplatin infusion, does not affect cisplatin-induced inhibition of tumor growth or cellular cytotoxicity in the preclinical setting, nor affect cisplatin efficacy and survival in children with localized disease in the clinical setting. CONCLUSION: Systemic administration of STS effectively reduces the development and degree of CIHL in both the preclinical and clinical settings. More studies are needed on the PK of STS and cisplatin drug combinations, the efficacy and safety of STS in patients with disseminated disease, and the ability of STS to prevent further deterioration of pre-established hearing loss.

Holographically Activatable Nanoprobe via Glutathione/Albumin-Mediated Exponential Signal Amplification for High-Contrast Tumor Imaging.

Glutathione (GSH)-activatable probes hold great promise for in vivo cancer imaging, but are restricted by their dependence on non-selective intracellular GSH enrichment and uncontrollable background noise. Here, a holographically activatable nanoprobe caging manganese tetraoxide is shown for tumor-selective contrast enhancement in magnetic resonance imaging (MRI) through cooperative GSH/albumin-mediated cascade signal amplification in tumors and rapid elimination in normal tissues. Once targeting tumors, the endocytosed nanoprobe effectively senses the lysosomal microenvironment to undergo instantaneous decomposition into Mn2+ with threshold GSH concentration of ≈ 0.12 mm for brightening MRI signals, thus achieving high contrast tumor imaging and flexible monitoring of GSH-relevant cisplatin resistance during chemotherapy. Upon efficient up-regulation of extracellular GSH in tumor via exogenous injection, the relaxivity-silent interstitial nanoprobe remarkably evolves into Mn2+ that are further captured/retained and re-activated into ultrahigh-relaxivity-capable complex by stromal albumin in the tumor, and simultaneously allows the renal clearance of off-targeted nanoprobe in the form of Mn2+ via lymphatic vessels for suppressing background noise to distinguish tiny liver metastasis. These findings demonstrate the concept of holographic tumor activation via both tumor GSH/albumin-mediated cascade signal amplification and simultaneous background suppression for precise tumor malignancy detection, surveillance, and surgical guidance.

A phase I trial of lurbinectedin in combination with cisplatin in patients with advanced solid tumors.

Background In vitro/in vivo data showed synergism of cisplatin and lurbinectedin in ovarian cancer cells and grafts. This phase I trial investigated the recommended phase II dose (RD) of cisplatin and lurbinectedin combination, with (Group A) or without aprepitant (Group B), in patients with advanced solid tumors. Patients and Methods All patients received 60 mg/m2 cisplatin 90-min intravenous (i.v.) infusion followed by lurbinectedin 60-min i.v. infusion at escalating doses on Day 1 every 3 weeks (q3wk). Patients in Group A additionally received orally 125 mg aprepitant one hour before cisplatin on Day 1 and 80 mg on Days 2 and 3. Toxicity was graded according to the NCI-CTCAE v.4. Results RD for Group A was cisplatin 60 mg/m2 plus lurbinectedin 1.1 mg/m2. RD for Group B was cisplatin 60 mg/m2 plus lurbinectedin 1.4 mg/m2. The most frequent grade ≥ 3 adverse events were hematological [neutropenia (41%), lymphopenia (35%), leukopenia (24%), thrombocytopenia (18%)] and fatigue (35%) in Group A (n = 17), and neutropenia (50%), leukopenia (42%), lymphopenia (29%), and fatigue (13%) and nausea (8%) in Group B (n = 24). Four patients (2 in each group) had a partial response. Disease stabilization for ≥ 4 months was observed in 4 and 10 patients, respectively. Conclusion The combination of lurbinectedin with cisplatin was not possible in meaningful therapeutic dosage due to toxicity. The addition of aprepitant in combination with cisplatin did not allow increasing the dose due to hematological toxicity, whereas omitting aprepitant increased the incidence of nausea and vomiting. Modest clinical activity was observed in general.Clinical trial registration www.ClinicalTrials.gov code: NCT01980667. Date of registration: 11 November 2013.

Genistein interferes with antitumor effects of cisplatin in an ovariectomized breast cancer xenograft tumor model.

