Liposomal Cisplatin Research Articles

Cisplatin-based Liposomal Nanocarriers for Drug Delivery in Lung Cancer Therapy: Recent Progress and Future Outlooks.

In order to improve the treatment of lung cancer, this paper looks at the development of cisplatinbased liposomal nanocarriers. It focuses on addressing the drawbacks of conventional cisplatin therapy, including systemic toxicity, inadequate tumor targeting, and drug resistance. Liposomes, or spherical lipid vesicles, offer a potentially effective way to encapsulate cisplatin, enhancing its transport and minimizing harmful effects on healthy tissues. The article discusses many liposomal cisplatin formulations, including pH-sensitive liposomes, sterically stabilized liposomes, and liposomes coupled with specific ligands like EGFR antibodies. These novel formulations show promise in reducing cisplatin resistance, optimizing pharmacokinetics, and boosting therapeutic results in the two in vitro and in vivo models. They also take advantage of the Enhanced Permeability and Retention (EPR) effect in the direction of improved tumor accumulation. The study highlights the need for more investigation to move these liposomal formulations from experimental to clinical settings, highlighting their potential to offer less harmful and more effective cancer therapy alternatives.

Stromal and tumor immune microenvironment reprogramming through multifunctional cisplatin-based liposomes boosts the efficacy of anti-PD-1 immunotherapy in pancreatic cancer.

The dense stromal barrier in pancreatic cancer tissues blocks intratumoral delivery and distribution of chemotherapeutics and therapeutic antibodies, causing poor chemoimmunotherapy responses. We designed a multi-targeted pH-sensitive liposome which encapsulates cisplatin (Pt) in its water core (denoted as ATF@Pt Lps) and shows high affinity for uPAR receptors in pancreatic cancer cells, tumor-associated macrophages, and cancer-associated fibroblasts. Systemic administration of ATF@Pt Lps enabled overcoming the central stromal cellular barrier and effective drug delivery into tumor cells, resulting in a strong therapeutic response in a Panc02 cell derived transplanted tumor mouse model. More importantly, ATF@Pt Lps degradation of collagen contributes to the infiltration of CD8+ T cells into tumors as well as an enhanced accumulation of anti PD-1 monoclonal antibodies. Furthermore, the killing of tumor cells by Pt also leads to the release of tumor antigens, which promote the proliferation of immune cells, especially CD83+ cells, Th1 CD4+ cells, and CD8+ cytotoxic T cells, that converted an immunoscore "cold" pancreatic cancer into a pro-immune "hot" tumor. A further combination with an immune checkpoint agent, anti PD-1 antibodies that inhibit PD-1, can enhance tumor specific cytotoxic T cell response. Accordingly, ATF@Pt Lps displays multi-targeting, controlled drug release, stromal disruption, enhanced penetration, killing of cancer cells, modification of the immunosuppressive microenvironment, and enhancement of immunity. This study provides important mechanistic information for the further development of a combination of ATF@Pt Lps and anti PD-1 antibodies for the effective treatment of pancreatic cancer.

Co-encapsulation of fisetin and cisplatin into liposomes: Stability considerations and in vivo efficacy on lung cancer animal model

Lung cancer is a highly vascularized tumor for which a combination between an antitumor agent, cisplatin, and an antiangiogenic molecule, fisetin, appears a promising therapeutic approach. In order to deliver both chemotherapies within the tumor, to enhance fisetin solubility and decrease cisplatin toxicity, an encapsulation of both drugs into liposomes was developed. Purification and freeze-drying protocols were optimized to improve both the encapsulation and liposome storage. The cytotoxicity of the encapsulated chemotherapies was evaluated on Lewis lung carcinoma (3LL) cell lines. The antitumor effect of the combination was evaluated in vivo on an ectopic mouse model of Lewis Lung carcinoma. The results showed that fisetin and cisplatin co-loaded liposomes were successfully prepared. Freeze-drying allowed a 30 days storage limiting the release of both drugs. The combination index between liposomal fisetin and liposomal cisplatin on 3LL cell line after 24 h of exposure showed a clear synergism: CI = 0.7 for the co loaded liposomes and CI = 0.9 for the mixture of cisplatin loaded and fisetin loaded liposomes. The co-encapsulating formulation showed in vivo efficacy against an ectopic murine model of Lewis Lung carcinoma with a probable reduction in the toxicity of cisplatin through co-encapsulation with fisetin.

