Environmentally Self-Adaptative Nanocarriers Suppress Glioma Proliferation and Stemness via Codelivery of shCD163 and Doxorubicin

Abstract

Gliomasdevastating intracranial tumors with a dismal outcomeare in dire need of innovative treatment. Although nanodrugs have been utilized as a target therapy for certain types of solid tumors, their therapeutic effects in gliomas are limited due to the complications of the systemic circulation, blood–brain barrier (BBB), and specific glioma environment. Thus, we aimed to establish a nanoliposome adaptable to different environments by codelivery of shCD163 and doxorubicin (DOX) to treat gliomas. In this study, we first synthesized pH-sensitive DSPE-cRGD-Hz-PEG2000 to form an environmentally self-adaptative nanoliposome (cRGD-DDD Lip) via a thin film method. We used in vitro BBB models, in vitro cell uptake experiments, and in vivo biodistribution assays to confirm the long circulation time and low cell uptake of the cRGD-DDD Lip as a result of the poly­(ethylene glycol) (PEG) shell of cRGD-DDD Lip in the neutral pH systemic circulation. Moreover, the cRGD-DDD Lip bypassed the BBB and attached to the intracranial glioma following the removal of the PEG shell and the exposure of cRGD to the weakly acidic tumor microenvironment. We further assembled the shCD163/DOX@cRGD-DDD Lip through cRGD-DDD Lip loading of shCD163 and DOX. In vitro, cell proliferation and self-renewal of glioma cells were inhibited by the shCD163/DOX@cRGD-DDD Lip due to the toxicity of DOX and the suppression of shCD163 via the CD163 pathway. In vivo, the shCD163/DOX@cRGD-DDD Lip disturbed the progression of in situ gliomas by inhibiting the growth and stemness of glioma cells and prevented the recurrence of gliomas after resection. In conclusion, the cRGD-DDD Lip may be a promising nanodrug-loading platform to cope with different environments and the shCD163/DOX@cRGD-DDD Lip may potentially be a novel nanodrug for glioma therapy.

Research progress of anti-glioma chemotherapeutic drugs (Review)

“…DOX is an anthracycline antibiotic chemotherapy agent and is one of the most extensively used antitumor drugs ( 94 ). Its main mechanism of action is by quickly entering the nuclei of tumor cells and inhibiting the proliferation of tumor cells by binding to DNA and blocking DNA replication ( 95 , 96 ). DOX has been found to inhibit the proliferation of glioma cells.…”

“…However, large doses or long-term use of DOX can cause cardiomyocyte toxicity, ultimately leading to heart failure. To minimize this toxic adverse effect, it has been proposed that DOX liposomes can be used for targeted delivery, where the combination of DOX liposomes with other drugs conferred superior antitumor activity ( 94 , 96 ). Vincristine can mediate cardioprotective effects against DOX-induced cardiomyocyte toxicity and chemical and hypoxic oxidative stress.…”

Small Interfering RNA for Gliomas Treatment: Overcoming Hurdles in Delivery

“…Smart nanocarriers such as those responsive to pH can be developed in siRNA delivery. Lipids complexed with polymers, mostly PEG, have been reported to prevent the immune system from recognizing liposomes and reduce liver clearance (Liu et al, 2020a). CD163 was reported to regulate cell proliferation and selfrenewal of gliomas via casein kinase 2 (Chen et al, 2019).…”

“…In the acidic glioma microenvironment, the PEG shell of the cRGD lipid would shed, exposing the cRGD lipid and facilitating the recognition of the cRGD lipid by cells and the drug release. Moreover, in vivo studies proved that it can inhibit the growth and stemness of glioma cells and prevent the recurrence of gliomas after resection (Liu et al, 2020a).…”

Enhanced anti-glioma efficacy of doxorubicin with BRD4 PROTAC degrader using targeted nanoparticles

“…As the cytotoxic effect is not cancer cells-selective, targeted delivery is adopted to decrease systemic toxicity. Moreover, the limited effects of DOX lie in the poor bioavailability, short half-life as well as failure to cross the BBB [ 22 ]. Meanwhile, PROTACs have aqueous solubility and permeability problems [ 23 ].…”