Genistein (GEN) has been demonstrated to interfere with antitumor effects of cisplatin (CIS) in vitro. To analyze whether these findings are also relevant in vivo, we examined the effects of combined GEN and CIS treatment in an ovariectomized nude mouse breast cancer xenograft model. Tumor growth and markers for antitumor activity were determined after three weeks of treatment. Furthermore, the concentrations of GEN metabolites were measured in serum, liver, and xenograft tumor tissues using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Three weeks' oral exposure to GEN at a dose of 5 mg kg-1·d-1 resulted in an average concentration of total GEN metabolite equivalent as high as 0.2729 nmol g-1 wet weight in xenograft tumor tissues. At this dosage, GEN significantly antagonized the antitumor effects of CIS. Mechanistically, GEN blocked both the inhibition of cell proliferation and induction of apoptosis triggered by CIS. Moreover, GEN concentrations in xenograft tumor tissues were found to be significantly higher than in serum and liver. In conclusion, our findings suggested that oral GEN exposure at a level comparable to dietary exposure in humans could interfere with CIS chemotherapy.

The association of cisplatin pharmacokinetics and skeletal muscle mass in patients with head and neck cancer: The prospective PLATISMA study.

BACKGROUND: Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with cisplatin-based chemoradiotherapy (CRT). Cisplatin is associated with severe toxicity, which negatively affects survival. In recent years, a relationship between low skeletal muscle mass (SMM) and increased toxicity has been described. This increased toxicity may be related to altered cisplatin distribution and binding in the fat-free body mass of which SMM is the largest contributor. This study aims to investigate the association between cisplatin pharmacokinetics and SMM in patients with HNSCC. METHODS: We performed a prospective observational study in patients with HNSCC treated with CRT. Patients received standard-of-care chemotherapy with three cycles of cisplatin at a dose of 100 mg/m2 per cycle. Quantitative data on SMM, measured on computed tomography scans and cisplatin pharmacokinetics (total and ultrafilterable plasma concentrations) were collected, as well as data on toxicity. RESULTS: A total of 45 evaluable patients were included in the study. A large proportion of the study population had a low SMM (46.7%). The majority of patients (57.8%) experienced cisplatin dose-limiting toxicities. Pharmacokinetic analysis showed a significant relationship between cisplatin pharmacokinetics and SMM, weight, fat-free mass and body surface area (p < 0.005). In a simulation, patients with a low SMM (<25.8 kg) were predicted to reach higher-bound cisplatin concentrations. CONCLUSION: We found an association between cisplatin pharmacokinetics and SMM; however, this relationship was also seen between cisplatin pharmacokinetics and other body composition descriptors.

Attomole-per Cell Atomic Mass Spectrometry Measurement of Platinum and Gold Drugs in Cultured Lung Cancer Cells.

In this study, we developed a strategy to determine atto- and femtomolar amounts of metal ions in lysates and mineralizates of cells (human non-small-cell lung carcinoma (NSCLC, A549) and normal lung (MRC-5)) exposed to cytotoxic metallo-drugs: cisplatin and auranofin at concentrations close to the half-maximal inhibitory drug concentrations (IC50). The developed strategy combines data obtained using biological and chemical approaches. Cell density was determined using two independent cell staining assays using trypan blue, calcein AM/propidium iodide. Metal concentrations in lysed and mineralized cells were established employing a mass spectrometer with inductively coupled plasma (ICP-MS) and equipped with a cross-flow nebulizer working in aspiration mode. It allowed for detecting of less than 1 fg of metal per cell. To decrease the required amount of sample material (from 1.5 mL to ~100 µL) without loss of sensitivity, the sample was introduced as a narrow band into a constant stream of liquid (flow-injection analysis). It was noticed that the selectivity of cisplatin accumulation by cells depends on the incubation time. This complex is accumulated by cells at a lower efficiency than auranofin and is found primarily in the lysate representing the cytosol. In contrast, auranofin interacts with water-insoluble compounds. Despite their different mechanism of action, both metallo-drugs increased the accumulation of transition metal ions responsible for oxidative stress.

Co-delivery of gemcitabine and cisplatin via Poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) micelle to improve the in vivo stability and antitumor effect.

