Co-delivery of plantamajoside and sorafenib by a multi-functional nanoparticle to combat the drug resistance of hepatocellular carcinoma through reprograming the tumor hypoxic microenvironment

Abstract

Sorafenib (SOR) is a multi-kinase inhibitor that was approved as the first-line systematic treatment agent of hepatocellular carcinoma (HCC). However, the anti-cancerous effect of SOR is dramatically impaired by the drug resistance, insufficient accumulation at tumor tissues, and limited tumor inner penetration. To combat the above issues, the PLA-based nanoparticles were first fabricated and co-loaded with SOR and plantamajoside (PMS), natural herbal medicines that possess excellent anti-cancerous effect on many types of drug resistant cancers. Then, the polypeptide CT, which is tumor-homing and cell membrane penetrable, was further decorated on the dual-agents loaded nanoparticles (CTNP-PMS/SOR) to enhance tumor accumulation of drugs. Importantly, the CT peptide is a conjugate derived from the covalent conjugation of CVNHPAFAC peptide, a tumor-homing peptide, on the fourth lysine of TAT, namely cell membrane penetrating peptide, through a pH-sensitive hydrazone bond. By this way, the cell penetrating ability of TAT was dramatically sealed under the normal condition and immediately recovered once the nanoparticles reached tumor sites. Both in vivo and in vitro experiments demonstrated that the anti-cancerous effect of SOR on malignant HCC was significantly enhanced after co-loaded with PMS. Mechanisms studies revealed that the PMS is capable of reprograming the tumor hypoxic microenvironment, which represents the main cause of drug-resistance of tumor cells. Besides, functionalization of the NP-PMS/SOR with CT peptides signally improved the accumulation of drugs at tumor sites and penetration of agents into tumor cells, which in turn resulted in stronger capacity of tumor growth inhibition.

Engineering precision nanoparticles for drug delivery

“…have been explored in depth in the tumour microenvironment, as NP penetration and stability are challenging in solid tumours 107,146 . Many characteristics of the tumour microenvironment -including the vasculature, interstitial fluid pressure and extracellular matrix (ECM) density -contribute to the limited permeation and penetration of NPs 3,[147][148][149][150] . Thus, the exact cause of successful NP accumulation in tumours has been highly debated, with only a few established trends correlating NP design to tumour delivery.…”

“…The heterogeneity of tumour microenvironments generates many obstacles to successful NP delivery, including reduced permeation. Within the tumour environment, cells may overproduce or generate altered ECM components that result in a dense ECM that physically hinders NP delivery 147 – 149 . This is especially true for cationic NPs as they adhere to the negatively charged tumour ECM, reducing permeation 71 , 153 .…”

“…Within the tumour microenvironment, responsive particles can improve tumour penetration, overcoming the high interstitial pressure and dense ECM that typically prevent NP permeation 150 , 202 . Endogenous triggers — such as the acidic and hypoxic environment of the tumour — can be used to induce NP degradation and drug release 147 , 150 , 203 , 204 . High enzyme levels of matrix metalloproteinases (MMPs) and other extracellular proteases can serve as triggers 10 , 205 – 207 , and the Warburg effect, a metabolic shift towards anaerobic glycolysis 195 , can be exploited as well 208 .…”

Nanotechnology of Tyrosine Kinase Inhibitors in Cancer Therapy: A Perspective

“…NPs were produced and co-loaded with Sorafenib and plantamajoside and decorated with a polypeptide which specifically binds to biomolecules overexpressed on the surface of cancer cells. The authors demonstrated that this functionalization improved drug accumulation and penetration at tumor sites, resulting in a strong inhibition of tumor growth [ 168 ]. Li et al [ 169 ] formulated a dual-targeting delivery system for enhanced HCC therapy by encapsulating Sorafenib and anti-miRNA21 (an antisense oligonucleotide with great potential in cancer therapy) in pentapeptide-modified reconstituted high-density lipoprotein NPs.…”

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

“…For the treatment of hepatocellular carcinoma, Zan and colleagues described the results obtained using a multifunctional delivery system in which polymeric NCs were co-loaded with two natural anti-cancer molecules that are able to reduce the tumor hypoxic microenvironment decorated with a cancer-related biomarker that also increases cellular uptake. The resulting multi-functional NC significantly reduced hypoxia and tumor drug resistance, thereby increasing the therapeutic effects [293]. Although NCs directed at cancer tissues limit the possible toxicity of the therapy, optimization of the dose and administration reduces the risk of their non-specific accumulation in normal organs.…”