Predictive biomarker for cisplatin in prospective phase 2 of liposomal cisplatin in metastatic breast cancer.

3130 Background: Heavily pretreated late-stage breast cancer patients of any subtype represent a huge treatment challenge. Cisplatin may work in selected patients but is often disqualified because of toxicity. LiPlaCis is a liposomal formulation of cisplatin in development utilizing the sPLA2-triggered targeted release of cisplatin. The prediction of cisplatin efficacy with a 205 mRNA profile has previously been demonstrated in a retrospective study in two NSCLC cancer patient cohorts receiving adjuvant cisplatin1. Methods: The dose-escalation part of a phase 1/2 study, of 20 patients with a variety of locally advanced or metastatic solid tumors, suggested a phase 2 dose of LiPlaCis to be 75mg on day 1 and 8 q 3 wks. In this phase 2 part, the cisplatin drug response predictor (DRP) was used to select metastatic breast cancer (mBC) patients with response likelihood scores from FFPE diagnostic or later biopsies. Patients were treated until progression or unacceptable toxicity. Halfway through phase 2 part, the dosing was changed to a per body surface schedule (40 mg/m2) after a fatal event with the flat dosing (in effect 51 mg/m2 for this patient). Among the 52 patients included in the phase 2 part, we here report data from the 37 patients with mBC platinum naïve, with DRP scores 34-100%, and with RECIST-defined response outcomes. Within this subgroup, we conducted a post hoc analysis of possible DRP cut-off values that could identify patients with a clinically meaningful response to treatment. Results: mBC patients had received a median of 7 previous treatment lines. A DRP score ≥80% (DRP80+) discriminated well between responders and non-responders to liposomal cisplatin. All 4 partial remissions in the study were in the DRP80+ group, and other key efficacy endpoints were in favor of the DRP80+ vs the lower scores (DRP80-). LiPlaCis was generally well tolerated, with a mean of 4.4 treatment cycles administered per patient. Only 1 SAE (pyelonephritis) was reported and considered related to treatment. One patient died whilst on treatment, but due to disease progression. From a total of 164 treatment cycles, 18 of the patients reported 1 grade 4 and 41 grade 3 AEs considered possibly related to treatment. Conclusions: LiPlaCis shows efficacy in heavily pretreated mBC patients, especially when using the DRP method as a companion diagnostic. Further, this is the first clinical study to prospectively validate DRP as a method to identify responders to chemotherapy cisplatin. 1) Buhl et al PLOS One doi: 10.1371/journal.pone0194609. Clinical trial information: NCT01861496 . [Table: see text]

Amino acid coordination complex mediates cisplatin entrapment within PEGylated liposome: An implication in colorectal cancer therapy

Cis-Diaminedichloroplatinum (cisplatin, CDDP) remained among the most widely used anti-cancer agents; however, management of the dose-limiting side effects is still a great hurdle to its therapeutic potential. In the framework of this investigation, novel approach was developed for CDDP encasement within liposome based on the formation of a coordination bond between the platinum (II) atom and a carboxylic group in aspartic acid (AA) and glutamic acid (GA). We have also compared two methods of preparation based on equilibration and conventional lipid film hydration. For this, first FTIR spectra of the conjugates confirmed coordination bond between Pt and the carboxylate moieties. The PEGylated liposomes composed of HSPC, cholesterol and DPPG had a size of 134 to 197 nm and negative zeta potential (−14.20 to −20.90 mv). Cytotoxicity study revealed IC50 values of <7 µg/ml for liposomes. In vivo plasma retention following iv administration indicated the potential of liposome in maintaining cisplatin levels within the circulation, while free cisplatin and cisplatin conjugates were promptly eliminated. Anti-tumor efficacy studies following iv injections at 3 mg/kg cisplatin weekly for three weeks in C26 tumor bearing BALB/c mice demonstrated the potential of the cisplatin liposomes in tumor growth inhibition. Pt-complexes were not as effective as liposomal formulations showing the crucial role of liposomes in maintaining cisplatin levels within blood circulation. Overall, the developed cisplatin liposome seems to be a promising therapeutic approach for targeting solid tumors.

