Optimization and Formulation of Nanostructured and Self-Assembled Caseinate Micelles for Enhanced Cytotoxic Effects of Paclitaxel on Breast Cancer Cells

Abstract

Background: Paclitaxel (PTX) is a widely used anti-cancer drug for treating various types of solid malignant tumors including breast, ovarian and lung cancers. However, PTX has a low therapeutic response and is linked with acquired resistance, as well as a high incidence of adverse events, such as allergic reactions, neurotoxicity and myelosuppression. The situation is compounded when its complex chemical structure contributes towards hydrophobicity, shortening its circulation time in blood, causing off-target effects and limiting its therapeutic activity against cancer cells. Formulating a smart nano-carrier may overcome the solubility and toxicity issues of the drug and enable its more selective delivery to the cancerous cells. Among the nano-carriers, natural polymers are of great importance due to their excellent biodegradability, non-toxicity and good accessibility. The aim of the present research is to develop self-assembled sodium caseinate nanomicelles (NaCNs) with PTX loaded into the hydrophobic core of NaCNs for effective uptake of the drug in cancer cells and its subsequent intracellular release. Methods: The PTX-loaded micelle was characterized with high-performance liquid chromatography (HPLC), Fourier Transform Infrared Spectra (FTIR), High Resolution-Transmission Electron Microscope (HR-TEM), Field Emission Scanning Electron Microscope (FESEM) and Energy Dispersive X-Ray (EDX). Following treatment with PTX-loaded NaCNs, cell viability, cellular uptake and morphological changes were analyzed using MCF-7 and MDA-MB 231 human breast cancer cell lines. Results: We found that PTX-loaded NaCNs efficiently released PTX in an acidic tumor environment, while showing an enhanced cytotoxicity, cellular uptake and in-vivo anti-tumor efficacy in a mouse model of breast cancer when compared to free drug and blank micelles. Additionally, the nanomicelles also presented improved colloidal stability for three months at 4 °C and −20 °C and when placed at a temperature of 37 °C. Conclusions: We conclude that the newly developed NaCNs is a promising carrier of PTX to enhance tumor accumulation of the drug while addressing its toxicity issues as well.

A Comparative Evaluation of Anti-Tumour Activity Following Oral And Intravenous Delivery of Doxorubicin In A Xenograft Model of Breast Tumour

“…………………… Equation 1…………… … Equation 22.2.3. Particle size analysis through dynamic light scattering (DLS) and stability test Particle size, distribution and the zeta-potential were measured based on the DLS technique using Malvern nano zeta sizer (Malvern, Worcestershire, U.K.) [39]. The formulations were diluted with water (1:10) at an ambient temperature followed by measurement using a Zetasizer.…”

“…NaCNs were prepared by allowing caseins in aqueous solution to self-assemble into micelles [39,48]. An aqueous solution of DOX was added to sodium caseinate powder (1 mg) prepared from raw skim milk [49].…”

“…The zeta size measurement through dynamic light scattering (DLS) reveal that the blank NaCNs had a particle size of around 470.2 ± 68.12 nm. Nevertheless, following DOX encapsulation, the particle size was 270.86 nm, indicating the self-assembled nature of casein [39] Furthermore, interactions of DOX within the micellar interior components of casseinate may reorganize and condense particles into smaller micelles which have a more heterogeneous size distribution and are less electronegative when compared to the empty micelles (Table 1). Additionally, DOX-NaCNs showed robust DLE (78.00%) and DLC of approximately 24.83% signifying the successful encapsulation of DOX inside the casein.…”

“…To our knowledge, this is the rst comprehensive study demonstrating the bio-distribution pro les and therapeutic potential of DOX-NaCNs for both intravenous and oral administrations. NaCNs were formulated by a gentle mixing on a nutating mixer at room temperature, as previously reported [36]. DOX was used a model drug in the current research to evaluate the e cacy of hydrophilic drug inside NaCNs.…”

Smart Polymeric Nanoparticles with pH-Responsive and PEG-Detachable Properties (II): Co-Delivery of Paclitaxel and VEGF siRNA for Synergistic Breast Cancer Therapy in Mice

“…The preparation of PTX into smart responsive micelles enhances its cytotoxicity to breast cancer cells, thereby increasing its antitumor effect. 17 , 18 …”