A review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer (original) (raw)
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Annals of Oncology, 2004
Background: This study was designed to demonstrate that efficacy [progression-free survival (PFS)] of CAELYX™ [pegylated liposomal doxorubicin HCl (PLD)] is non-inferior to doxorubicin with significantly less cardiotoxicity in first-line treatment of women with metastatic breast cancer (MBC). Patients and methods: Women (n = 509) with MBC and normal cardiac function were randomized to receive either PLD 50 mg/m 2 (every 4 weeks) or doxorubicin 60 mg/m 2 (every 3 weeks). Cardiac event rates were based on reductions in left ventricular ejection fraction as a function of cumulative anthracycline dose. Results: PLD and doxorubicin were comparable with respect to PFS [6.9 versus 7.8 months, respectively; hazard ratio (HR) = 1.00; 95% confidence interval (CI) 0.82-1.22]. Subgroup results were consistent. Overall risk of cardiotoxicity was significantly higher with doxorubicin than PLD (HR = 3.16; 95%CI 1.58-6.31; P <0.001). Overall survival was similar (21 and 22 months for PLD and doxorubicin, respectively; HR = 0.94; 95%CI 0.74-1.19). Alopecia (overall, 66% versus 20%; pronounced, 54% versus 7%), nausea (53% versus 37%), vomiting (31% versus 19%) and neutropenia (10% versus 4%) were more often associated with doxorubicin than PLD. Palmar-plantar erythrodysesthesia (48% versus 2%), stomatitis (22% versus 15%) and mucositis (23% versus 13%) were more often associated with PLD than doxorubicin. Conclusions: In first-line therapy for MBC, PLD provides comparable efficacy to doxorubicin, with significantly reduced cardiotoxicity, myelosuppression, vomiting and alopecia.
Advances in nano delivery systems for doxorubicin an updated insight.pdf
Doxorubicin (DOX) is the most effective chemotherapeutic drug developed against broad range of cancers such as solid tumours, transplantable leukemias and lymphomas. Conventional DOX-induced cardiotoxicity has limited its use. FDA approved drugs i.e. non-pegylated liposomal (Myocet V R ) and pegylated liposomal (Doxil V R ) formulations have no doubt shown comparatively reduced cardiotoxicity, but has raised new toxicity issues. The entrapment of DOX in biocompatible, biodegradable and safe nano delivery systems can prevent its degradation in circulation minimising its toxicity with increased half-life, enhanced pharmacokinetic profile leading to improved patient compliance. In addition, nano delivery systems can actively and passively target the tumour resulting increase in therapeutic index and decreased side effects of drug. Foreseeing the need of a comprehensive review on DOX nanoformulations, in this article we for the first time have given an updated insight on DOX nano delivery systems.
Advances in nano-delivery systems for doxorubicin: an updated insight
2018
Doxorubicin (DOX) is the most effective chemotherapeutic drug developed against broad range of cancers such as solid tumors, transplantable leukemias and lymphomas. Conventional DOX induced cardiotoxicity has limited its use. FDA approved drugs i.e. non-pegylated liposomal (Myocet®) and pegylated liposomal (Doxil®) formulations have no doubt shown comparatively reduced cardiotoxicity, but has raised new toxicity issues. The entrapment of doxorubicin in biocompatible, biodegradable and safe nano delivery systems can prevent its degradation in circulation minimizing its toxicity with increased half life, enhanced pharmacokinetic profile leading to improved patient compliance. In addition, nano delivery systems can actively and passively target the tumor resulting increase in therapeutic index and decreased side effects of drug. Foreseeing the need of a comprehensive review on doxorubicin nanoformulations, in this article we for the first time have given an updated insight on doxorubicin nano delivery systems. Key words: Doxorubicin; Myocet®; Doxil®; Cardiotoxicity; Nano delivery systems
Anticancer and cardio-protective effects of liposomal doxorubicin in the treatment of breast cancer
Breast Cancer: Targets and Therapy, 2018
Breast cancer (BC) is a highly prevalent disease, accounting for the second highest number of cancer-related mortalities worldwide. The anthracycline doxorubicin (DOX), isolated from Streptomyces peucetius var. caesius, is a potent chemotherapeutic drug that is successfully used to treat various forms of liquid and solid tumors and is currently approved to treat BC. DOX exerts its effects by intercalation into DNA and inhibition of topoisomerases I and II, causing damage to DNA and the formation of reactive oxygen species (ROS), resulting in the activation of caspases, which ultimately leads to apoptosis. Unfortunately, DOX also can cause cardiotoxicity, with patients only allowed a cumulative lifetime dose of 550 mg/m 2. Efforts to decrease cardiotoxicity and to increase the blood circulation time of DOX led to the US Food and Drug Administration (FDA) approval of a PEGylated liposomal formulation (L-DOX), Doxil ® (known internationally as Caelyx ®). Both exhibit better cardiovascular safety profiles; however, they are not currently FDA approved for the treatment of metastatic BC. Here, we provide detailed insights into the mechanism of action of L-DOX and its most common side effects and highlight results of its use in clinical trials for the treatment of BC as single agent and in combination with other commonly used chemotherapeutics.