Liposomal formulations for lung cancer treatment in the last two decades: a systematic review.

Lung cancer is the leading cause of cancer mortality worldwide. To improve the therapeutic outcomes, drug delivery systems, and particularly liposomes, have been widely investigated. Therefore, this review analyzed systematically the literature to inquire about the safety and efficacy of liposomal formulations in lung cancer treatment. Three electronic databases (PubMed, Web of Science and Cochrane CENTRAL) were systematically searched until May 2020. Clinical trials containing information about the effects of liposomal formulations in lung cancer patients were considered eligible. Twenty two selected studies present different treatment options for both small and non-small-cell lung cancers. After compiling and analyzing all the published information, we verified that combination of liposomal cisplatin and paclitaxel led to a statistically significant improvement of the evaluated outcomes. Moreover, tecemotide, a liposome-based immunotherapy, demonstrated lower toxicity compared to control groups. Evidences that other subgroups could benefit from this formulation were also provided. This systematic review (registration number CRD42021246587) demonstrates that liposomal formulations are promising alternatives to overcome limitations of traditional cancer therapy. However, larger, longer, randomized and double-blinded clinical trials, selecting their patients' cohort considering more responsive subgroups would be beneficial to strengthen the scientific and clinical evidence of the results herein reported.

Cisplatin and paclitaxel-loaded liposomes induced cervical cancer (HeLa) cell death with multiple copies of human papillomavirus by apoptosis and decreased their cytotoxic effect on non-tumor cells

In the research and development of new anticancer treatments, nanotechnology is a powerful tool in the fight against cancer. Considering that cancer is a global health problem, we co-encapsulated cisplatin (CP) and paclitaxel (PTX) in liposomes and evaluated their cytotoxicity in fibroblasts (NIH3T3) and HeLa cells containing multiple copies of human papillomavirus 18 (HeLa-HPV18). CP and PTX were successfully encapsulated into liposomes with a particle size distribution <180 nm, poly dispersion index (PDI) < 0.2, spherical morphology, high negative zeta potential, and encapsulation efficiency of 59% (CP), 88% (PTX) and 57% + 87% (CP + PTX). FTIR suggests that the drugs were successfully encapsulated in liposomes. The liposomes ensured a higher cytotoxic effect on HeLa-HPV18 cells and a smaller cytotoxic effect on NIH3T3 cells when the drugs were encapsulated. In addition, combined treatment with CP and PTX encapsulated in liposomes ensured a synergic effect between the drugs, inducing cell death by apoptosis.

PH-Responsive Liposomes of Dioleoyl Phosphatidylethanolamine and Cholesteryl Hemisuccinate for the Enhanced Anticancer Efficacy of Cisplatin.

The current study aimed to develop pH-responsive cisplatin-loaded liposomes (CDDP@PLs) via the thin film hydration method. Formulations with varied ratios of dioleoyl phosphatidylethanolamine (DOPE) to cholesteryl hemisuccinate (CHEMS) were investigated to obtain the optimal particle size, zeta potential, entrapment efficiency, in vitro release profile, and stability. The particle size of the CDDP@PLs was in the range of 153.2 ± 3.08–206.4 ± 2.26 nm, zeta potential was −17.8 ± 1.26 to −24.6 ± 1.72, and PDI displayed an acceptable size distribution. Transmission electron microscopy revealed a spherical shape with ~200 nm size. Fourier transform infrared spectroscopic analysis showed the physicochemical stability of CDDP@PLs, and differential scanning calorimetry analysis showed the loss of the crystalline nature of cisplatin in liposomes. In vitro release study of CDDP@PLs at pH 7.4 depicted the lower release rate of cisplatin (less than 40%), and at a pH of 6.5, an almost 65% release rate was achieved compared to the release rate at pH 5.5 (more than 80%) showing the tumor-specific drug release. The cytotoxicity study showed the improved cytotoxicity of CDDP@PLs compared to cisplatin solution in MDA-MB-231 and SK-OV-3 cell lines, and fluorescence microscopy also showed enhanced cellular internalization. The acute toxicity study showed the safety and biocompatibility of the developed carrier system for the potential delivery of chemotherapeutic agents. These studies suggest that CDDP@PLs could be utilized as an efficient delivery system for the enhancement of therapeutic efficacy and to minimize the side effects of chemotherapy by releasing cisplatin at the tumor site.

