Liposomal topotecan

Figure S An electron micrograph of unloaded liposomes or liposomal topotecan stabilized in a SO4 complex following loading using MnS04 gradients in the presence of the ionophore A23187 at a ratio of topotecan-to-lipid of 0.2 (wt wt). Source From Ref. 35.

Liposomal doxorubicin also received initial approval on the basis of response rafe in patients with refractory cancer followed up with a randomized trial of the agent vs. topotecan. The alkylating agent temozolomide was approved in a Phase 11 trial for treatment of patients with anaplastic astrocytoma. Of note is that, although not yet filed for full approval, temozolomide has been recently added on to radiation therapy (e.g., a major trial of radiation therapy with or without temozolomide) for patients with glioblastoma multiforme. The result of this trial showed a major improvement in survival for patients treated with the radiation plus temozolomide vs. those treated with radiation therapy alone (median survival 15 vs. 12 months, p < 0.0001 and 1 year survival 26 vs. 8%, p < 0.0001).25... 

Cordon, A.N. et al.. Recurrent epithelial ovarian carcinoma a randomized phase III study of pegylated liposomal doxorubicin versus topotecan, /. Clin. Oncol., 19, 3312-3322,2001. 

Tardi P, Choice E, Masin D, Redelmeier T, Bally M, Madden TD. Liposomal encapsulation of topotecan enhances anticancer efficacy in murine and human xenograft models. Cancer Res 2000 60 3389. 

Abraham SA, Edwards K, Karlsson G, Hudon N, Mayer LD, Bally MB. An evaluation of transmembrane ion gradient-mediated encapsulation of topotecan within liposomes. J Control Release 2004 96 449. 

Figure 1 Chemical structures of some amphipathic weak bases that have been loaded and stabilized in liposomes using trialkylammonium salts of polyanionic trapping agents in our lab. (A) Doxorubicin, (B) epirubicin, (C) vinorelbine, (D) vincristine, (E) vinblastine, (E) topotecan, (G) irinotecan, (H) swainsonine, (I) 2-diethylami-noethyl-ellipticinium, (J) 6-(3-aminopropyl)ellipticine, and (K) LAQ824.

Liu JJ, Hong RL, Cheng WF, et al. Simple and efficient liposomal encapsulation of topotecan by ammonium sulfate gradient stability, pharmacokinetic and therapeutic evaluation. Anti-Cancer Drugs 2002 13(7) 709. 

Combination chemotherapy is the standard approach to stage III and stage IV disease. Randomized clinical studies have shown that the combination of paclitaxel and cisplatin provides survival benefit compared with the previous standard combination of cisplatin plus cyclophosphamide. More recently, several studies have shown that carboplatin and paclitaxel yields clinical results similar to what is achieved with the cisplatin plus paclitaxel combination however, because of reduced toxicity and greater ease of administration, carboplatin plus paclitaxel has now become the treatment of choice. In patients who present with recurrent disease, the topoisomerase I inhibitor topotecan, the alkylating agent altretamine, and liposomal doxorubicin are used as single agent monotherapy. 

In addition to the remote or active loading techniques mentioned above, metal complexation reactions have been demonstrated to achieve accumulation of doxorubicin in liposomes [148,149], Furthermore, copper-topotecan complexation has been recently seen to mediate drug accumulation into liposomes and is proposed as a methodology to prepare liposomal camptothecin formulations [72],... 

Chemotherapy refers to drug administration with highly serious side effects, such as nausea, hand and foot rashes, mouth sores, and increased risk of infection, easy bruising, and so on. Therefore, liposomal carriers have been used in order to improve the drug s biodistribution and protect the patient from those side effects. The main anticancer drugs used to treat ovarian cancer are carboplatin and cisplatin, paclitaxel, topotecan, and lurtotecan. PEGylated liposomal doxorubicin has been approved as a regimen for patients with metastatic ovarian cancer refractory to both paclitaxel and platinum based-therapy [449],... 

A phase III study was conducted to compare PEG-liposomal DXR (50 mg/m2 every 4 weeks) with paclitaxel (175 mg/m2 every 3 weeks) using 214 patients with relapse after first-line platinum-based chemotherapy [420], As previously, the response rates and PFS were not significantly different, but again the liposomal formulation was notably less toxic as fewer patients recorded with grade 4 adverse effects (17% compared to 71% for topotecan) and thus was more tolerable. 

Taggar, A. S., Alnajim, J., Anantha, M., Thomas, A., Webb, M., Ramsay, E., and Bally, M. B. (2006), Copper-topotecan complexation mediates drug accumulation into liposomes, /. Controlled Release, 114,78-88. 

Seideii, M. V., Muggia, F., Astrow, A., Matulonis, U., Campos, S., Roche, M., Sivret, J., Rusk, J., and Barrett, E. (2004), A phase II study of liposomal lurtotecan (OSI-211) in patients with topotecan resistant ovarian cancer, Gynecol. Oncol., 93, 229-232. 

Ovary Carboplatin paclitaxel Topotecan liposomal doxorubicin (caelyx)... 

Current clinical investigations with topoisomerase I inhibitors include the feasibihty of oral administration of topotecan and irinotecan, the use of a liposomal lurtotecan formulation (NX211), and the use of a pegylated derivative of the naturally occurring camptothecin, which is soluble in aqueous solutions even at low pH values (3,10). 

Seiden MV et al (2004) A phase II study of liposomal lurtotecan (OSI-211) in patients with topotecan resistant ovarian cancer. Gynecol Oncol 93 229-232... 

The NCCN guidelines recommend retreatment with either paclitaxel or platinum, or the combination of paclitaxel and a platinum compound if disease recurs more than 6 months after the initial treatment with paclitaxel in combination with a platinum analog. Treatment options for patients with refractory disease or disease recurrence within 6 months after treatment include topotecan, altretamine, oral etopo-side, liposomal doxorubicin, gemcitabine, tamoxifen, referral for a clinical trial, or supportive care therapy. 

Du J, Lu WL, Ying X, Liu Y, Du P, Tian W, et al. Dual-targeting topotecan liposomes modified with tamoxifen and wheat germ agglutinin significantly improve dmg transport across the hlood—brain barrier and survival of brain tumor-bearing animals. Mol Pharm 2009 6(3) 905-17. 

Difficulties associated with CPTs administration, toxicity, and pharmacokinetics were a reason for the development of more favorable alternative forms of their dehvery or prodrug systems [35 10]. Delivery of CPT and its derivatives was studied by using hposomes (see also lurtotecan). Examples of such lipid formulations of CPTs in clinical trials include CPX-1 (irinotecan-floxuridine hposome in Phase 1) firom Celator Pharmaceuticals [285] and Brakiva (Topotecan Optisome) liposomal formulation of topotecan from Hana Biosciences [286]. 

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