Designing of nanoplatforms for improved delivery of anticancer drugs
Creators: name: TUNKI, Lakshmi
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 310607
subject: Nanobiotechnology

description: Globally, one in six deaths is reported due to cancer suggesting the critical need for development of advanced treatment regimens using nanotechnology. The present advanced technology in the field of medicine is nanomedicine, which is in boom in various fields of diagnosis, treatment and prevention. The physicochemical properties associated with the drug molecule can be improved in terms of both pharmacokinetic and pharmacodynamic properties by encapsulating in nanoparticles. The art of encapsulating the drug and anchoring the nanocarrier with targeting ligand is one of the current areas of research in cancer chemotherapy. This kind of approach is aimed at reducing the adverse side effects by directing the drug to reach the target organ. In addition, nanoparticles also release the encapsulated drug in controlled manner which helps in reducing the dose as well as number of doses.

In this framework PEGylated galactose, cRGDfk and serotonin were used as targeting ligands. Solid lipid nanoparticles (SLN) and nanomicelles were used for carrying of the anticancer drugs. In research project 1, PEGylated galactose and multikinase inhibitor sorafenib were used as targeting ligand and chemotherapeutic drug, respectively for hepatocellular carcinoma. The required matrix for encapsulating the drug and reactive surface for anchoring targeting ligand were provided by solid lipid nanoparticles which are made up of biodegradable and biocompatible lipids. Nanoparticles were prepared by solvent emulsification and evaporation method with particle size below 150 nm. The targeting potential of the nanoparticles was established in in vitro cell culture through cellular uptake, apoptosis, ROS generation assays etc. In vivo pharmacokinetic &amp; pharmacodynamic studies were performed in healthy Balb/c mice. The pharmacokinetic parameters clearly demonstrated the role of PEGylation in improving the bioavailability of the drug. The real time biodistribution studies showed the ability of the newly synthesized ligand in targeting the liver and thus avoiding unnecessary trafficking into other organs.

In research project 2, cRGDfk was chosen as targeting ligand for integrin receptors which are known to overexpress in various types of cancer like ovarian, pancreatic, breast etc., Gemcitabine was chosen as drug to be encapsulated into SLN which are prepared by double emulsion and solvent evaporation method. cRGDfK conjugated nanoparticles showed a particle size of 130.1 ±10.2 nm which is very well less than 200 nm thus avoiding the reticuloendothelial system (RES) clearance. Stability of the prepared nanoparticles was established through various stability studies like colloidal and steric stabilities. The targeting potential of the final formulation was evaluated through various 2D, 3D in vitro cell culture studies on breast cancer cell line and in vivo tumor regression studies in orthotopic breast cancer induced by 4T1 cells (mouse breast cancer cells) in Balb/c mice. cRGDfK conjugated gemcitabine loaded solid lipid nanoparticles showed significant decrease in the tumor volume compared  to  pure gemcitabine  and  gemcitabine loaded SLN that proves the supremacy of targeted drug delivery in the treatment of cancer.

In research project 3, serotonin, a less explored targeting ligand was chosen to target prostate cancer. Serotonin receptors are overexpressed in various cancers like liver, prostate, pancreatic, ovarian etc., The water-soluble irinotecan was chosen as a drug candidate and D-alpha-Tocopheryl polyethylene glycol 1000 succinate (TPGS), an amphiphilic polymer made up of hydrophobic vitamin E and hydrophilic PEG molecules was selected as a matrix for the preparation of nanomicelles. TPGS is a FDA approved safe pharmaceutical carrier that improves solubility and permeation of the drug molecules. It is a P-glycoprotein (P-gp) inhibitor with inherent anti-cancer properties and can be used in multi drug resistance types of cancers. The optimized drug loaded non-targeted and targeted nanomicelles showed the particle size of 13.7 ±1.7 and 14.9± 2.1 nm respectively with minimum polydispersity index. The prepared drug loaded nanomicelles were checked for their anti-cancer properties through various 2D and 3D in vitro cell culture studies on prostate cancer cell lines. The half maximal inhibitory concentration (IC50) of non targeted and targeted irinotecan hydrochloride loaded nanomicelles was found to be as 11.9±0.39 and 5.3±1.69 microgram/mL respectively indicating the importance of ligand conjugation for targeting the cancer cells through the specific over expressed receptors.

Overall, this thesis displays the research done on formulating the anticancer drugs into nanocarriers and targeting them with ligands that help in driving them towards cancerous tissue. Results of the research revealed the importance of the nanomedicine in the field of targeted drug delivery system that in turn opens up new rays of hope in the treatment of the cancer.