In Vitro Characteristics of Glioma Cells Targeting by OX26-modified Liposomal Cisplatin

Background: Drug delivery to the brain tumor is limited due to the presence of the blood-brain barrier (BBB). Objective: This study aimed to evaluate the therapeutic effects of cisplatin-loaded PEGylated liposomes, targeted with the OX26 antibody (targeted liposomal cisplatin) against transferrin receptor expressing rat glioma C6 cells in vitro. Method: The liposomes were synthesized using reverse phase evaporation method and were conjugated to the OX26 monoclonal antibody. They were characterized in terms of size, drug encapsulation efficiency, morphology and drug release experiments using dynamic light scattering, atomic absorption spectrometry, scanning electron microscopy, and dialysis membrane methods. Then, their biological activities were evaluated on targeting the BBB. Results: The characterization results showed that spherical nanodrug with a size of 157 nm and drug loading efficiency of 24% was synthesized, which released 64% of the loaded cisplatin after 72 h in a controlled release manner. The nanoparticles caused an increase in the cisplatin cytotoxicity effects by 1.7-, 1.8- and 1.8-fold, compared to cisplatin-loaded PEGylated liposomes (liposomal cisplatin) after 24, 48 and 72h incubation, respectively against C6 cells. Moreover, targeted liposomal cisplatin showed promising results in the transport of cisplatin across the BBB, in which it caused an increase in the cisplatin cytotoxicity on C6 cells by 2.7- and 2.4-fold, compared to cisplatin and liposomal cisplatin, respectively. Conclusion: Regarding the properties of the targeted liposomal cisplatin, it suggests that the potency of the formulation, to be evaluated, for the transport of cisplatin across the BBB, delivers it to the brain tumor in vivo.

In vivo Glioblastoma Therapy Using Targeted Liposomal Cisplatin.

BackgroundDrug delivery systems have demonstrated promising results to cross blood–brain barrier (BBB) and deliver the loaded therapeutics to the brain tumor. This study aims to utilize the transferrin receptor (TR)-targeted liposomal cisplatin (Cispt) for transporting Cispt across the BBB and deliver Cispt to the brain tumor.MethodsTargeted pegylated liposomal cisplatin (TPL-Cispt) was synthesized using reverse phase evaporation method and thiolated OX26 monoclonal antibody. The formulation was characterized in terms of size, size distribution, zeta potential, drug encapsulation and loading efficiencies, bioactivity, drug release profile, stability and cellular uptake using dynamic light scattering, flame atomic absorption spectroscopy (AAS), ELISA, dialysis membrane, and fluorescence assay. Next, the potency of the formulation to increase the therapeutic effects of Cispt and decrease its toxicity effects was evaluated in the brain tumor-bearing rats through measuring the mean survival time (MST), blood factors and histopathological studies.ResultsThe results showed that TPL-Cispt with a size of 157±8 nm and drug encapsulation efficiency of 24%±1.22 was synthesized, that was biologically active and released Cispt in a slow-controlled manner. The formulation compared to Cispt-loaded PEGylated liposome nanoparticles (PL-Cispt) caused an increase in the cellular uptake by 1.43-fold, as well as an increase in the MST of the brain tumor-bearing rats by 1.7-fold compared to the PL-Cispt (P<0.001). TPL-Cispt was potent enough to cause a significant decrease in Cispt toxicity effects (P<0.001).ConclusionOverall, the results suggest that targeting the Cispt-loaded PEGylated liposome is a promising approach to develop formulation with enhanced efficacy and reduced toxicity for the treatment of brain tumor.

