Gold nanorod embedded reduction responsive block copolymer micelle-triggered drug delivery combined with photothermal ablation for targeted cancer therapy

Abstract

Background: Gold nanorods, by virtue of surface plasmon resonance, convert incident light energy (NIR) into heat energy which induces hyperthermia. We designed unique, multifunctional, gold nanorod embedded block copolymer micelle loaded with GW627368X for targeted drug delivery and photothermal therapy. Methods: Glutathione responsive diblock co-polymer was synthesized by RAFT process forming self-assembled micelle on gold nanorods prepared by seed mediated method and GW627368X was loaded on to the reduction responsive gold nanorod embedded micelle. Photothermal therapy was administered using cwNIR laser (808 nm; 4 W/cm²). Efficacy of nanoformulated GW627368X, photothermal therapy and combination of both were evaluated in vitro and in vivo. Results: In response to photothermal treatment, cells undergo regulated, patterned cell death by necroptosis. Combining GW627368X with photothermal treatment using single nanoparticle enhanced therapeutic outcome. In addition, these nanoparticles are effective X-ray CT contrast agents, thus, can help in monitoring treatment. Conclusion: Reduction responsive nanorod embedded micelle containing folic acid and lipoic acid when treated on cervical cancer cells or tumour bearing mice, aggregate in and around cancer cells. Due to high glutathione concentration, micelles degrade releasing drug which binds surface receptors inducing apoptosis. When incident with 808 nm cwNIR lasers, gold nanorods bring about photothermal effect leading to hyperthermic cell death by necroptosis. Combination of the two modalities enhances therapeutic efficacy by inducing both forms of cell death. General significance: Our proposed treatment strategy achieves photothermal therapy and targeted drug delivery simultaneously. It can prove useful in overcoming general toxicities associated with chemotherapeutics and intrinsic/acquired resistance to chemo and radiotherapy. Graphical abstract: Glutathione responsive diblock copolymer containing folic acid and lipoic acid forms self-assembled micelle around gold nanorods (AuNRs). GW627368X loaded AuNR embedded block copolymer micelles served dual purpose of targeted drug delivery and an effective photothermal agent. On reaching tumour vicinity, GSH triggered disassembly of micelles takes place releasing the drug which then binds EP4 receptors bringing about downstream effects. AuNRs start accumulating in and around the tumour/cancerous cells rendering it susceptible to hyperthermal demise. On irradiation with 808 nm NIR lasers, light energy is efficiently converted into heat energy owing to surface plasmon resonance of AuNRs leading to hyperthermal cell death.