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Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics.

ABSTRACT: Topotecan is currently approved for relapsed small-cell lung cancer and ovarian cancer. Topotecan's efficacy in the second-line setting and novel mechanism of action suggest broad antitumour activity. We utilised a clinically validated, cell-death, ex vivo assay in human tumour explants to examine the activity profile of topotecan alone and in combination with other antitumour agents. Serial dilutions of topotecan alone and in combination with other cytotoxic agents were applied to biopsy specimens of non-small-cell lung cancer (NSCLC) and breast, colon, and prostate cancers. Dose-response curves were interpolated to provide 50% lethal concentrations (LC(50)). The degree of synergy (by median effect) and normalised Z-scores (raw scores converted to relative activity distributed around the mean) were then computed. Single-agent activity was observed for topotecan in all four tumour types. In 57 chemotherapy-naive specimens, NSCLC revealed the highest activity, demonstrated by the lowest LC(50) value (0.26+/-0.06 microg ml(-1); P=0.002). Overall, previously treated and chemotherapy-naive specimens revealed no significant differences in mean LC(50)'s. Synergy was observed for several combinations, including topotecan plus cisplatin in prostate and for topotecan plus 5-fluorouracil in breast cancers. The Z-score analyses conducted suggest activity for previously unexplored drug regimens, including topotecan plus 5-fluorouracil, vinorelbine, and mitomycin-C in NSCLC and breast cancer. Phase II studies are underway to determine the degree to which these ex vivo findings will translate into improved clinical results.

SUBMITTER: Nagourney RA

PROVIDER: S-EPMC2394409 | biostudies-other | 2003 Nov

REPOSITORIES: biostudies-other

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Project description:BACKGROUND:"Nanomedicine" is the application of purposely designed nano-scale materials for improved therapeutic and diagnostic outcomes, which cannot be otherwise achieved using conventional delivery approaches. While "translation" in drug development commonly encompasses the steps from discovery to human clinical trials, a different set of translational steps is required in nanomedicine. Although significant development effort has been focused on nanomedicine, the translation from laboratory formulations up to large scale production has been one of the major challenges to the success of such nano-therapeutics. In particular, scale-up significantly alters momentum and mass transfer rates, which leads to different regimes for the formation of nanomedicines. Therefore, unlike the conventional definition of translational medicine, a key component of "bench-to-bedside" translational research in nanomedicine is the scale-up of the synthesis and processing of the nano-formulation to achieve precise control of the nanoscale properties. This consistency requires reproducibility of size, polydispersity and drug efficacy. METHODS:Here we demonstrate that Flash NanoPrecipitation (FNP) offers a scalable and continuous technique to scale up the production rate of nanoparticles from a laboratory scale to a pilot scale. FNP is a continuous, stabilizer-directed rapid precipitation process. Lumefantrine, an anti-malaria drug, was chosen as a representative drug that was processed into 200 nm nanoparticles with enhanced bioavailability and dissolution kinetics. Three scales of mixers, including a small-scale confined impinging jet mixer, a mid-scale multi-inlet vortex mixer (MIVM) and a large-scale multi-inlet vortex mixer, were utilized in the formulation. The production rate of nanoparticles was varied from a few milligrams in a laboratory batch mode to around 1 kg/day in a continuous large-scale mode, with the size and polydispersity similar at all scales. RESULTS:Nanoparticles of 200 nm were made at all three scales of mixers by operating at equivalent Reynolds numbers (dynamic similarity) in each mixer. Powder X-ray diffraction and differential scanning calorimetry demonstrated that the drugs were encapsulated in an amorphous form across all production rates. Next, scalable and continuous spray drying was applied to obtain dried powders for long-term storage stability. For dissolution kinetics, spray dried samples produced by the large-scale MIVM showed 100% release in less than 2 h in both fasted and fed state intestinal fluids, similar to small-batch low-temperature lyophilization. CONCLUSIONS:These results validate the successful translation of a nanoparticle formulation from the discovery scale to the clinical scale. Coupling nanoparticle production using FNP processing with spray drying offers a continuous nanofabrication platform to scale up nanoparticle synthesis and processing into solid dosage forms.

Project description:Reconstruction of bone defects, especially the critical-sized defects, with mechanical integrity to the skeleton is important for a patient's rehabilitation, however, it still remains challenge. Utilizing biomaterials of human origin bone tissue for therapeutic purposes has provided a facilitated approach that closely mimics the critical aspects of natural bone tissue with regard to its properties. However, not only efficacious and safe but also cost-effective and convenient are important for regenerative biomaterials to achieve clinical translation and commercial success. Advances in our understanding of regenerative biomaterials and their roles in new bone formation potentially opened a new frontier in the fast-growing field of regenerative medicine. Taking inspiration from the role and multicomponent construction of native extracellular matrix (ECM) for cell accommodation, the ECM-mimicking biomaterials and the naturally decellularized ECM scaffolds were used to create new tissues for bone restoration. On the other hand, with the going deep in understanding of mesenchymal stem cells (MSCs), they have shown great promise to jumpstart and facilitate bone healing even in diseased microenvironments with pharmacology-based endogenous MSCs rescue/mobilization, systemic/local infusion of MSCs for cytotherapy, biomaterials-based approaches, cell-sheets/-aggregates technology and usage of subcellular vesicles of MSCs to achieve scaffolds-free or cell-free delivery system, all of them have been shown can improve MSCs-mediated regeneration in preclinical studies and several clinical trials. Here, following an overview discussed autogenous/allogenic and ECM-based bone biomaterials for reconstructive surgery and applications of MSCs-mediated bone healing and tissue engineering to further offer principles and effective strategies to optimize MSCs-based bone regeneration. Highlights • Focusing on MSCs based bone regeneration.• Discussed cytotherapy, cell-free therapies and cell-aggregates technology in detail.• Stating the approaches of MSCs in diseased microenvironments.

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Ex vivo analysis of topotecan: advancing the application of laboratory-based clinical therapeutics.

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