Stimuli-responsive combination therapy of cisplatin and Nrf2 siRNA for improving antitumor treatment of osteosarcoma

Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma. However, its clinical applications have been hindered due to low efficacy and bioavailability, and particularly frequent emergence of reactive oxygen species (ROS)-decrease induced drug resistance. The transcription factor NF-E2-related factor 2 (Nrf2) is increased in cancer patients and induces poor outcome in osteosarcoma treatment, making it a novel target to improve the efficacy of chemotherapy. Herein, a hyaluronidase-responsive multi-layer liposome (HLCN) for co-delivery of cisplatin and Nrf2 siRNA (siNrf2) is developed. It is composed of Vpr52-96 modified liposome covered with hyaluronic acid (HA). HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44, and can be degraded by endosomal hyaluronidase to generate cationic liposome, which promotes the endosomal escape of Vpr52-96, cisplatin and siNrf2. HLCN can effectively decrease Nrf2 level, promote ROS generation, activate itochondrial apoptotic pathway, and consequently enhance anticancer efficacy of cisplatin. Particularly, HLCN shows high cytotoxicity to osteosarcoma cells with an IC50 value of about 1 µM, which is four-fold lower than liposomal cisplatin (IC50 4 µM), indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells. Importantly, HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects. Therefore, this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.

Enhanced Efficacy of PEGylated Liposomal Cisplatin: In Vitro and In Vivo Evaluation.

This study aims to evaluate the potency of cisplatin (Cispt)-loaded liposome (LCispt) and PEGylated liposome (PLCispt) as therapeutic nanoformulations in the treatment of bladder cancer (BC). Cispt was loaded into liposomes using reverse-phase evaporation method, and the formulations were characterized using dynamic light scattering, scanning electron microscopy, dialysis membrane, and Fourier-transform infrared spectroscopy (FTIR) methods. The results showed that the particles were formed in spherical monodispersed shapes with a nanoscale size (221–274 nm) and controlled drug release profile. The cytotoxicity effects of LCispt and PLCispt were assessed in an in vitro environment, and the results demonstrated that PLCispt caused a 2.4- and 1.9-fold increase in the cytotoxicity effects of Cispt after 24 and 48 h, respectively. The therapeutic and toxicity effects of the formulations were also assessed on BC-bearing rats. The results showed that PLCispt caused a 4.8-fold increase in the drug efficacy (tumor volume of 11 ± 0.5 and 2.3 ± 0.1 mm3 in Cispt and PLCispt receiver rats, respectively) and a 3.3-fold decrease in the toxicity effects of the drug (bodyweight gains of 3% and 10% in Cispt and PLCispt receiver rats, respectively). The results of toxicity were also confirmed by histopathological studies. Overall, this study suggests that the PEGylation of LCispt is a promising approach to achieve a nanoformulation with enhanced anticancer effects and reduced toxicity compared to Cispt for the treatment of BC.

Pharmacokinetic evaluation and antitumor potency of liposomal nanoparticle encapsulated cisplatin targeted to CD24-positive cells in ovarian cancer.

CD24, which is upregulated in several human malignancies, is related to Epithelial-mesenchymal-transition (EMT) and has characteristics of cancer stem-like cells, especially in cisplatin-resistant ovarian carcinoma cells. Drug delivery systems represent a promising therapeutic approach for diseases with treatment resistance, and the present study investigated a novel CD24-targeted drug delivery system for advanced ovarian carcinoma. We produced liposomal cisplatin with a red fluorescent substance - cyanine 5.5 (GL-CDDP-Cy5.5). In order to target CD24-positive cells, an anti-CD24 monoclonal antibody was modified to the above drug (CD24-GL-CDDP-Cy5.5). Specific uptake of CD24-GL-CDDP-Cy5.5 was confirmed using a therapeutically resistant ovarian cancer cell line, Caov-3 cells. Antitumor effects of CD24-GL-CDDP-Cy5.5 were then evaluated in Caov-3 ×enograft mice. CD24-GL-CDDP-Cy5.5 showed more specific uptake by flow cytometry than GL-CDDP-Cy5.5. In xenograft mice, GL-CDDP-Cy5.5 and CD24-GL-CDDP-Cy5.5 treatment had significantly higher platinum concentration in disseminated tumor cells than cisplatin (P<0.05). Moreover, CD24-GL-CDDP-Cy5.5 suppressed tumor growth and prolonged survival time compared with other treatments. Median survival times of the control, cisplatin, GL-CDDP-Cy5.5 and CD24-GL-CDDP-Cy5.5 groups were 37, 36, 46 and 54 days after inoculation, respectively. Immunohistochemical analysis showed that CD24-GL-CDDP-Cy5.5 treatment, compared with GL-CDDP-Cy5.5, decreased the number of CD24-positive cells and suppressed the EMT phenomenon significantly (P<0.05). The present study demonstrated that CD24-GL-CDDP-Cy5.5, compared with other treatments, improved therapeutic efficacy. The present results suggested the potential for targeting anticancer therapeutics for CD24-positive cells to prevent disease progression.

