Doxorubicin pegylated liposomal 20mg/10ml solution for infusion vials

Importance: There are substantial unmet therapeutic needs in patients with platinum-resistant recurrent ovarian cancer (PROC), and novel therapeutic strategies should be explored. Objective: To evaluate the efficacy and safety of treatment with apatinib (a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) plus pegylated liposomal doxorubicin (PLD) for PROC. Design, Setting, and Participants: The APPROVE trial was performed as an open-label, randomized clinical trial at 11 hospitals in China between March 22, 2018, and November 16, 2020. Patients with histologically confirmed ovarian cancer who had experienced disease progression during or within 6 months of discontinuing any prior line of treatment with platinum-based chemotherapy were eligible. This primary analysis was based on data that were current as of January 28, 2021. Interventions: Patients received PLD alone (40 mg/m2, intravenously, every 4 weeks, for up to 6 cycles) or PLD plus apatinib (250 mg, orally, daily). Main Outcomes and Measures: The primary end point was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, in the intent-to-treat population. Results: In total, 152 female patients were randomized, with 78 (51.3%) in the apatinib plus PLD group (median age, 54 years; range, 22-76 years) and 74 (48.7%) in the PLD group (median age, 56 years; range, 33-72 years). The median follow-up duration was 8.7 months (IQR, 4.7-14.1 months). The median PFS was 5.8 months (95% CI, 3.8-8.8) for treatment with apatinib plus PLD vs 3.3 months (95% CI, 2.1-3.8) for PLD (hazard ratio, 0.44; 95% CI, 0.28-0.71; P < .001). The median overall survival was 23.0 months (95% CI, 18.9 to not reached) with treatment with apatinib plus PLD vs 14.4 months (95% CI, 12.1-23.4) with PLD (hazard ratio, 0.66; 95% CI, 0.40-1.09). The most frequent grade 3 or higher treatment-emergent adverse events were decreased neutrophil counts (11 [14.9%] in the apatinib plus PLD group vs 6 [8.3%] in the PLD group), hypertension (6 [8.1%] vs none), and decreased white blood cell count (5 [6.8%] vs 3 [4.2%]). Two patients receiving treatment with apatinib plus PLD experienced grade 2 fistulas. Conclusions and Relevance: This randomized clinical trial found that treatment with apatinib plus PLD showed promising efficacy and manageable toxic effects in patients with PROC and may be a new alternative treatment option in this setting. Trial Registration: Clinicaltrials.gov Identifier: NCT04348032.

Abstract licence: CC BY

In 2025, it will be 30 years since the initial clinical approval of pegylated liposomal doxorubicin (PLD) by the Food and Drug Administration. PLD predated the field of nanomedicine and became a model nanomedicine setting key pharmacological principles (prolonged circulation, slow drug release and the enhanced permeability and retention (EPR) effect) for clinical application of other nano-drugs in cancer therapy. The impressive reduction of cardiotoxicity conferred by PLD is the most valuable clinical asset. While PLD has gained a strong foothold in relapsed ovarian cancer and metastatic breast cancer, it has not been extensively tested in primary (neoadjuvant) and adjuvant therapy and has not fulfilled the expectations from the results in animal models efficacy-wise. This discrepancy may be due to the large dose gap between mice and humans and the apparent variability of the EPR effect in human cancer. PLD is a complex product and we are still in a learning curve regarding a number of factors such as its interaction with the complement system and its immune modulatory properties, as well as its integration in multimodality therapy that may potentiate its value and role in cancer therapy.

Abstract licence: CC BY-NC

Pegylated liposomal doxorubicin (PLD) is a nano-doxorubicin anticancer agent. It was used as early as 2014 to treat ovarian and breast cancer, multiple myeloma and Kaposi's sarcoma. The 2018 National Comprehensive Cancer Network guidelines listed PLD as first-line chemotherapy for ovarian cancer. PLD has significant anticancer efficacy and good tolerance. Although PLD significantly reduces the cardiotoxicity of conventional doxorubicin, its cumulative-dose cardiotoxicity remains a clinical concern. This study summarizes the high-risk factors for PLD-induced cardiotoxicity, clinical dose thresholds, and cardiac function testing modalities. For patients with advanced, refractory, and recurrent malignant tumors, the use of PLD is still one of the most effective strategies in the absence of evidence of high risk such as cardiac dysfunction, and the lifetime treatment dose should be unlimited. Of course, they should also be comprehensively evaluated in combination with the high-risk factors of the patients themselves and indicators of cardiac function. This review can help guide better clinical use of PLD.

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Anthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non-pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450–480 mg/m2. Following three pivotal first-line phase III trials in HER2-negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2-negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms.

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Intrahepatic accumulation dominates organ distribution for most nanomedicines. However, obscure intrahepatic fate largely hampers regulation on their in vivo performance. Herein, PEGylated liposomal doxorubicin is exploited to clarify the intrahepatic fate of both liposomes and the payload in male mice. Kupffer cells initiate and dominate intrahepatic capture of liposomal doxorubicin, following to deliver released doxorubicin to hepatocytes with zonated distribution along the lobule porto-central axis. Increasing Kupffer cells capture promotes doxorubicin accumulation in hepatocytes, revealing the Kupffer cells capture-payload release-hepatocytes accumulation scheme. In contrast, free doxorubicin is overlooked by Kupffer cells, instead quickly distributing into hepatocytes by directly crossing fenestrated liver sinusoid endothelium. Compared to free doxorubicin, liposomal doxorubicin exhibits sustained metabolism/excretion due to the extra capture-release process. This work unveils the pivotal role of Kupffer cells in intrahepatic traffic of PEGylated liposomal therapeutics, and quantitively describes the intrahepatic transport/distribution/elimination process, providing crucial information for guiding further development of nanomedicines.

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High-risk childhood leukemia has a poor prognosis because of treatment failure and toxic side effects of therapy. Drug encapsulation into liposomal nanocarriers has shown clinical success at improving biodistribution and tolerability of chemotherapy. However, enhancements in drug efficacy have been limited because of a lack of selectivity of the liposomal formulations for the cancer cells. Here, we report on the generation of bispecific antibodies (BsAbs) with dual binding to a leukemic cell receptor, such as CD19, CD20, CD22, or CD38, and methoxy polyethylene glycol (PEG) for the targeted delivery of PEGylated liposomal drugs to leukemia cells. This liposome targeting system follows a "mix-and-match" principle where BsAbs were selected on the specific receptors expressed on leukemia cells. BsAbs improved the targeting and cytotoxic activity of a clinically approved and low-toxic PEGylated liposomal formulation of doxorubicin (Caelyx) toward leukemia cell lines and patient-derived samples that are immunophenotypically heterogeneous and representative of high-risk subtypes of childhood leukemia. BsAb-assisted improvements in leukemia cell targeting and cytotoxic potency of Caelyx correlated with receptor expression and were minimally detrimental in vitro and in vivo toward expansion and functionality of normal peripheral blood mononuclear cells and hematopoietic progenitors. Targeted delivery of Caelyx using BsAbs further enhanced leukemia suppression while reducing drug accumulation in the heart and kidneys and extended overall survival in patient-derived xenograft models of high-risk childhood leukemia. Our methodology using BsAbs therefore represents an attractive targeting platform to potentiate the therapeutic efficacy and safety of liposomal drugs for improved treatment of high-risk leukemia.

Abstract licence: CC BY-NC-ND