Reshaping Tumor Blood Vessels to Enhance Drug Penetration with a Multistrategy Synergistic Nanosystem

Abstract

Due to the abnormal tumor vasculature and dense stroma, there is limited tumor perfusion in the immunosuppressive tumor microenvironment (TME). In order to reshape tumor blood vessels and enhance the penetration of anticancer drugs into the tumor tissue, an anionic liposome nanosystem with a “sandwich” structure was prepared. The chemotherapeutic agent topotecan (TPT) was encapsulated in the lipid hydrophilic layer, and the sensitizer indocyanine green (ICG) was loaded into the hydrophobic layer. In addition, the positively charged vascular normalization drug erlotinib (ERL) was adsorbed to the outermost layer of the microenvironment. The nanosystem showed superior tumor permeability in vitro/in vivo experiments compared with the ERL-treated group. The nanosystem entered the tumor through normalization of blood vessels after the action of ERL. Ultrasound treatment improves the vascular permeability, allowing the nanoparticles to penetrate blood vessels and reach tumor cells. Finally, in addition to cytotoxic effects, TPT can also down-regulate the expression of HIF-1α and so prolong the vascular normalization time. These experimental results showed that the nanosystem effectively improves the tumor microenvironment. This work indicates the great potential of vascular normalization combined with sonodynamic therapy and chemotherapy to enhance efficiency.

Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology

“…The nanosystem delivery technology was considered a promising means for reshaping abnormal tumor vasculature to vascular normalization ( Liang et al, 2022 ). On the other hand, vessel normalization was beneficial to the enhancement of drug penetration ( Li et al, 2020b ). Another strategy for co-targeting angiogenesis and TME is chosen as delivery platforms with functional decorations, in which loaded two or more molecules or drugs achieved the aforementioned goals with a designed enhancement of pharmacokinetics, while nanosystems loading single candidates are also that we are interested in.…”

“…Another strategy for co-targeting angiogenesis and TME is chosen as delivery platforms with functional decorations, in which loaded two or more molecules or drugs achieved the aforementioned goals with a designed enhancement of pharmacokinetics, while nanosystems loading single candidates are also that we are interested in. The normalization of blood vessels based on the scheme of angio-blocker delivery has been reported to reprogram TME for improving immune cell infiltration ( Li et al, 2020b ). For instance, the nomoplatform based on anti-angiogenic low molecular weight heparin (LMWH) transformed M2 polarized macrophage to M1 type and induced the vessel normalization ( Xu et al, 2020 ).…”

“…Pleiotropic nanodelivery was vastly commendable to co-modulate suppressive TME and tumor angiogenesis with multiple components, and the evidence entailed poly-lactic-glycolic acid (PLGA) and liposome nanoparticles ( Hameed et al, 2018 ). The abundant multi-potency nanosystems indicated a synergistic strategy by introducing chemotherapy and dynamic therapy (sonodynamic and photothermal dynamics) for anti-angiogenesis ( Li et al, 2020b ; Zhu et al, 2021b ). We expect that a multi-strategy delivery system and single molecules with multi-efficiency emerge to illuminate unlisted angiogenesis blockers for reshaping suppressive TME, while the role of the classic recipe of TCM remains underlying.…”

Recent advances of nanotechnology-based tumor vessel-targeting strategies

“…NMs also can achieve multi-strategy synergistic therapy. Li [ 77 ] prepared an anionic liposome NMs with a sandwich structure for vascular normalization in combination with chemotherapy and sonodynamic therapy. Indocyanine green (ICG), an ultrasonic sensitizer, was encapsulated in the external hydrophobic region, while topotecan (TPT), a chemotherapeutic agent, was loaded in the internal hydrophilic region, and the erlotinib (ERL)a vascular-normalizing drug with positively charged was loaded in the outermost layer of anionic NPs via electrostatic interaction.…”

Multifunctional Mitochondria-Targeting Nanosystems for Enhanced Anticancer Efficacy

“…SDT has a great potential to inhibit the growth of tumor cells and trigger antitumor immune responses ( Gao G. et, al., 2019 ; Gong et, al., 2020 ; Son et al, 2020 ). However, insufficient blood perfusion, limited oxygen (O 2 ) diffusion, and immunosuppressive TME in solid tumors severely limit the anticancer effect of SDT ( Jing et al, 2019 ; Li et al, 2020 ; Yang et al, 2020 ). Perfluorocarbon (PFC), a widely used artificial blood substitute with high oxygen-carrying capacity and excellent biocompatibility, has been proven to explosively release O 2 and significantly enhance PDT under ultrasound (US) ( Zhou et al, 2018 ; Krafft and Riess, 2021 ).…”