Tumor-targeted hybrid protein oxygen carrier to simultaneously enhance hypoxia-dampened chemotherapy and photodynamic therapy at a single dose

Abstract

Hypoxia is a characteristic feature of solid tumors and an important causation of resistance to chemotherapy and photodynamic therapy (PDT). It is challenging to develop efficient functional nanomaterials for tumor oxygenation and therapeutic applications.Methods: Through disulfide reconfiguration to hybridize hemoglobin and albumin, tumor-targeted hybrid protein oxygen carriers (HPOCs) were fabricated, serving as nanomedicines for precise tumor oxygenation and simultaneous enhancement of hypoxia-dampened chemotherapy and photodynamic therapy. Based on encapsulation of doxorubicin (DOX) and chlorin e6 (Ce6) into HPOCs to form ODC-HPOCs, the mechanism and therapeutic efficacy of oxygen-enhanced chemo-PDT was investigated in vitro and in vivo.Results: The precise oxygen preservation and release of the HPOC guaranteed sufficient tumor oxygenation, which is able to break hypoxia-induced chemoresistance by downregulating the expressions of hypoxia-inducible factor-1α (HIF-1α), multidrug resistance 1 (MDR1) and P-glycoprotein (P-gp), resulting in minimized cellular efflux of chemodrug. Moreover, the oxygen supply is fully exploited for upgrading the generation of reactive oxygen species (ROS) during the photodynamic process. As a result, only a single-dose treatment of the HPOCs-based chemo-PDT exhibited superior tumor suppression. The combination therapy was guided by in vivo fluorescence/photoacoustic imaging with nanoparticle tracking and oxygen monitoring.Conclusion: This well-defined HPOC as a versatile nanosystem is expected to pave a new way for breaking multiple hypoxia-induced therapeutic resistances to achieve highly effective treatment of solid tumors.

In Situ Photocatalyzed Oxygen Generation with Photosynthetic Bacteria to Enable Robust Immunogenic Photodynamic Therapy in Triple‐Negative Breast Cancer

“…Compared with the currently available cancer vaccines with specific proteins or peptides as antigens for tumor immunotherapy, PDT‐mediated ICD generates vaccine‐like functions in situ and does not need foreign antigens. However, due to the abnormal proliferation of the vascular system in solid tumor tissues, normal blood circulation cannot be formed, and solid tumors often develop a specialized hypoxic, acidic and nutrient‐deficient microenvironment, which significantly dampens the efficacy of PDT 3a,6. To achieve successful tumor therapies, previous studies have taken steps to ameliorate tumor hypoxia by increasing the oxygen concentration in tumors with tumor‐targeted oxygen‐carrying and intratumoral oxygen generation strategies 1a,7.…”

Fighting Hypoxia to Improve PDT

“…More importantly, CDM NPs dramatically improved antitumour efficiency against MCF-7 tumour-bearing mouse mode. Luo et al [167] elaborated tumour-targeted hybrid protein O2 carriers loaded with DOX and Ce6 (ODC-HPOCs) ( Figure 37). According to both in vitro and in vivo studies on HeLa cells, DOX/CP-NI NPs could efficiently generate ROS when exposed to light irradiation (532 nm, 0.1 W•cm −2 , 20 min).…”

“…More importantly, CDM NPs dramatically improved antitumour efficiency against MCF-7 tumour-bearing mouse mode. Luo et al [167] elaborated tumour-targeted hybrid protein O 2 carriers loaded with DOX and Ce6 (ODC-HPOCs) ( Figure 37). Laser irradiation (660 nm, 100 mW•cm −2 , 2 min) of tumour-targeted ODC-HPOCs allowed outstanding performance in tumour accumulation of O2, DOX and Ce6.…”

Oxygen Nanoshuttles for Tumor Oxygenation and Enhanced Cancer Treatment

“…51 Such nanoformulations show passive tumor homing via the enhanced permeability and retention effect, leading to efficient tumor oxygenation. 35,52,53 Cai and co-workers 34,36,54 have encapsulated hemoglobin within either poly(lactic-co-glycolic acid) (PLGA) nanoparticles, lipids, or cancer cell membranes and have also formed intermolecular disulfide bonds of hemoglobin and reduced human serum albumin (HSA) to create hybrid hemoglobin-based oxygen nanocarriers. In addition, Zhang and co-workers 55 have coated polydopamineencapsulated hemoglobin with a red blood cell membrane "ghost," thus achieving man-made red blood cells for tumor-targeted oxygen shuttling that enhances cancer treatment.…”