Chemotherapy regimen for recurrent uterine leiomyosarcoma.

INTRODUCTION: Uterine leiomyosarcoma is a rare gynecological malignancy, the limited literature indicated that doxorubicin alone or gemcitabine/docetaxel combination is the preferred chemotherapy regimen. Given the rarity of the disease and the lack of high-level clinical evidence, there is no consensus on the best treatment. CASE REPORT: We report a case of a patient with uterine leiomyosarcoma who recurred after adjustment treatment with doxorubicin, gemcitabine, docetaxel, and anlotinib; and required a new chemotherapy regimen. MANAGEMENT AND OUTCOMES: The follow-up chemotherapy regimen was doxorubicin-liposome 40 mg/m2 on one day in combination with dacarbazine 250 mg/m2 on one to five days of intravenous infusion every 21 days. We monitored adverse effects during chemotherapy and the process was smooth. DISCUSSION: It is important to comprehensively consider the patient's condition, and fully consider the efficacy, dosage, and adverse reactions of the chemotherapy regimen to determine the appropriate plan, in order to achieve the best therapeutic benefits for patients.

Sialic acid-modified doxorubicin liposomes target tumor-related immune cells to relieve multiple inhibitions of CD8+ T cells.

In different types of cancer treatments, cancer-specific T cells are required for effective anticancer immunity, which has a central role in cancer immunotherapy. However, due to the multiple inhibitions of CD8+ T cells by tumor-related immune cells, CD8+ T-cell mediated antitumor immunotherapy has not achieved breakthrough progress in the treatment of solid tumors. Receptors for sialic acid (SA) are highly expressed in tumor-associated immune cells, so SA-modified nanoparticles are a drug delivery nanoplatform using tumor-associated immune cells as vehicles. To relieve the multiple inhibitions of CD8+ T cells by tumor-associated immune cells, we prepared SA-modified doxorubicin liposomes (SL-DOX, Scheme 1A). In our study, free SA decreased the toxicity of SL-DOX to tumor-associated immune cells. Compared with common liposomes, SL-DOX could inhibit tumor growth more effectively. It is worth noting that SL-DOX could not only kill tumor-related neutrophils and monocytes to relieve the multiple inhibitions of CD8+ T cells but also induce immunogenic death of tumor cells to promote the infiltration and differentiation of CD8+ T cells (Scheme 1B). Therefore, SL-DOX has potential value for the clinical therapeutic effect of CD8+ T cells mediating anti-tumor immunotherapy.

Radiopharmaceuticals for Treatment of Osteosarcoma.

Although trace amounts of radioactivity are routinely used to detect osteosarcoma, the use of larger therapeutic amounts of radiation is often an unrecognized opportunity to treat metastatic osteosarcoma. This chapter will review a number of approaches to use ionizing radiation in the form of injectable radiopharmaceuticals. Since bone metastases are a common pattern of metastatic spread of cancer in general, a number of bone-seeking radiopharmaceuticals have been developed and FDA approved for treatment of bone metastases. Although osteosarcoma, a bone-forming cancer, would seem ideally suited to be treated with bone seekers, patterns of relapse involving non-ossifying metastases remain a major problem to be overcome. Thus, this review will not only describe experience using a number of bone-seeking radiopharmaceuticals such as 153-samarium-EDTMP, 153-samarium-DOTMP, and 223-radium against osteosarcoma, but also approaches to identify patients who may benefit as well as some means to the improve overall efficacy including combination therapy with routine agents and using nuclear imaging to develop best strategy for use. These include imaging with not only 99mTc-MDP standard bone scans, but also 99mTc-MDP bone scans with SPECT CT, bone-specific sodium fluoride PET-CT (Na18F), and 18FDG-PET-CT. Accurate knowledge of oligometastatic active disease can facilitate more effective use of combination therapy, including radiosensitizers and local control measures, for example, stereotactic body radiotherapy (SBRT) and/or cryoablation to reduce disease burden as well as manage and prevent micrometastatic disease from growing and metastasizing. Finally, a new tumor-specific radiopharmaceutical, CLR 131, may also provide another radiopharmaceutical to treat both osteoblastic and non-ossifying areas of osteosarcoma.

Membrane-Loaded Doxorubicin Liposomes Based on Ion-Pairing Technology with High Drug Loading and pH-Responsive Property.

In order to achieve high drug loading and high entrapment efficiency, a doxorubicin-cholesteryl hemisuccinate ion-pair complex (DCHIP) was formed, and the ion-pair complex liposomes (DCHIP-Lip) were prepared based on conventional thin-film dispersion method. Firstly, DCHIP was fabricated and confirmed with FTIR, 1H-NMR, DSC, and XRD techniques. Afterwards, DCHIP-Lip were prepared and evaluated in terms of particle size, zeta potential, entrapment efficiency, and drug loading content. Finally, the in vitro and in vivo behavior of liposomes was further investigated. The DCHIP-Lip had a nanoscale particle size of about 120 nm with a negative zeta potential of about -22 mV. In addition, the entrapment efficiency and drug loading content of DOX reached 6.4 ± 0.05 and 99.29 ± 0.3%, respectively. Importantly, the release of DCHIP-Lip was pH sensitive and increased cell toxicity against MCF-7 cells was achieved. Upon dilution, the liposomes were fairly stable under physiological conditions. The in vivo pharmacokinetic study indicated that the AUC of DOX in DCHIP-Lip was 11.48-fold higher than that of DOX-HCl solution and the in vivo antitumor activity of DCHIP-Lip showed less body weight loss and a significant prohibition effect of tumor growth. Based on these findings, it can be seen that the ion-pairing technology combined with conventional liposome drug loading method could be used to achieve high drug loading and it could be valuable for the study of liposomal delivery system.

