Pharmacological studies of cisplatin encapsulated in long-circulating liposomes in mouse tumor models

Bandak, Suzan; Goren, Dorit; Horowitz, Aviva T.; Tzemach, Dina; Gabizón, Alberto

doi:10.1097/00001813-199911000-00007

Cited by 127 publications

(78 citation statements)

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“…However, studies have demonstrated that carrier-mediated delivery of an effective agent to the tumor site is not in its self sufficient to achieve therapy. Furthermore, the concentration of drug achieved within the site of tumor growth does not necessarily predict therapeutic activity (48,49). This apparent contradiction can be attributed to the properties of the liposomal carrier.…”

Section: Discussionmentioning

confidence: 99%

Liposomal Irinotecan

Messerer

Ramsay

Waterhouse

et al. 2004

Clinical Cancer Research

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Purpose:The purpose is to demonstrate whether an appropriately designed liposomal formulation of irinotecan is effective in treating mice with liver-localized colorectal carcinomas.Experimental Design: Irinotecan was encapsulated in 1,2-distearoyl-sn-glycero-3-phosphocholine/cholesterol (55:45 molar ratio) liposomes using an ionophore (A23187)-generated transmembrane proton gradient. This formulation was evaluated in vivo by measuring plasma elimination of liposomal lipid and drug after i.v. administration. Therapeutic activity was determined in SCID/Rag-2M mice bearing s.c. LS180 tumors or orthotopic LS174T colorectal metastases.Results: Drug elimination from the plasma was significantly reduced when irinotecan was administered in the liposomal formulation. At 1 hour after i.v. administration, circulating levels of the liposomal drug were 100-fold greater than that of irinotecan given at the same dose. High-performance liquid chromatographic analysis of plasma samples indicated that liposomal irinotecan was protected from inactivating hydrolysis to the carboxylate form. This formulation exhibited substantially improved therapeutic effects. For the LS180 solid tumor model, it was shown that after a single injection of liposomal irinotecan at 50 mg/kg, the time to progress to a 400-mg tumor was 34 days (as compared with 22 days for animals treated with free drug at an equivalent dose). In the model of colorectal liver metastases (LS174T), a median survival time of 79 days was observed after treatment with liposomal irinotecan (50 mg/kg, given every 4 days for a total of three doses). Saline and free drug treated mice survived for 34 and 53 days, respectively.Conclusions: These results illustrate that liposomal encapsulation can substantially enhance the therapeutic activity of irinotecan and emphasize the potential for using liposomal irinotecan to treat liver metastases.

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Section: Discussionmentioning

confidence: 99%

Liposomal Irinotecan

Messerer

Ramsay

Waterhouse

et al. 2004

Clinical Cancer Research

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“…This reaction can be used to reduce membrane surface charge: incubating a suspension of nanocapsules with 1 mM cisplatin in water for 24 hours at 37 °C changed the ζ (zeta) potential, a direct measure of surface charge, from -44 ± 1 mV to a value identical to that of PC liposomes (data not shown). Reduction of membrane surface charge is an important tool to improve the stability of drug-lipid formulations in A major problem of the lipid formulations of cisplatin used so far, appears to be the low drug-to-lipid ratio, which limits the bioavailability of cisplatin in the tumor and which may result in low cytotoxicity 18 and in regrowth of platinum-resistant tumors 9 . Our method is expected to overcome these problems.…”

