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    S. Li, Efficacy of SERD/SERM Hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer, Clin. Cancer Res. 21 (22) (2015)
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    Colloids and Surfaces B: Biointerfaces
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    Antineoplastic nano-lipobubbles for passively targeted ovarian cancer therapy 
    Derusha Frank, Sunaina Indermun, Mershen Govender, Pradeep Kumar, Yahya E. Choonara, Lisa C. du Toit, Viness Pillay
    Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown, 2193, South Africa
    Ovarian cancer 
    The multivariate challenges associated with successful ovarian cancer therapy severely compromises the out-come of therapy and patient quality of life. Coated cholesterol (CHO) and distearoylphosphatidylethanolamine (DSPE) nano-lipobubbles (NLBs) loaded with silibinin and camptothecin were synthesized and evaluated as a possible intravenous delivery system for the treatment of ovarian cancer. Cytotoxicity analysis in addition to in vitro release, zeta potential and drug entrapment studies were conducted on the NLBs. Results of the cytotoxicity evaluation on A2780 epithelial ovarian cancer Kainic acid corroborated the benefits of the altered drug release char-acteristics achieved following polymeric coating. Cumulative cytotoxicity demonstrated by the NLBs 72 h post-treatment ranged between 85%–95%. Cellular internalization of the NLBs was swiftly achieved, with the extent of internalization exhibiting time-dependent characteristics. A size-dependent cellular internalization correlation between the NLB systems was also achieved. Evaluation of the prepared NLBs displayed favorable characteristics for the achievement of passive targeting and satisfactory drug incorporation for application in ovarian cancer treatment.
    1. Introduction
    Ovarian cancer is the most aggressive, and the foremost cause of death, of all gynecological cancers [1–3]. The primary factors con-tributing to the poor prognosis and high mortality rate associated with ovarian cancer is a combination of non-specific symptoms and a lack of early detection modalities, leading to advanced disease and often sig-nificant metastasis at time of diagnosis [1–4]. In addition, ovarian cancer has also displayed a high degree of recurrence, leading to an overall 5-year survival rate of between 30%–45% [4,5].
    Antineoplastic drugs exhibit limited specificity for tumor tissue and have a tendency to act indiscriminately, particularly on rapidly dividing tissue. This indiscriminate activity results in deleterious and often life-threatening side-effects, such as cardiovascular complications, severe myelosuppression, compromised immunity, altered gastric function, myalgia and neurotoxicity, among others [2,6–10]. In addition, anti-neoplastic drugs are known to have a substantially narrow therapeutic window [11]. Maintaining drug concentrations within the therapeutic window is therefore particularly challenging.
    As such, specificity for cancer cells will therefore be a principal criterion in determining the success of new cancer therapies. This study
    Corresponding author.
    E-mail address: [email protected] (V. Pillay). 
    therefore provides for the development of a novel intravenously ad-ministered nano-lipobubble drug delivery system (NLB-DDS) consisting of both cholesterol (CHO) and distearoylphosphatidylethanolamine (DSPE) NLBs with camptothecin (CPT) used as the active drug. The incorporation of CPT within the NLBs has a dual function. Firstly, the physiologically labile drug, CPT, is protected from the unfavorable physiological environment prior to reaching the target tissue. Conversion to the inactive carboxylate form and subsequent association with human serum albumin is thus prevented. Secondly, retardation of drug release from the NLBs allows for adequate accumulation of the NLB-DDS within the target tumor tissue before significant drug is re-leased in the systemic circulation. Combined with these passive tar-geting characteristics, prolonged drug release will improve the side-effect profile associated with CPT. The NLB formulations were further modified to incorporate silibinin (SB), for the achievement of sy-nergistic antineoplastic activity with CPT.
    Formulation as a nano-DDS allows for enhanced solubilization of the strongly lipophilic CPT which is further augmented by the presence of a phospholipoidal NLB shell. Additionally, the shell facilitates in-corporation of the lipophilic drug, whilst conferring aqueous compat-ibility characteristics on the formulation. This enables intravenous