A case of diffuse large B-cell lymphoma with interstitial pneumonia.

This report involves a 54-year-old female patient diagnosed with diffuse large B-cell lymphoma who developed interstitial pneumonia (IP) during treatment. The patient presented to the ward with enlarged lymph nodes in the neck and was treated with the standard regimen, which included rituximab, cyclophosphamide, doxorubicin liposomes, vincristine, and prednisone (R-CDOP regimen). After 3 cycles, the treatment was assessed as effective. However, following the 4th cycle, the patient experience shortness of breath after physical activity. A repeat lung computer tomography indicated IP, which completely recovered after receiving "full coverage" treatment. Subsequently, the patient underwent 2 cycles of cyclophosphamide, doxorubicin liposomes, vincristine, and prednisone (CDOP), followed by local radiotherapy. Currently, the patient is now being followed up with regular reviews.

Increasing the antitumor efficacy of doxorubicin liposomes with coupling an anti-EGFR affibody in EGFR-expressing tumor models.

Epidermal growth factor receptor (EGFR) is overexpressed in a wide range of solid tumors. In this study, we exploited a high-affinity EGFR-antagonistic affibody (ZEGFR) coupled to a doxorubicin loaded pegylated liposome (LS-Dox) for concurrent passive and active targeting of EGFR+ A431 tumor cells in vitro and in vivo. The in vitro studies revealed that the Dox liposomes coupled with ZEGFR (AS-Dox) showed a higher Dox uptake than LS-Dox in EGFR+ A431 cells but not in EGFR- B16F10 cells, resulting in a selectively enhanced cytotoxicity. In vivo, AS-Dox confirmed its long circulation time and efficient accumulation in tumors. This targeted chemotherapy achieved greater tumor suppression. Further, this low-dose but effective targeted treatment reduced systemic toxicity such as body weight loss and organ injury demonstrated by H&E staining. Thus, selective targeting of LS-Dox coupled with ZEGFR enhanced antitumor effects and improved systemic safety. These results demonstrated that LS-Dox coupled with ZEGFR might be developed as a potential tool for therapy of EGFR+ tumors.

Development of a Flow-Through USP-4 Apparatus Drug Release Assay to Evaluate Doxorubicin Liposomes.

Doxil® is a complex parenteral doxorubicin (DOX) liposome formulation approved by the FDA. For generic doxorubicin liposomes, analyzing the release profile of DOX is important for quality control and comparability studies. However, there is no robust standard drug release assay available for doxorubicin liposomes. In this study, we describe a USP-4 apparatus assay capable of discriminating DOX liposomal formulations based on release profile. Establishment of the assay was hindered by limited DOX release from liposomes in physiological conditions at 37°C. The addition of NH4HCO3 to the release media facilitated DOX release proportionally to the salt concentration added but caused precipitation of released drug in USP-4 apparatus. Precipitation of DOX was avoided by adding hydroxypropyl-cyclodextrin (HP-CD) to the release medium. We optimized conditions for DOX release by varying a number of parameters such as: concentration of HP-CD, testing temperature, and concentration of tested samples. The optimized release medium contained: 100 mM NH4HCO3, 75 mM 2-(N-morpholino) ethanesulfonic acid (MES) and 5% w/v HP-CD, 5% w/v sucrose, 0.02% w/v NaN3 (pH 6). The drug release assay was performed at 45°C. The optimized release assay can discriminate between DOX liposomal formulations of different compositions, physicochemical properties, and prepared by different manufacturing methods. This indicates that the assay could be used to compare DOX release from generic DOX formulations to the innovator product Doxil®.

Doxorubicin liposomes as an investigative model to study the skin permeation of nanocarriers.

The objectives of this study were to develop an innovative investigative model using doxorubicin as a fluorophore to evaluate the skin permeation of nanocarriers and the impact of size and surface characteristics on their permeability. Different doxorubicin-loaded liposomes with mean particle size <130 nm and different surface chemistry were prepared by ammonium acetate gradient method using DPPC, DOPE, Cholesterol, DSPE-PEG 2000 and 1,1-Di-((Z)-octadec-9-en-1-yl) pyrrolidin-1-ium chloride (CY5)/DOTAP/1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) as the charge modifier. There was minimal release of doxorubicin from the liposomes up to 8h; indicating that fluorescence observed within the skin layers was due to the intact liposomes. Liposomes with particle sizes >600 nm were restricted within the stratum corneum. DOTAP (p<0.01) and CY5 (p<0.05) liposomes demonstrated significant permeation into the skin than DOPA and PEG liposomes. Tape stripping significantly (p<0.01) enhanced the skin permeation of doxorubicin liposomes but TAT-decorated doxorubicin liposomes permeated better (p<0.005). Blockage of the hair follicles resulted in significant reduction in the extent and intensity of fluorescence observed within the skin layers. Overall, doxorubicin liposomes proved to be an ideal fluorophore-based model. The hair follicles were the major route utilized by the liposomes to permeate skin. Surface charge and particle size played vital roles in the extent of permeation.