PURPOSE: The intention of the study was to co-delivery gemcitabine and cisplatin with totally different nature by prodrug and micelle strategy to improve its in vivo stability and antitumor effect. METHODS: A prodrug of gemcitabine (mPEG-PLG-GEM) was synthesized through the covalent conjugation between the primary amino group of gemcitabine and the carboxylic group of poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) (mPEG-PLG). It was prepared into micelles by a solvent diffusion method, and then combined with cisplatin through chelation to prepare gemcitabine and cisplatin co-loaded mPEG-PLG micelles (mPEG-PLG-GEM@CDDP micelles). RESULTS: Gemcitabine and cisplatin in each micelle group were released more slowly than in solutions. In addition, pharmacokinetics behaviors of them were improved after encapsulated in prodrug micelles. T1/2z of gemcitabine and cisplatin encapsulated in micelles were prolonged to 6.357 h (mPEG-PLG-GEM), 10.490 h (mPEG-PLG@CDDP), 5.463 h and 12.540 h (mPEG-PLG-GEM@CDDP) compared with GEM@CDDP solutions (T1/2z = 1.445 h and 7.740 h). The ratio of synergy between gemcitabine and cisplatin (3:1 ~ 1:1(n/n)) was guaranteed in the systemic circulation, thus improving its antitumor effect. The results of biochemical analysis showed that GEM@CDDP-Sol was more toxic to kidneys and marrow compared with mPEG-PLG-GEM@CDDP micelles. CONCLUSIONS: By prodrug strategy, gemcitabine and cisplatin with totally different nature were prepared into micelles and obtained a better pharmacokinetic behavior. And the dual drug delivery system performed a better in vivo stability and antitumor effect compared with each single drug delivery system in the experiment. Scheme. Schematic of mPEG-PLG-GEM@CDDP micelles' formation and action process.

Silmitasertib-induced macropinocytosis promoting DDP intracellular uptake to enhance cell apoptosis in oral squamous cell carcinoma.

Cisplatin (DDP) is a first-line chemotherapeutic drug applied for the treatment of oral squamous cell carcinoma (OSCC). The anticancer activity of DDP is tightly linked to its intracellular uptake. It is unwise to increase the DDP intake by increasing the dose or shortening the dosing interval because of the severe systemic toxicity (nephrotoxicity, ototoxicity and neurotoxicity) in DDP application. The main uptake pathways of DDP include passive diffusion and active transporter transport. Therefore, finding additional uptake pathways that can improve the effective intracellular concentration of DDP is critical. Macropinocytosis, an endocytic mechanism for extracellular material absorption, contributes to the intracellular uptake of anticancer drugs. No research has been conducted to determine whether macropinocytosis can augment the intracellular uptake of DDP in OSCC cells or not. Based on that, we proved for the first time that silmitasertib (previously CX-4945) could trigger macropinocytosis, which may increase the intracellular uptake of DDP and enhance apoptosis via in vivo and in vitro experiments. We hope that our findings will inspire a new approach for the application of DDP in cancer treatment.

A convergent synthetic platform for dual anticancer drugs functionalized by reduced graphene nanocomposite delivery for hepatocellular cancer.

Hepatocellular carcinoma (HCC) is widespread cancer with a high degree of morbidity and mortality in individuals worldwide and a serious concern for its resistance to present chemotherapy drugs. In this investigation, the combination of cisplatin (CPT) and metformin (MET) to kill the HepG2 and caco-2 cells was developed into a new pH-responding magnetic nanocomposite based on reduced graphene oxide. Polyhydroxyethyl methacrylic (PHEA) was then linked employing grafting from approach to the reduced graphene oxide by ATRP polymerization (Fe3O4@rGO-G-PSEA). FT-IR, SEM, XRD, DLS, and TGA analyses evaluated physicochemical characteristics of the nanocomposite. In addition, the cellular uptake property of the nanocomposites was examined by the HepG2 cells. The outcomes of cell viability results indicate that the nanoparticles loaded with MET&CPT showed the lowest concentration rate of HepG2 and Caco-2 cells compared to the drug-loaded single nanocomposite groups and free drugs. The histological analysis has demonstrated relatively safe and does not produce different stress such as swelling and inflammation of the mice organs. Our results show the enhancement in cytotoxicity in HepG2 and Cocoa-2 cells by MET and CPT graphene oxide-based nanocomposite by promoting apoptotic response. Moreover, Fe3O4@rGO-G-PSEA showed potent in vivo antitumor efficacy but showed no adverse toxicity to normal tissues. Together, this study can provide insight into how surface embellishment may tune these nanocomposites' tumor specificity and provide the basis for developing anticancer efficacy.

