Clinical Trials with Pegylated Liposomal Doxorubicin in the Treatment of  Ovarian Cancer

Pisano, Carmela; Cecere, Sabrina Chiara; Napoli, Marilena Di; Cavaliere, Carla; Tambaro, Rosa; Facchini, Gaetano; Scaffa, Cono; Losito, Simona; Pizzolorusso, Antonio; Pignata, Sandro

doi:10.1155/2013/898146

Cited by 52 publications

(31 citation statements)

References 79 publications

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“…With this respect, to improve the efficacy of DOXIL, DOXIL in combination with various drugs including platinum (carboplatin) [58–61], oxaliplatin [62], gemcitabine [63, 64], paclitaxel [65], topotecan [66], vinorelbine [67], ifosfamide [68], olaparib [69], cyclophosphamide and 5-fluorouracil [33], checkpoint blockers antibodies such as PD-L1, PD-1, and CTLA-4 mAbs [32], and trabectedin [70] have been explored in patients with cisplatin-sensitive or cisplatin-resistance recurrent ovarian cancer. A low to moderate increase in response rate, overall survival (OS), and progression free survival (PFS) has been reported for various combinations [71]. Among these combinations, carboplatin/DOXIL has been reported to be a valid alternate in both first line and recurrent ovarian cancer, compared to actual standard options [71].…”

Section: Discussionmentioning

confidence: 99%

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DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer

Kakar

Worth

Wang

et al. 2016

J Cancer Stem Cell Res

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Ovarian cancer is a highly aggressive and deadly disease. Currently, the treatment for ovarian cancer entails cytoreductive surgery followed by chemotherapy, mainly cisplatin or carboplatin combined with paclitaxel. Although this regimen is initially effective in a high percentage of cases, unfortunately, after few months of initial treatment, tumor relapse occurs due to platinum-resistance. DOXIL (liposomal preparation of doxorubicin) is a choice of drug for recurrent ovarian cancer. However, its response rate is very low and is accompanied by myocardial toxicity. Resistance to chemotherapy and recurrence of cancer is primarily attributed to the presence of cancer stem cells (CSCs), a small population of cells present in cancer. Effect of DOXIL and withaferin A (WFA), both alone and in combination, was investigated on cell proliferation of ovarian cancer cell line A2780 and tumor growth in SCID mice bearing i.p. ovarian tumors. ALDH1 cells were isolated from A2780 using cell sorter, and effect of DOXIL and WFA both alone and in combination on tumorigenic function of ALDH1 was studied using spheroids formation assays in vitro. Western blots were performed to examine the expression of ALDH1 and Notch 1 genes. In our studies, we showed, for the first time, that DOXIL when combined with withaferin A (WFA) elicits synergistic effect on inhibition of cell proliferation of ovarian cancer cells and inhibits the expression of ALDH1 protein, a marker for ALDH1 positive cancer stem cells (CSCs), and Notch1, a signaling pathway gene required for self-renewal of CSCs. Inhibition of expression of both ALDH1 and Notch1 genes by WFA was found to be dose dependent, whereas DOXIL (200 nM) was found to be ineffective. SCID mice, bearing i.p. ovarian tumors, were treated with a small dose of DOXIL (2 mg/kg) in combination with a sub-optimal dose of WFA (2 mg/kg) which resulted in a highly significant (60% to 70%) reduction in tumor growth, and complete inhibition of metastasis compared to control. In contrast, WFA treatment showed a significant reduction in tumor growth but no change in metastasis compared to control. DOXIL showed non-significant reduction in tumor growth and no change in metastasis compared to control. Isolated ALDH1 positive CSCs treated with the combination of DOXIL and WFA resulted in a significant reduction in spheroids formation (tumorigenic function of CSCs) and expression of ALDH1 protein. WFA when used alone at a concentration of 1.5 μM was found to be highly effective in suppression of ALDH1 expression, whereas DOXIL at a concentration of 200 nM was found to be ineffective. DOXIL in combination with WFA elicits synergistic effects, targets cancer stem cells, and has potential to minimize induction of drug resistance and reoccurrence of cancer. Based on our studies, we conclude that the combination of DOXIL with WFA has the potential to be an effective therapy for ovarian cancer and may ameliorate DOXIL related side effects as well as recurrence of ovarian cancer leading to increase in patients’ survival ...

