Hypoxia-Active Nanoparticles Used In Tumor Theranostic

ABSTRACT

Hypoxia, caused by insufficient oxygen supply in solid tumors, leads to drug resistance and reduced efficiency of chemotherapy. A cancer cell membrane veiled nanocarrier consisting of a polymeric core encasing Haemoglobin (Hb) and Doxorubicin (DOX) was developed to improve the effectiveness of chemotherapy. These designed nanoparticles (DHCNPs) exhibit the oxygen-carrying capacity of Hb while simultaneously retaining on their surface, the cancer cell adhesion molecules, for homologous targeting to provide O2-interfered chemotherapy. The results show that DHCNPs not only achieve higher tumor specificity and lower toxicity by homologous targeting but also significantly reduce the exocytosis of DOX by suppressing the expressions of hypoxia-inducible factor-1 α, multidrug resistance gene 1, and P-glycoprotein, consequently resulting in safe and highly-efficient chemotherapy. Recent research provides a new paradigm for targeted oxygen interference therapy by conquering hypoxia-involved therapeutic resistance and achieves effective treatment of solid tumors.

INTRODUCTION

The FDA has approved as many as 97 molecules as novel, anti-cancer agents between 2010 and 2017. This shows the substantial efforts made by various pharmaceutical and biotechnological companies on oncology research to meet the immediate need for newer, more effective treatments. Further, an improved understanding of the complex networks of molecular mechanisms involved in cancer biology has led to a shift from traditional, broad-spectrum anti-cancer agents to molecular and target specific therapies. Extensive research is being carried out to develop biomimetic-based technologies to replace, assist or augment the conventional treatments. The availability of combinatorial chemistry and high-throughput screening has powered the challenge to identify novel compounds that mimic nature's chemistry and to predict their macromolecular targets. Studies on deceiving and redirecting disseminated cancer cells by exploiting the cancer-associated fibroblasts to create a biomimetic trap, has shown to delay peritoneal metastasis formation. Researchers have also developed heterocellular 3D scaffolds mimicking the architecture of peritoneal metastases to recapitulate the tumor microenvironment (TME) that can be used as a preclinical model to enhance therapeutic progress. Tumour environment biomimetics has strongly improve our understanding of the communication between CAFs, cancer cells and other host cells. Several experimental drugs targeting CAFs are in clinical trials for multiple tumour entities. The continuous interaction between tissue engineers, biomaterial experts and cancer researchers creates the possibility to biomimic the tumour-environment and provides new opportunities in cancer diagnostics and management.

Tumor hypoxia, a characteristic of the TME, is a consequence of a disrupted balance between the supply and consumption of O2 due to tumor growth and vascular abnormalities. Tumor hypoxia has been proven to cause resistance to current anticancer therapeutics including chemotherapy, photodynamic therapy, and radiotherapy. To adapt to a hypoxic environment, cancer cells participate in the transcriptional activity of hypoxia-inducible factor-1 α (HIF-1 α), involved in angiogenesis, invasion, and metastasis of cancer cells. The HIF-1 α also enhances the expression of P-glycoprotein (P-gp), a membrane efflux pump that recognizes different chemotherapeutic agents and transports them out of the cells, causing chemoresistance. Hence, modulation of tumor hypoxia is requisite for elevating the efficacy of cancer chemotherapy. Recent reports show that O2 carrying/generating materials, like Hb, perfluorohexane, and manganese dioxide, have the potential to improve intratumoral O2 supplementation and enhance the efficiency of cancer therapies. However, tumor-specific delivery is essential to prevent side-effects from oxygen toxicity. Therefore, development of target-specific O2 nanocarriers are necessary to achieve enhanced chemotherapy outcomes by breaching tumor hypoxia.

For instance, hyperbaric oxygen therapy, which promotes oxygen transport from blood circulation to hypoxic tumor tissue by raising the oxygen (O2) pressure in plasma, may strengthen the chemotherapy. Among those materials, Hb is a natural protein in red blood cells that delivers oxygen to tissues. As a biosafe oxygen carrier, our recent work had adopted Hb into nanosystems for oxygenenhanced photodynamic therapy. For specific cancerous cell targeting, nanoparticles have been commonly modified with targeting ligands (e. g. , peptides, antibodies, and nucleic acids). [8] Currently, the biomimetic cell membrane-based drug delivery systems have attracted more attention for the development of intelligent materials such as cancer cell membrane-coated nanoparticles, blood cell membrane-derived nanoparticles, and platelet membrane-modified nanoparticles. [9] By replicating the surface antigenic diversity from the cancer cells to engineered nanovehicle, cancer cell membrane-biomimetic nanoparticles were endowed with the ability of targeting to homologous tumor cells. [10] This approach could result in a promising targeted nanodelivery system for cancer therapies. Herein, we developed a cancer cell membrane-biomimetic oxygen nanocarrier to overcome hypoxia-induced chemoresistance.

HYPOXIA-INDUCED CHEMORESISTANCE

A solid tumor forms an organ like structure composed of cancer cells as well as stromal cells embedded in the ECM and nourished by the vascular network. The abnormal vasculature network and high proliferation rate of cancerous cells makes the TME highly heterogeneous and consequently there are some regions deficient in O2. Hypoxia (both transient-caused by inadequate blood flow, and chronic-consequence of increased O2 diffusion distance because of tumor expansion) is linked with poor chemotherapy results in addition to enhancing chemoresistance of cancer cells. Along with abnormal vasculature, vascular insufficiency, treatment or malignancy related anemia, low intratumor blood flow, are responsible for tumor hypoxia. Most tumors are at least partially hypoxic. The delivery of drugs in hypoxic area and cellular uptake of it are affected by hypoxia or associated acidity.

Moreover, some chemotherapeutic drugs require oxygen to generate free radicals that contribute to their cytotoxicity. Hypoxia also induces cellular adaptations compromising the success of chemotherapy. In response to hypoxia-induced nutrient deprivation, the rate of proliferation of cancer cells decreases but so does the effectiveness of the chemotherapeutic drugs as they work better against proliferating cells. On the other hand, hypoxia induces adaptation by post-translational and transcriptional changes that promote cell survival and resistance to chemotherapy. It is through these changes that hypoxia promotes angiogenesis, shift to glycolytic metabolism, expression of ABC transporters, cell survival by inducing the expression of genes encoding growth factors and the modulation of apoptotic process. [image: Image result for hypoxia induced chemoresistance]Figure 2: Hypoxia-Fibrosis cycle in Pancreatic cancerHypoxia promotes the accumulation of HIF-1α which, under normoxic conditions, is promptly degraded by proteasomal ubiquitination. However, under hypoxic conditions, the ubiquitination system for HIF-1α is inhibited by inactivation of prolyl hydroxylase which is responsible for hydroxylation of proline in the oxygen-dependent degradation domain of HIF-1α. HIF-1α is an important transcriptional factor coding hundreds of genes involved in erythropoiesis, angiogenesis, induction of glycolytic enzymes in tumor tissues, modulation of cancer cell cycle, cancer proliferation, and cancer metastasis. Further, production of vascular endothelial growth factor (VEGF) in cancer cells is also regulated by the activated HIF-1 mediated system. An increase in VEGF levels subsequently induces HIF-1α accumulation and sencourages tumor metastasis by angiogenesis.