Growth of Metastatic Triple-Negative Breast Cancer Is Inhibited by Deep Tumor-Penetrating and Slow Tumor-Clearing Chemotherapy: The Case of Tumor-Adhering Liposomes with Interstitial Drug Release.

The poor prognosis of triple-negative breast cancer (TNBC) is attributed largely to the lack of tumor-selective therapeutic modalities that effectively deliver lethal doses at the sites of metastatic disease. Tumor-selective drug delivery strategies that aim to improve uniformity in intratumoral drug microdistributions and to prolong exposure of these cancer cells to delivered therapeutics may improve therapeutic efficacy against established TNBC metastases. In this study, we present lipid carriers for selective (due to their nanometer size) tumor delivery, which are loaded with cisplatin and designed to exhibit the following properties when in the tumor interstitium: (1) interstitial drug release (for deeper tumor penetration of cisplatin) and/or (2) intratumoral/interstitial adhesion of the carriers to tumors' extracellular matrix (ECM)-not accompanied by cell internalization-for delayed tumor clearance of carriers prolonging cancer cell exposure to the cisplatin being released. We show that on large multicellular spheroids, used as surrogates of avascular solid tumor regions, greater growth inhibition was strongly correlated with spatially more uniform drug concentrations (due to interstitial drug release) and with longer exposure to the released drug (i.e., higher time-integrated drug concentrations enabled by slow clearing of adhesive nanoparticles). Lipid nanoparticles with both the release and adhesion properties were the most effective, followed by nanoparticles with only the releasing property and then by nanoparticles with only the adhering property. In vivo, cisplatin-loaded nanoparticles with releasing and/or adhering properties significantly inhibited the growth of spontaneous TNBC metastases compared to conventional liposomal cisplatin, and the efficacy of different property combinations followed the same trends as in spheroids. This study demonstrates the therapeutic potential of a general strategy to bypass treatment limitations of established TNBC metastases due to the lack of cell-targeting markers: aiming to optimize the temporal intratumoral drug microdistributions for more uniform and prolonged drug exposure.

Chronotherapeutic regimen with liposomal cisplatin for systemic treatment of primary liver cancer.

e15678 Background: Primary liver cancer (HCC) treatment is one of the priority issues of clinical oncology due to inefficiency and quantitative lack of medicines. The goal of our research was to perform treatment of Primary Liver Cancer, based on chronobiological mechanisms, assessment of treatment efficiency and advantage over the standard regimen. Methods: A total of 21 patients with HCC participated in the study. The treatment was performed by Liposomal Cisplatin. Assessment of cancer cells sensitivity to platinum group medicines was performed using RT-PCR method by expression of DNA methyltransferase I gene. During 24 hours, with 2-hour intervals, circulating tumor cells (CTC) were taken from peripheral venous blood. At the end, in all samples circadian regimens of DNA methyltransferase I gene expression were studied. According to obtained results, the circadian peak of gene expression was registered at 02:00-04:30 am time interval. Results: According to the study design of the 21 patients 12 ones received treatment based on chronotherapy regimens (investigated group, infusions were made at 02:00-04:30 am), 9 patients received treatment with standard regimen (control group, infusion was performed at 10:00-12:00 am). Infusions were performed according to the protocol with 1 week intervals for 9 weeks (a single infusion dose 150mg/m2). The treatment efficiency was evaluated 9 weeks later by the following parameters: AFP serum level and computer tomography of the liver. Results of the study demonstrated significant differences in treatment efficacy. During chemotherapy performed in chronotherapy regimen in patient's blood plasma, the AFP concentration decreased on average by 36.5% compared to the initial value, however in the control group the AFP concentration decreased on average by 13.7%. By CT positive dynamics was detected in both groups, but with significant advantage in case of chronotherapy regimen, size reduction of tumor growth by 27.1% on average was associated with fibrous transformation and prominent decrease of vascularization was found. In the control group, size reduction of the tumour growth was seen, however only by 6.3% on average. Patients clinical condition as well as CBC data differed with significant prevailing in case of chronotherapy. Conclusions: Obtained results confirm high clinical significance of chronobiological features of gene expression in antitumour therapy as well as importance of the development of new, up-to-date protocols for HCC – highly aggressive tumour therapy based on chronotherapy principles.