2021
Simple Summary Anthracyclines are among the most active chemotherapies in breast cancer (BC). However, they can cause structural and cumulative dose-related cardiac damage; hence, they require careful administration after preliminary functional cardiac assessment and subsequent monitoring, along with a limitation in the cumulative dose delivered. Non-pegylated liposomal doxorubicin (NPLD) has been precisely developed to optimize the doxorubicin toxicity profile, while retaining its therapeutic efficacy, thanks to a reduced diffusion in normal tissues with preserved drug penetrance into cancer sites. This has allowed administration of NPLD beyond a conventional doxorubicin maximum cumulative dose, as well as in patients with cardiac comorbilities or anthracycline pretreatment. At present, NPLD is approved in Europe and Canada in combination with cyclophosphamide as the first line of metastatic HER2-negative BC. However, given the increasing complexity of the therapeutic scenario in t...
2020
Aim: To investigate the toxicity of nab-paclitaxel (wNP)/nonpegylated liposome-encapsulated doxorubicin (wNPLD) combination in HER2-negative metastatic breast cancer (MBC) patients as first-line treatment. Materials & methods: Phase I, single-arm study in metastatic breast cancer patients naive to previous chemotherapy for advanced disease. A 3 + 3 dose-escalation design was used to determine the safety. Primary endpoints were the identification of dose-limiting toxicity and maximum tolerated dose. Results: In total, 12 patients (mean age: 52 years; median metastatic sites: 2) were enrolled and 97 cycles were completed. Maximum tolerated dose was wNP + wNPLD 25 mg/m 2. The most common adverse events were neutropenia, nausea, diarrhea and mucositis. The objective response rate was 68% (response mean duration: 12.6 months). Conclusion: wNP/wNPLD combination constitutes an active regimen with mild toxicity. Conventional anthracyclines (doxorubicin and epirubicin) are an important mainstay in breast cancer (BC) treatment. Use of anthracyclines and taxanes have been limited because of the intrinsic cardiotoxicity, although they have proven to be effective for both metastatic and early disease [1]. Similarly, the efficacy of taxanes has been hindered by solvent-related severe toxicities, such as hypersensitivity reactions and peripheral neuropathy. In addition, an entrapment of the active drug into plasma micelles may affect efficacy, since it can lead to increased systemic drug exposure, reduced drug clearance, nonlinear pharmacokinetics and lack of dose-dependent antitumor activity [2-4]. One of the most promising strategies designed to curtail these effects is represented by the use of nanoparticles as potential drug nanocarriers to facilitate a specific drug delivery, to increase efficacy while minimizing the undesired effects of the anthracycline-and taxane-based chemotherapy [5]. Liposome encapsulation and colloidal suspension of the target drug with albumin stand as one of the most promising applications of nanomedicine in metastatic BC (MBC) management. Liposomal anthracyclines have achieved a highly efficient drug encapsulation and have a reduced cardiotoxicity. They have also proven to be effective as an agent on its own or in combination with other drugs for the treatment of either anthracycline-treated or-naive MBC patients [6]. Nonpegylated liposomal doxorubicin (NPLD) consists of doxorubicin complexed with citrate inside nonpegylated liposomes. NPLD reduced cardiac toxicity with antitumor responses comparable with those of conventional doxorubicin. In MBC patients, NPLD was associated with a significantly reduced risk of cardiac toxicity, significantly less mucositis and the absence of palmar-plantar erythrodysesthesia, while also maintaining antitumor efficacy [2,7,8].