Section: Medical and Pharmaceutical Implicationsmentioning

confidence: 99%

Nanocapsules: lipid-coated aggregates of cisplatin with high cytotoxicity

Burger

Staffhorst

Vijlder

et al. 2002

Nat Med

173

160

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Cisplatin is one of the most widely used agents in the treatment of solid tumors, but its clinical utility is limited by toxicity. The development of less toxic, liposomal formulations of cisplatin has been hampered by the low water solubility and low lipophilicity of cisplatin, resulting in very low encapsulation efficiencies. We describe a novel method allowing the efficient encapsulation of cisplatin in a lipid formulation; it is based on repeated freezing and thawing of a concentrated solution of cisplatin in the presence of negatively charged phospholipids. The method is unique in that it generates nanocapsules, which are small aggregates of cisplatin covered by a single lipid bilayer. The nanocapsules have an unprecedented drug-to-lipid ratio and an in vitro cytotoxicity up to 1000-fold higher than the free drug. Analysis of the mechanism of nanocapsule formation suggests that the method may be generalized to other drugs showing low water solubility and lipophilicity.The clinical use of cis-diamminedichloroplatinum(II) (cisplatin) and many of its analogs faces three major problems: 1) serious dose-limiting toxicities in particular nephrotoxicity and neurotoxicity; 2) rapid inactivation of the drug as a result of complexation to plasma and tissue proteins; and 3) the frequent occurrence of platinum resistance [1][2][3][4][5] . In general, these problems can be reduced by shielding of a drug from the extracellular environment by means of a lipid coating. However, in many cases this approach fails because of inefficient encapsulation of the drug in lipid formulations resulting in low drug uptake by the tumor 6 . This is particularly true for cisplatin: the low water solubility and low lipophilicity of cisplatin result in lipid formulations with a very low drug-to-lipid ratio 7-9 . One approach is to synthesize lipophilic derivatives of cisplatin that can be efficiently encapsulated in large multilamellar liposomes 10 . Here, we describe a new method to efficiently encapsulate native, non-derivitized cisplatin in a lipid formulation. Nanocapsules of cisplatinOur method involves hydration of a dry lipid film composed of equimolar amounts of dioleoyl-phosphatidylserine (PS) and dioleoyl-phosphatidylcholine (PC), with a buffered solution (pH 7.4) of 5 mM cisplatin followed by 10 freeze-thaw (FT) cycles, and removal of free (extravesicular) cisplatin by centrifugation. The cisplatincontaining lipid suspension (cisPt-PS/PC) was extremely cytotoxic (Fig. 1a) with a typical IC 50 (the drug concentration at which cell growth is inhibited by 50%) of approximately 2 nM as compared with 0.5 µM for the free drug (conventional cisplatin). A lipid suspension not loaded with cisplatin (blank) was not cytotoxic, and mixing conventional cisplatin with the blank lipid suspension did not increase the cytotoxicity of cisplatin.Omitting the freeze-thaw step, or leaving out the negatively charged PS in the lipid mixture, resulted in a dramatic decrease in cytotoxicity (Fig. 1b). This decrease in cytotoxicity was paralleled by a sim...

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“…[114,117] In another clinical studies, liposomal cisplatin formulation (SPI-077) shown a substantial tumor accumulation with almost no anticancer activity due to diffusional limitation of cisplatin through the intact liposomal membrane. [118,119] Active targeting to tumor cells have been envisioned to increase the intracellular delivery and bioavailability of drugs. In recent Phase II clinical trials, actively targeted BIND-014 nanomedicines showed higher accumulation in tumor, yet better therapeutic efficacy was not evidenced.…”

Section: Controlled Drug Releasementioning

confidence: 99%

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

Balasubramanian

Liu

Hirvonen

et al. 2017

Adv Healthcare Materials

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Explosive growth of nanomedicines continues to significantly impact the therapeutic strategies for effective cancer treatment. Despite the significant progress in the development of advanced nanomedicines, successful clinical translation remains challenging. As cancer nanomedicine is a multidisciplinary field, the fundamental problem is that the knowledge gaps stem from different vantage points in the understanding of cancer nanomedicines. The complexities and heterogenecity of both nanomedicines and cancer are further demanding the integration of highly diverse expertise to develop clinically translatable cancer nanomedicines. This progress report aims to discuss the current understanding of cancer nanomedicines between different research areas in terms of nanoparticle engineering, formulation, tumor patho-physiology and clinical medicine, as well as to identify the knowledge gaps lying at the interface between the different fields of research in nanomedicine. Here we also highlight for the necessity to harmonize the multidisciplinary effort in the research of nanomedicines in order to bridge the knowledge and to advance the full understanding in cancer nanomedicines. A paradigm shift is needed in the strategic development of disease specific nanomedicines in order to foster the successful translation into clinic of future cancer nanomedicines.

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Pharmacological studies of cisplatin encapsulated in long-circulating liposomes in mouse tumor models

Cited by 127 publications

References 0 publications

Liposomal Irinotecan

Liposomal Irinotecan

Nanocapsules: lipid-coated aggregates of cisplatin with high cytotoxicity

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

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