Linear-Dendritic Polymer-Platinum Complexes Forming Well-Defined Nanocapsules for Acid-Responsive Drug Delivery.

Polymeric nanocapsules hold considerable applications in cancer drug delivery, but the synthesis of well-defined nanocapsules with a tunable drug release property remains a significant challenge in fabrication. Herein, we demonstrate a supramolecular complexation strategy to assemble small molecular platinum (Pt) compounds into well-defined nanocapsules with high drug loading, acidity-sensitivity, and tunable Pt releasing profile. The design utilizes poly(ethylene glycol)-dendritic polylysine-G4/amides to complex with Pt compounds, forming stable nanocapsules with diameters approximately ∼20 nm and membrane thickness around several nanometers. The stability, drug content, and release profiles are tunable by tailoring the dendritic structure. The designated polymer-Pt nanocapsules, PEG-G4/MSA-Pt, showed sustained blood retention, preferential tumor accumulation, enhanced cellular uptake, lysosomal drug release, and nuclear delivery capability. PEG-G4/MSA-Pt showed enhanced antitumor efficacy compared to free cisplatin and other nanocapsules, which stopped the progression of both A549 cell xenografts and patient-derived xenografts (PDXs) of hepatocellular carcinoma on a mice tumor model. Thus, we believe this strategy is promising for developing Pt-based nanomedicine for cancer drug delivery.

Circadian clock, carcinogenesis, chronochemotherapy connections.

The circadian clock controls the expression of nearly 50% of protein coding genes in mice and most likely in humans as well. Therefore, disruption of the circadian clock is presumed to have serious pathological effects including cancer. However, epidemiological studies on individuals with circadian disruption because of night shift or rotating shift work have produced contradictory data not conducive to scientific consensus as to whether circadian disruption increases the incidence of breast, ovarian, prostate, or colorectal cancers. Similarly, genetically engineered mice with clock disruption do not exhibit spontaneous or radiation-induced cancers at higher incidence than wild-type controls. Because many cellular functions including the cell cycle and cell division are, at least in part, controlled by the molecular clock components (CLOCK, BMAL1, CRYs, PERs), it has also been expected that appropriate timing of chemotherapy may increase the efficacy of chemotherapeutic drugs and ameliorate their side effect. However, empirical attempts at chronochemotherapy have not produced beneficial outcomes. Using mice without and with human tumor xenografts, sites of DNA damage and repair following treatment with the anticancer drug cisplatin have been mapped genome-wide at single nucleotide resolution and as a function of circadian time. The data indicate that mechanism-based studies such as these may provide information necessary for devising rational chronochemotherapy regimens.

Redirecting Cisplatin and Doxorubicin to Mitochondria Affords Highly Effective PlatinumIV Prodrug Against Triple Negative Breast Cancer.

A mitochondria targeting dual-action platinumIV prodrug exhibits high anticancer activity in triple negative breast cancer cells. The complex intervenes in several cellular processes including DNA damage, perturbation of mitochondrial bioenergetics and induction of necrosis to kill cancer cells.

Subcellular localization of biomolecules and drug distribution by high-definition ion beam imaging.