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Section: Discussionmentioning

confidence: 99%

“…A low to moderate increase in response rate, overall survival (OS), and progression free survival (PFS) has been reported for various combinations [71]. Among these combinations, carboplatin/DOXIL has been reported to be a valid alternate in both first line and recurrent ovarian cancer, compared to actual standard options [71]. …”

Section: Discussionmentioning

confidence: 99%

DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer

Kakar

Worth

Wang

et al. 2016

J Cancer Stem Cell Res

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“…[53] Doxil is commonly used in ovarian cancer treatment in the clinic. [57] Therefore, we chose SKOV-3 ovarian xenograft mouse models to challenge our Rf-containing DOX-TD nanoformulations with the side-by-side comparison with Doxil in cancer treatment. We observed the significantly prolonged circulation, increased MTDs (2~2.5-fold increase), and the improved tumor-growth inhibition in ovarian cancer treatment for our nanoformulations in comparison with both free DOX and Doxil ® .…”

Section: Introductionmentioning

confidence: 99%

Riboflavin-containing telodendrimer nanocarriers for efficient doxorubicin delivery: High loading capacity, increased stability, and improved anticancer efficacy

et al. 2017

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We have developed two linear-dendritic telodendrimers (TDs) with rational design using amphiphilic riboflavin (Rf) as building blocks for efficient doxorubicin (DOX) delivery. Micellar TD nanoparticles (NPs) are composed of a hydrophilic polyethylene glycol (PEG) shell and a Rf-containing affinitive core for DOX encapsulation. Strong DOX-Rf interactions and amphiphilic Rf structure render these nanocarriers with an ultra-high DOX loading capacity (>1/1, DOX/TD, w/w), ~100% loading efficiency, the sustained drug release and the optimal particle sizes (20~40 nm) for efficient tumor-targeted drug delivery. These nanoformulations significantly prolonged DOX circulation time in the blood without the accelerated clearance observed after multiple injections. DOX-TDs target several types of tumors efficiently in vivo, e.g. Raji lymphoma, MDA-MB-231 breast cancer, and SKOV3 ovarian cancer. In vivo maximum tolerated dose (MTD) of DOX was increased by 2~2.5 folds for the nanoformulations in mice relative to those of free DOX and Doxil®. These nanoformulations significantly inhibited tumor growth and prolonged survival of mice bearing SKOV3 ovarian cancer xenografts. In summary, Rf-containing nanoformulations with high DOX loading capacity, improved stability and efficient tumor targeting lead to superior antitumor efficacy, which merit the further development for clinical application.

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“…PLD has become a major component in the routine management of epithelial ovarian cancer (extensively reviewed in Pisano et al). 71 Nonrandomized Phase II trials of PLD in platinum-resistant ovarian cancer patients documented the biological activity of this agent in this clinical setting, with objective response rates of approximately 10%-20% being reported in several trials. [72][73][74] Data indicated that palmar-plantar erythrodysesthesia (hand-foot syndrome), toxic acral erythema, and mucositis were the most common toxicities of PLD, reported in up to 50% of treated patients.…”

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confidence: 99%

Liposomes as nanomedical devices

Bozzuto¹,

Molinari²

2015

IJN

1,733

1,114

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Since their discovery in the 1960s, liposomes have been studied in depth, and they continue to constitute a field of intense research. Liposomes are valued for their biological and technological advantages, and are considered to be the most successful drug-carrier system known to date. Notable progress has been made, and several biomedical applications of liposomes are either in clinical trials, are about to be put on the market, or have already been approved for public use. In this review, we briefly analyze how the efficacy of liposomes depends on the nature of their components and their size, surface charge, and lipidic organization. Moreover, we discuss the influence of the physicochemical properties of liposomes on their interaction with cells, half-life, ability to enter tissues, and final fate in vivo. Finally, we describe some strategies developed to overcome limitations of the “first-generation” liposomes, and liposome-based drugs on the market and in clinical trials.

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Clinical Trials with Pegylated Liposomal Doxorubicin in the Treatment of Ovarian Cancer

Cited by 52 publications

References 79 publications

DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer

DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer

Riboflavin-containing telodendrimer nanocarriers for efficient doxorubicin delivery: High loading capacity, increased stability, and improved anticancer efficacy

Liposomes as nanomedical devices

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