Novel Cu-LDH-based nanomedicine for combination cancer therapy

Abstract

Cancer is one of the most devastating diseases and its complexity and heterogeneity lead to significant morbidity and mortality in patients. Several well-known treatment approaches including chemotherapy, radiotherapy, genotherapy, phototherapy and immunotherapy, have been extensively explored in clinic settings. However, intolerable systemic toxicity towards normal tissues has resulted from repeated single treatment, for which excessive chemotherapeutic agents may be responsible. Therefore, combining two or more different types of anticancer therapeutics has been developed in clinical practice to conquer these challenges. In the past decades, advancements in nanotechnology have opened up promising opportunities for improving the efficacy and specificity of drug delivery to the tumour lesions. Compared with the free drug form, drug-loaded nanoparticles (NPs) with rational physico-biochemical properties exhibit several advantages, including prolonged circulating half-life, enhanced tumour accumulation, increased cellular uptake and the capacity to integrate multiple regimens and thereby facilitate combination therapy. This PhD project aims to engineer inorganic layered double hydroxide (LDH)-based nanocarriers that have enhanced target delivery of multiple anticancer agents and controlled their release profile for an optimal combination of various cancer therapies.The PhD thesis first designed a tri-functional LDH-based nanomedicine for combined photochemotherapy of skin cancer at very low therapeutic doses to reduce the side effects induced by the high amount of toxic antitumour drug. This nanosystem co-delivered three therapeutic agents via coating indocyanine green (ICG)-intercalated Cu-doped LDH (Cu-LDH) NPs with acid-responsive bovine serum albumin-doxorubicin (BSA-DOX). The prepared nanomedicine controllably released toxic DOX in an acid-triggered manner, efficiently generated heating and reactive oxygen species (ROS) upon 808 nm laser irradiation, and synergistically induced apoptosis of skin cancer cells. In B16F0-bearing mouse model, the tumour tissues were nearly eradiated upon one course treatment using very low doses of therapeutic agents (0.175 mg/kg of DOX, 0.5 mg/kg of Cu, and 0.25 mg/kg of ICG) upon very mild 808 nm laser irradiation (0.3 W/cm2 for 2 min).Moreover, we loaded two FDA-approved 5-fluorouracil (5-FU) and albumin-bound paclitaxel (nAb-PTX) into Cu-LDH NPs for efficient combination chemo-photo-therapy of breast cancer. The nanomedicine showed pH-sensitive heat-facilitated therapeutic on-demand release and demonstrated the synergy of photothermal therapy and chemotherapy in inducing apoptosis of 4T1 cancer cells. Nearly elimination of 4T1 tumours in vivo at very low doses of 5-FU and nAb-PTX (0.25 and 0.5 mg/kg) demonstrated the synergistical effect between efficient photothermal therapy and controllably-released chemotherapies even under mild irradiation conditions (0.75 W/cm2 for 3 min).To simultaneously enhance tumour accumulation and cell uptake, we further modified LDH NPs with a pH-sensitive charge-reversible polymer to possess long circulation in blood but reverse surface charges in the weakly acidic tumour tissues to re-expose therapeutic LDH NPs. The obtained charge-reversible nanohybrids mitigated the cell uptake in the physiological conditions (pH 7.4), but significantly promoted cell internalisation after charge conversion in the acidic tumour extracellular microenvironment (pH 6.8), contributing to remarkable synergistic effect between photothermal therapy (Cu-doped LDH, Cu-LDH) and RNAi therapy (Allstar Cell Death siRNA, CDsiRNA). Notably, in vivo therapeutic evaluations demonstrated that about 6.0% of intravenously injected charge-conversional nanohybrids accumulated at the tumour site after 24 h injection and >95% inhibition of B16F0 tumour growth was achieved via only one treatment under very mild irradiation (808 nm laser, 0.3 W/cm2 for 3 min).In summary, several Cu-LDH-based hybrid nanomedicines were well developed as promising therapeutic formulations with minimum adverse effect for combination cancer treatment.