Acidic microenvironment responsive polymeric MOF-based nanoparticles induce immunogenic cell death for combined cancer therapy.

BACKGROUND: The complex tumor microenvironment and non-targeting drugs limit the efficacy of clinical tumor therapy. For ensuring the accurate delivery and maximal effects of anticancer drugs, it is important to develop innovative drug delivery system based on nano-strategies. RESULT: In this study, an intracellular acidity-responsive polymeric metal organic framework nanoparticle (denoted as DIMP) has been constructed, which can co-deliver the chemotherapy agent of doxorubicin (DOX) and phototherapy agent of indocyanine green (ICG) for breast carcinoma theranostics. Specifically, DIMP possesses a suitable and stable nanometer size and can respond to the acidic microenvironment in cells, thus precisely delivering drugs into target tumor sites and igniting the biological reactions towards cell apoptosis. Following in vivo and in vitro results showed that DIMP could be effectively accumulated in tumor sites and induced powerful immunogenic cell death (ICD) effect. CONCLUSION: The designed DIMP displayed its effectiveness in combined photo-chemotherapy with auxiliary of ICD effect under a multimodal imaging monitor. Thus, the present MOF-based strategy may offer a potential paradigm for designing drug-delivery system for image-guided synergistic tumor therapy.

Template-free synthesis and metalation of hierarchical covalent organic framework spheres for photothermal therapy.

Uniform micron sized hierarchical COF (HCOF) spheres were fabricated by a template-free solution-based aging method at room temperature for the first time. The postsynthetic metalation of HCOF with Fe3+ makes the metalated HCOF an excellent photothermal agent (PTA) for photothermal therapy (PTT).

An aluminum adjuvant-integrated nano-MOF as antigen delivery system to induce strong humoral and cellular immune responses.

Metal-organic frameworks (MOFs) have high surface area, tunable pore size, and high loading capacity, making them promising for drug delivery. However, their synthesis requires organic solvents, high temperature and high pressure that are incompatible with biomacromolecules. Zeolitic imidazole frameworks (ZIF-8) which forms through coordination between zinc ions and 2-methylimidazole (MeIM) have emerged as an advanced functional material for drug delivery due to its unique features such as high loading and pH-sensitive degradation. In this study, we took advantage of a natural biomineralization process to create aluminum-containing nanoZIF-8 particles for antigen delivery. Without organic solvents or stabilizing agent, nanoparticles (ZANPs) were synthesized by a mild and facile method with aluminum, model antigen ovalbumin (OVA) and ZIF-8 integrated. A high antigen loading capacity (%) of 30.6% and a pH dependent antigen release were achieved. A Toll-like receptor 9 agonist cytosine-phosphate-guanine oligodeoxynucleotides (CpG) was adsorbed on the surface of ZANPs (hereafter CpG/ZANPs) to boost the immune response. After subcutaneous injection in vivo, CpG/ZANPs targeted lymph nodes (LNs), where their cargo was efficiently internalized by LN-resident antigen-presenting cells (APCs). ZANPs decomposition in lysosomes released antigen into the cytoplasm and enhanced cross-presentation. Moreover, CpG/ZANPs induced strong antigen-specific humoral and cytotoxic T lymphocyte responses that significantly inhibited the growth of EG7-OVA tumors while showing minimal cytotoxicity. We demonstrate that ZANPs may be a safe and effective vehicle for the development of cancer vaccines.

Metal-Organic Framework as a Microreactor for in Situ Fabrication of Multifunctional Nanocomposites for Photothermal-Chemotherapy of Tumors in Vivo.

Metal-organic frameworks (MOFs) have been applied in chemotherapeutic drug loading for cancer treatment, but challenging for cases with large and malignant lesions. To overcome these difficulties, combinational therapies of chemotherapy and photothermal therapy (PTT) with potentially high selectivity and slight aggressiveness have drawn tremendous attention to treat various tumors. However, current MOF-based nanohybrids with photothermal agents involve tedious synthesis processes and heterogeneous structures. Herein, we employ MIL-53 as a microreactor to grow polypyrrole (PPy) nanoparticles in situ for the fabrication of PPy@MIL-53 nanocomposites. Fe3+ in MIL-53, as an intrinsic oxidizing agent, can oxidize the pyrrole monomer to generate PPy nanoparticles. The prepared PPy@MIL-53 nanocomposites integrate the intrinsic advantages of MOFs with high drug loading ability and magnetic resonance imaging (MRI) capacity, and PPy nanoparticles with outstanding PTT ability and excellent biocompatibility. The versatile PPy@MIL-53 nanocomposites with multiple functions displayed in vitro and in vivo synergism of photothermal-chemotherapy for cancer, potentially MRI-guided. The proposed MOF microreactor-based synthesis strategy shows a promising prospect in the fabrication of diverse multifunctional nanohybrids for tumor theranostics in vivo.

Metal-carbenicillin framework-based nanoantibiotics with enhanced penetration and highly efficient inhibition of MRSA.

The development of effective therapies to control methicillin-resistant Staphylococcus aureus (MRSA) infections is challenging because antibiotics can be degraded by the production of certain enzymes, for example, ß-lactamases. Additionally, the antibiotics themselves fail to penetrate the full depth of biofilms formed from extracellular polymers. Nanoparticle-based carriers can deliver antibiotics with better biofilm penetration, thus combating bacterial resistance. In this study, we describe a general approach for the construction of ß-lactam antibiotics and ß-lactamase inhibitors co-delivery of nanoantibiotics based on metal-carbenicillin framework-coated mesoporous silica nanoparticles (MSN) to overcome MRSA. Carbenicillin, a ß-lactam antibiotic, was used as an organic ligand that coordinates with Fe3+ to form a metal-carbenicillin framework to block the pores of the MSN. Furthermore, these ß-lactamase inhibitor-loaded nanoantibiotics were stable under physiological conditions and could synchronously release antibiotic molecules and inhibitors at the bacterial infection site to achieve a better elimination of antibiotic resistant bacterial strains and biofilms. We confirmed that these ß-lactamase inhibitor-loaded nanoantibiotics had better penetration depth into biofilms and an obvious effect on the inhibition of MRSA both in vitro and in vivo.