Macrophage-mediated tumor homing of hyaluronic acid nanogels loaded with polypyrrole and anticancer drug for targeted combinational photothermo-chemotherapy

Abstract

Rationale: Development of nanosystems that can be integrated with macrophages (MAs), an emerging carrier system, for effective tumor therapy remains to be challenging. We report here the development of MAs specifically loaded with hyaluronic acid (HA) nanogels (NGs) encapsulated with a photothermal agent of polypyrrole (PPy) and anticancer drug doxorubicin (DOX) (HA/DOX@PPy NGs) for tumor homing and combination photothermo-chemotherapy. Methods: Cystamine dihydrochloride-crosslinked HA NGs were first prepared through a double emulsification method, then loaded with PPy via an in-situ oxidization polymerization and physically encapsulated with DOX. The created HA/DOX@PPy NGs were well characterized and subjected to be endocytosed by MAs (MAs-NGs). The MAs-mediated tumor-homing property, phenotype changes and photothermal performance of MAs-NGs were investigated in vitro , and a subcutaneous tumor model was also established to confirm their targeting capability and enhanced antitumor therapy effect in vivo . Results: The generated hybrid NGs possess a size around 77 nm and good colloidal stability, and can be specifically endocytosed by MAs without appreciably affecting their normal biofunctionalities. In particular, NG-loaded MAs display excellent in-vitro cancer cell and in-vivo tumor homing property. Systemic administration of the MAs-NGs leads to the significant inhibition of a subcutaneous tumor model through combination photothermo-chemotherapy under laser irradiation. Conclusions: The developed hybrid HA-based NG nanosystem incorporated with PPy and DOX fully integrates the coordination and heating property of PPy to regulate the optimized DOX release in the tumor region with the assistance of MA-mediated tumor homing, providing a promising cell therapy strategy for enhanced antitumor therapy.

Intelligent design of polymer nanogels for full-process sensitized radiotherapy and dual-mode computed tomography/magnetic resonance imaging of tumors

“…Nanogels (NGs), possessing physically or chemically crosslinked 3D networks, have been known as a promising colloidal container for the integration of NPs, as they can be designed to own excellent colloidal stability and compatibility to biological systems 40 - 42 . For instance, we have proven that MnO 2 NPs can be in-situ loaded within poly( N -vinylcaprolactam) (PVCL) NGs with a controlled size 27 , and conducting polymeric NPs are able to be in-situ loaded within poly(γ-glutamic acid) NGs 43 , 44 or hyaluronic acid NGs 45 . The major advantages of the in-situ incorporation method are the controllability of NP size and density in the matrix, the prevention of NP leakage, and the flexibility of NP types.…”

Macrophage Membrane-Camouflaged Responsive Polymer Nanogels Enable Magnetic Resonance Imaging-Guided Chemotherapy/Chemodynamic Therapy of Orthotopic Glioma

“…This should be due to the fact that TEM measures the size of the shrunken NGs in a dried state, while DLS measures the NGs swelled in water. 42 Compared with the empty membrane vesicles in Figure S4D, we apparently see that the MPM@P NGs are successfully coated with macrophage membranes with a thickness of about 25 nm (Figure S4E,F). It is noteworthy that the NGs can only be partially covered by membranes at a low membrane/NGs mass ratio (e.g., 0.4:1, Figure S4E), and the complete coverage can be achieved through increasing the membrane/NGs mass ratio (e.g., 1:1, Figure S4F).…”

“…TEM images reveal that the PM@P NGs display uniformed spherical shape and good monodispersity with an average diameter of 106.3 ± 8.4 nm (Figure S4A–C), which is dramatically smaller than their hydrodynamic size (301.5 ± 3.1 nm) measured by DLS. This should be due to the fact that TEM measures the size of the shrunken NGs in a dried state, while DLS measures the NGs swelled in water . Compared with the empty membrane vesicles in Figure S4D, we apparently see that the MPM@P NGs are successfully coated with macrophage membranes with a thickness of about 25 nm (Figure S4E,F).…”

“…For instance, alginate or γ-polyglutamic acid NGs formed through a double emulsion method can be loaded with iron oxide, , manganese oxide, or gold NPs through the use of polyethyleneimine-stabilized corresponding NPs as cross-linkers for magnetic resonance (MR) or computed tomography imaging applications. Furthermore, NGs formed through either a double emulsion method , or a precipitation polymerization method can be employed as nanoreactors to in situ load functional components such as conducting polymers or MnO 2 NPs to achieve combination therapy or theranostics of tumors. It is expected that with these promising properties of NGs and CM-enabled biomimetic coating, an effective theranostic NG-based platform that can transport theranostic agents into the brain parenchyma for imaging and treatment of CNS diseases can be developed.…”

Fenton/Fenton-like metal-based nanomaterials combine with oxidase for synergistic tumor therapy

“…There are several advantages of using nanovectors to deliver chemotherapeutic agents: (1) Drugs can be accumulated selectively in tumors, successfully enhancing the specific killing ability of tumors [ 97 ]. (2) Chemotherapeutic agents are all protected by nanovectors before reaching tumor tissues, greatly minimizing systemic toxic adverse effects [ 98 ]. (3) There are smaller needs of chemotherapeutic drugs due to the antitumor effects nanomaterials own [ 99 ].…”