br Introduction br Ovarian cancer is the
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 . Maintaining drug concentrations within the therapeutic window is therefore particularly challenging.
As such, specificity for cancer Polybrene will therefore be a principal criterion in determining the success of new cancer therapies. This study
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
administration, barring the use of a delivery vehicle. Systemic circula-tion will be minimized due to the passively targeted nature of the NLB and the nano-size of the particles on account of the Enhanced Permeability and Retention (EPR) phenomenon, ultimately favorably altering the biodistribution of antineoplastic drugs.
Tumor targeting will enable the attainment of augmented levels of CPT at the tumor site by favorably altering biodistribution of the drug following intravenous administration, whilst preserving the state of healthy tissue. Hence, anti-tumor efficacy will be substantially in-creased while the side-effects associated with conventional che-motherapy will be dramatically reduced. Furthermore, the existence and concurrent treatment of co-morbidities will pose less of a challenge in the realm of cancer treatment due to site-specific release of che-motherapeutic drugs, which will minimize drug-disease and drug-drug interactions with co-existing morbidities and their treatment. Targeted therapy Rolling circle displays increased mean residence time (MRT) in tumor tissue, will allow for reduced frequency and duration of therapy, which will provide psychological and physiological benefits for the patient.