Repurposing of Guanabenz acetate by encapsulation into long-circulating nanopolymersomes for treatment of triple-negative breast cancer.

Poor patient response and limited treatment modalities are the major challenges against combating triple-negative breast cancer (TNBC). The high related mortality urges for novel cancer therapeutics. Guanabenz acetate (GA) is an orphan antihypertensive drug with a short half-life. Re-purposing (GA) by developing a polymersome (PS)-based cancer nanomedicine is an innovative approach in treating TNBC. Formulation and optimization of GA-loaded PEGylated Polycaprolactone PS through different process variables (solvent selection, the order of addition, pH of the aqueous phase, and drug to polymer ratio) were achieved by the nanoprecipitation method. The in vitro cellular uptake, anti-cancer, and anti-metastatic activity of GA and GA-loaded PS were tested in MDA-MB 231(TNBC cell line) and MCF-7 cell line. Western blot analysis was performed to elucidate the molecular anti-cancer mechanism. The in vivo biodistribution study and antitumor activity were investigated in the TNBC-xenograft model implanted in mice. Under optimized formulation conditions, GA-loaded PS had a nanosize of 90.5 nm with PDI < 0.2, a zeta potential -9.11 mV, drug encapsulation efficiency of 92.11% and sustained drug release for 6-days. GA-loaded PS exhibited enhanced cellular uptake and achieved a significantly lower IC50 in both breast cancer cell lines compared to free GA. Treatment with GA-loaded PS (60 µM) showed a significant reduction of 60.5 and 78.1% in cancer migration and metastasis in the case of MDA-MB 231 and MCF-7, respectively. Besides, drug-loaded PS increased phosphorylation of translational regulator eIF2α and decreased expression of Rac1 which were essential for decreasing cancer cell survival and metastasis. In vivo biodistribution study of GA-loaded PS showed long-circulating PS with high passively targeted tumor accumulation. Treatment with GA-loaded PS resulted in a significant decrease in tumor size and weight compared to free GA. In conclusion, GA-loaded PS is a new promising cancer therapeutics for the treatment of TNBC.

Using Properties of Tumor Microenvironments for Controlling Local, On-Demand Delivery from Biopolymer-Based Nanocarriers.

BACKGROUND: The 'tumor microenvironment' comprised of tumor cells, non-malignant stromal tissues, signaling molecules and the extracellular matrix. Tumor microenvironment has unique physical and physiological characteristics including vascular abnormalities, hypoxia, acidic pH, specific enzymes and growth factors upregulation and high reducing potential. It is these endogenous properties of the tumor environment that can be used to trigger the release of cancer therapeutics both locally and as a function of disease state. Biopolymers such as proteins, polypeptides and polysaccharides are actively being designed to be bioresponsive nanocarriers for drug delivery due to their relative biocompatibility, biodegradability and low immunogenicity. OBJECTIVE: This review focuses on the use of physicochemical attributes of the endogenous tumor microenvironment to provide the impetus for on-demand release of therapeutics from biopolymer-based nanocarriers that are sensitive to pH, enzymes, redox conditions and combinations thereof. CONCLUSION: The development of multifunctional nanocarriers based upon a rational approach for targeting and delivering therapeutics to tumors is an area of active research. Despite the huge amount of work done in this area, especially using pH as a means of eliciting drug release at tumor sites, there is a dearth of work whereby different stages during tumor development are targeted for treatment. Although nanocarriers that are able to react to multiple components of the tumor microenvironment are starting to become common-place, it seems that the ability to release various factors at specific times crucial to therapy has not been studied to a large extent as a means of regaining tissue homeostasis.