Meta-analysis of clinical trials comparing the efficacy and safety of liposomal cisplatin versus conventional nonliposomal cisplatin in nonsmall cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN).

While liposomal cisplatin has shown enhanced drug tolerability and higher targeting property as compared with the conventional cisplatin, the doubt remains whether lipoplatin could improve its anticancer efficacy. What's more, there is still no systematic evaluation of the safety profiles of lipoplatin comparing with original cisplatin. Thus, we performed a systematic literature search for randomized clinical trials directly comparing efficacy and safety of liposomal cisplatin versus its conventional nonliposomal cisplatin. The electronic search was conducted in PubMed, Embase, The Cochrane Library, and ClinicalTrials.gov from inception to February 10, 2018. The pooled odds ratio (OR) and 95% confidence intervals (CIs) of progressive disease (PD), partial response (PR), stable disease (SD), and adverse events (AEs) were obtained to assess the efficacy and safety. Heterogeneity was estimated using the I test (I > 50%, significant heterogeneity). The search yielded 5 clinical trials that meet inclusion criteria, with a total of 523 patients. We found that the liposome encapsulated cisplatin was more clinical efficacious than cisplatin as assessed by PD rate (OR, 0.46; 95% CI, 0.28-0.74; P = .002), while subgroup analysis of the only nonsmall cell lung cancer (NSCLC) patients showed higher response rates in PR (OR, 0.46; 95% CI, 0.28-0.74; P = .002) and PD (OR, 0.46; 95% CI, 0.28-0.74; P = .002) simultaneously. In addition, the toxicity meta-analysis revealed lipoplatin was much less toxic than the original cisplatin, with respect to grade 3 to 4 neurotoxicity (OR, 0.18; 95% CI, 0.04-0.74; P = .02), grade 3 to 4 leukopenia (OR, 0.47; 95% CI, 0.26-0.85; P = .01), grade 3 to 4 neutropenia (OR, 0.26; 95% CI, 0.09-0.71; P = .009), grade 1 and 2 nausea/vomiting (OR, 0.50; 95% CI, 0.32-0.77; P = .002), and grade 3 and 4 asthenia (OR, 0.11; 95% CI, 0.03-0.42; P = .001). This meta-analysis revealed that with both NSCLC and squamous cell carcinoma of the head and neck (SCCHN) patients, liposomal cisplatin-based chemotherapy offers significant advantages regarding the PD and reduced toxicities relative to conventional cisplatin.

Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy

Human pleural mesothelioma is an incurable and chemoresistant cancer. Using a nude mouse xenograft model of human pleural mesothelioma, we show that RAPTA-T, a compound undergoing preclinical evaluation, enhances tumor vascular function by decreasing blood vessel tortuosity and dilation, while increasing the coverage of endothelial cells by pericytes and vessel perfusion within tumors. This in turn significantly reduces the interstitial fluid pressure and increases oxygenation in the tumor. Consequently, RAPTA-T pre-treatment followed by the application of cisplatin or liposomal cisplatin (Lipoplatin) leads to increased levels of the cytotoxin in the tumor and enhanced mesothelioma growth inhibition. We demonstrate that the vascular changes induced by RAPTA-T are related, in part, to the inhibition of poly-(ADP-ribose) polymerase 1 (PARP-1) which is associated to tumor vascular stabilization. These findings suggest novel therapeutic implications for RAPTA-T to create conditions for superior drug uptake and efficacy of approved cytotoxic anti-cancer drugs in malignant pleural mesothelioma and potentially other chemoresistant tumors.