Cancer Gene Therapy, 2017
Despite benefits of systemic chemotherapy in breast cancer treatment, several patients with early-stage breast cancer will develop metastatic breast cancer (MBC). Doxorubicin is among the most active agents against MBC. However, the use of doxorubicin is related to some life-threatening side effects including cardiotoxicity. Many efforts were made to lessen the side effects of doxorubicin and improve its efficacy. Pegylated liposomal doxorubicin (PLD) is a product claimed to achieve these two objectives because of its different pharmacokinetic profile. The aim of this study was to determine the side-effect profile of PLD in MBC through a systematic review of phase II clinical trials. A literature search in PubMed-MEDLINE was performed using terms covering nano-based pharmaceutical systems, 'breast cancer' and 'doxorubicin'. Articles were evaluated according to the inclusion criteria. Reported hematological and non-hematological side effects were categorized. Out of 718 articles that were initially identified, 8 were in accordance with the inclusion criteria. We found that the most important side effects of PLD were skin toxicity and mucositis, but the proportion of patients who showed grade III and IV of these side effects was relatively low. On the other hand, the occurrence of cardiotoxicity, the most important problem with doxorubicin, was considerably reduced in patients treated with PLD. Although PLD has demonstrated a lower toxicity profile than conventional anthracyclines, it has also new side effects. However, it seems that the reduced cardiotoxicity of PLD has made it a more appropriate option in patients with MBC, especially in those with risk factors for cardiac diseases.
Journal of Controlled Release, 2010
Doxorubicin (DOX) is among the most effective chemotherapeutics used for the treatment of cancers including breast, ovarian, sarcomas, pediatric solid tumors, Hodgkin's disease, multiple myeloma, and non-Hodgkin's lymphomas. Despite the success of DOX against many cancers, its use can be severely limited by its cardiac toxicity including development of a cardiomyopathy, often refractory to common medications, which can progress to biventricular failure and even death (reviewed in ). Technologies such as polymeric micelles , synthetic polymer conjugates , and antibody targeted carriers have demonstrated reduced or altered toxicity in Phase I trials, yet the therapeutic efficacy of these formulations has yet to demonstrated. In the absence of safer, efficacious systemic formulations, localized delivery of DOX may improve tolerability and improve efficacy, especially in the treatment of early breast cancer.
BMC Cancer, 2011
The therapeutic success of chemotherapeutic agents is often limited by severe adverse effects. To reduce toxicity of these drugs, nanoscale particle-based drug delivery systems (DDS) are used. DDS accumulate to some extent in tumor tissues, but only a very small portion of a given dose reaches this target. Accumulation of DDS in tumor tissues is supposed to be much faster than in certain other tissues in which side effects occur ("Kinetic Targeting"). Once saturation in tumor tissue is achieved, most of the administered DDS still circulate in the plasma. The extracorporeal elimination of these circulating nanoparticles would probably reduce toxicity. Methods: For the CARL-trial (Controlled Application and Removal of Liposomal chemotherapeutics), pegylated liposomal doxorubicin (PLD) was used as chemotherapeutic agent and double filtration plasmapheresis (DFPP) was performed for extracorporeal elimination of liposomes. PLD was given as 40 mg/m 2 every 3 weeks in combination with vinorelbine 2 × 25 mg/m 2 (neoadjuvant treatment of breast cancer, 12 patients), or as 40 mg/m 2 every 4 weeks (recurrent ovarian cancer, 3 patients). Primary endpoints were the efficiency and safety profile of DFPP, and secondary endpoints were side effects and tumor response. Results: DFPP eliminated~62% of circulating PLD, corresponding to~45% of the total dose (n = 57 cycles). AUC of doxorubicin was reduced by 50%. No leakage of doxorubicin was detected during elimination, and no relevant DFPP-related side effects occurred. Reduction in tumor size > 30% occurred in 10/12 (neoadjuvant) and in 1/3 patients (recurrent). Only five grade 2 events and one grade 3 event (mucositis, neutropenia or leucopenia) and a single palmar-plantar erythrodysesthesia grade 2 were reported. Conclusion: Extracorporeal elimination of PLD by DFPP is safe and efficient. CARL can diminish the main doselimiting side effects of PLD, and probably many different DDS alike.