Simultaneous visualization of the relationship between multiple biomolecules and their ligands or small molecules at the nanometer scale in cells will enable greater understanding of how biological processes operate. We present here high-definition multiplex ion beam imaging (HD-MIBI), a secondary ion mass spectrometry approach capable of high-parameter imaging in 3D of targeted biological entities and exogenously added structurally-unmodified small molecules. With this technology, the atomic constituents of the biomolecules themselves can be used in our system as the "tag" and we demonstrate measurements down to ~30 nm lateral resolution. We correlated the subcellular localization of the chemotherapy drug cisplatin simultaneously with five subnuclear structures. Cisplatin was preferentially enriched in nuclear speckles and excluded from closed-chromatin regions, indicative of a role for cisplatin in active regions of chromatin. Unexpectedly, cells surviving multi-drug treatment with cisplatin and the BET inhibitor JQ1 demonstrated near total cisplatin exclusion from the nucleus, suggesting that selective subcellular drug relocalization may modulate resistance to this important chemotherapeutic treatment. Multiplexed high-resolution imaging techniques, such as HD-MIBI, will enable studies of biomolecules and drug distributions in biologically relevant subcellular microenvironments by visualizing the processes themselves in concert, rather than inferring mechanism through surrogate analyses.

Combination of Chemotherapy and Photodynamic Therapy with Oxygen Self-Supply in the Form of Mutual Assistance for Cancer Therapy.

INTRODUCTION: Photodynamic therapy (PDT) has been widely researched by cancer therapists in recent years. This study aims to establish a drug delivery system combining PDT and chemotherapy to show that chemotherapeutic drugs provide oxygen to PDT, while PDT promotes the release of chemotherapeutic drug. METHODS: Firstly, poly(ethylene glycol)-lysine(Ce6)-block-poly(L-glutamate)-imidazole (mPEG-lys(Ce6)-PGA-AIM) was synthesized and self-assembled into micelles that exhibited pH- and ROS-responsiveness and buffering capacity. Perfluorohexanoate-modified cisplatin (FCP), as oxygen carriers, was encapsulated into mPEG-lys(Ce6)-PGA-AIM micelles. Then, the properties of micelles and their biological functions in vivo and in vitro were investigated. RESULTS: The micelles exhibited remarkabe stability, pH regulated drug release, good biocompatibility and effective tumor penetration. Cellular uptake demonstrated the efficient endosome/lysosome escape of CFMs, which facilitates the intracellular drug release. Both in vitro and in vivo experiments reflected that CFMs with laser irradiation showed significantly improved therapeutic activity compared with single PDT or chemotherapy. CONCLUSION: Chemotherapy and PDT were combined in the form of mutual assistance to provide a promising strategy for clinical treatment.

Combination Chemotherapy with Cisplatin and Chloroquine: Effect of Encapsulation in Micelles Formed by Self-Assembling Hybrid Dendritic-Linear-Dendritic Block Copolymers.

Clinical outcomes of conventional drug combinations are not ideal due to high toxicity to healthy tissues. Cisplatin (CDDP) is the standard component for many cancer treatments, yet its principal dose-limiting side effect is nephrotoxicity. Thus, CDDP is commonly used in combination with other drugs, such as the autophagy inhibitor chloroquine (CQ), to enhance tumor cell killing efficacy and prevent the development of chemoresistance. In addition, nanocarrier-based drug delivery systems can overcome chemotherapy limitations, decreasing side effects and increasing tumor accumulation. The aim of this study was to evaluate the toxicity of CQ and CDDP against tumor and non-tumor cells when used in a combined treatment. For this purpose, two types of micelles based on Pluronic® F127 hybrid dendritic-linear-dendritic block copolymers (HDLDBCs) modified with polyester or poly(esteramide) dendrons derived from 2,2'-bis(hydroxymethyl)propionic acid (HDLDBC-bMPA) or 2,2'-bis(glycyloxymethyl)propionic acid (HDLDBC-bGMPA) were explored as delivery nanocarriers. Our results indicated that the combined treatment with HDLDBC-bMPA(CQ) or HDLDBC-bGMPA(CQ) and CDDP increased cytotoxicity in tumor cells compared to the single treatment with CDDP. Encapsulations demonstrated less short-term cytotoxicity individually or when used in combination compared to the free drugs. However, and more importantly, a low degree of cytotoxicity against non-tumor cells was maintained, even when drugs were given simultaneously.

Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours.

BACKGROUND: Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin. METHODS: Adult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W). RESULTS: Thirty-one patients received berzosertib (90-210 mg/m2) and cisplatin (40-75 mg/m2) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m2 (days 2 and 9) and cisplatin 75 mg/m2 (day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy. CONCLUSIONS: Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting. CLINICAL TRIALS IDENTIFIER: NCT02157792.