Liposomal cisplatin response prediction in heavily pretreated breast cancer patients: A multigene biomarker in a prospective phase 2 study.

e13077Background: In an ongoing, open-label Phase 2 study liposomal cisplatin (LiPlaCis) was evaluated in metastatic breast cancer (mBC) patients selected by a cisplatin-specific mRNA-based drug re...

Hyperthermia-mediated drug delivery induces biological effects at the tumor and molecular levels that improve cisplatin efficacy in triple negative breast cancer

Triple negative breast cancer is an aggressive disease that accounts for at least 15% of breast cancer diagnoses, and a disproportionately high percentage of breast cancer related morbidity. Intensive research efforts are focused on the development of more efficacious treatments for this disease, for which therapeutic options remain limited. The high incidence of mutations in key DNA repair pathways in triple negative breast cancer results in increased sensitivity to DNA damaging agents, such as platinum-based chemotherapies. Hyperthermia has been successfully used in breast cancer treatment to sensitize tumors to radiation therapy and chemotherapy. It has also been used as a mechanism to trigger drug release from thermosensitive liposomes. In this study, mild hyperthermia is used to trigger release of cisplatin from thermosensitive liposomes in the vasculature of human triple negative breast cancer tumors implanted orthotopically in mice. This heat-triggered liposomal formulation of cisplatin resulted in significantly delayed tumor growth and improved overall survival compared to treatment with either non-thermosensitive liposomes containing cisplatin or free cisplatin, as was observed in two independent tumor models (i.e. MDA-MB-231 and MDA-MB-436). The in vitro sensitivity of the cell lines to cisplatin and hyperthermia alone and in combination was characterized extensively using enzymatic assays, clonogenic assays, and spheroid growth assays. Evaluation of correlations between the in vitro and in vivo results served to identify the in vitro approach that is most predictive of the effects of hyperthermia in vivo. Relative expression of several heat shock proteins and the DNA damage repair protein BRCA1 were assayed at baseline and in response to hyperthermia both in vitro and in vivo. Interestingly, delivery of cisplatin in thermosensitive liposomes in combination with hyperthermia resulted in the most significant tumor growth delay, relative to free cisplatin, in the less cisplatin-sensitive cell line (i.e. MDA-MB-231). This work demonstrates that thermosensitive cisplatin liposomes used in combination with hyperthermia offer a novel method for effective treatment of triple negative breast cancer.

Cisplatin liposome and 6-amino nicotinamide combination to overcome drug resistance in ovarian cancer cells.

Ovarian cancer is an aggressive and lethal cancer usually treated by cytoreductive surgery followed by chemotherapy. Unfortunately, after an initial response, many patients relapse owing mainly to the development of resistance against the standard chemotherapy regime, carboplatin/paclitaxel, which is also affected by heavy side effects. In view to addressing such issues here, an association of liposomal cisplatin with 6-amino nicotinamide is investigated. It is known that resistant cells increase their demand for glucose, which is partially redirected toward the pentose phosphate pathway (PPP). Interestingly, we have found that also a cisplatin-resistant subclone of the ovarian cancer cells IGROV1 switch their metabolism toward the glycolytic pathway and rely on PPP to elude cisplatin cytotoxicity. The drug 6-amino nicotinamide, an inhibitor of the enzyme glucose-6-phosphate dehydrogenase (the rate-limiting step of the PPP) can restore the sensitivity of resistant cells to cisplatin. Then, to reduce the toxicity of cisplatin and prolong its action, a lyophilized stealth liposomal formulation of cisplatin was developed. The combination treatment of liposomal cisplatin and 6-amino nicotinamide showed promising cytotoxic activities in drug-resistant cells and a prolonged pharmacokinetics in rats, thus opening the way for a new therapeutic option against ovarian cancer.