Nanoscale coordination polymer synergizes photodynamic therapy and toll-like receptor activation for enhanced antigen presentation and antitumor immunity.

While activating antitumor immunity with toll-like receptor (TLR) agonists provides a promising approach toward cancer immunotherapy, existing TLR agonists, including resiquimod (R848), have shown poor tumor selectivity and ineffective TLR activation in tumors for optimal antitumor effects. We hypothesized that improved delivery of TLR agonists to tumors and their effective combination with tumor antigens could significantly enhance their antitumor efficacy. Here, we report a novel nanoscale coordination polymer, Ce6/R848, for the co-delivery of Ce6 photosensitizer to elicit immunogenic cell death via photodynamic therapy (PDT) and cholesterol-conjugated R848 (Chol-R848) for tumor-selective TLR7/8 activation. Upon light irradiation, Ce6-mediated PDT released tumor antigens while selectively delivered R848 activated TLR7/8 in the tumors to synergistically activate antigen-presenting cells and prime T cells for enhanced innate and adaptive antitumor immune responses. Ce6/R848 achieved a 50% cure rate and 99.4% inhibition of tumor growth in subcutaneous MC38 colorectal tumors with minimal systemic toxicity.

Co-delivery of three synergistic chemotherapeutics in a core-shell nanoscale coordination polymer for the treatment of pancreatic cancer.

The combination chemotherapy regimen FOLFIRINOX comprising folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin is the first-line treatment for patients with advanced pancreatic cancer, but its use remains prohibitive for the majority of patients due to severe side effects. Here, we report a core-shell nanoscale coordination polymer (NCP) nanoparticle co-delivering a potent and synergistic combination of oxaliplatin, gemcitabine, and SN38 (OGS), for the treatment of pancreatic cancer in mouse models. OGS contains key synergistic components of FOLFIRINOX in a controllable drug ratio., It exhibited particle stability in blood circulation and enhanced deposition of the drugs in acidic tumor environments. In vitro, OGS showed superior cytotoxicity over free drug combinations and robust cytotoxic synergism among its three components. In vivo, OGS improved drug circulation, increased tumor deposition, and exhibited superior antitumor efficacy over the free drug combination in both subcutaneous and orthotopic pancreatic tumor models. OGS treatment achieved 75-91% tumor growth inhibition and prolonged mouse survival by 1.6- to 2.8-folds while minimizing systemic toxicities such as neutropenia, hepatotoxicity, and renal toxicity. This work uncovers a novel and clinically relevant nanomedicine strategy to co-deliver synergistic combination chemotherapies for difficult-to-treat cancers.

Pharmacological ascorbate potentiates combination nanomedicines and reduces cancer cell stemness to prevent post-surgery recurrence and systemic metastasis.

Conventional chemotherapy targets proliferative cancer cells to halt tumor progression or regress tumors. However, the plasticity of tumor cells enables their phenotypical changes to acquire chemo-resistance, leading to treatment failure or tumor recurrence after a successful treatment course. Here, we report the use of high-dose pharmacologic ascorbate to potentiate treatment efficacy of nanoscale coordination polymers (NCPs) delivering two clinical combinations of chemotherapeutics, carboplatin/docetaxel and oxaliplatin/SN38, and to target metabolic plasticity of tumor cells. Combination treatments of high-dose ascorbate and NCPs overcome multi-drug resistance by significantly reducing the abundance of cancer stem cells (CSCs) in solid tumors, as evidenced by reduced expression of tumor pluripotency factors. The clearance of CSCs inhibits post-surgery recurrence and systemic metastasis in multiple mouse models of cancer.

A Three-in-One Nanoscale Coordination Polymer for Potent Chemo-Immunotherapy.

The addition of immune checkpoint blockade to standard chemotherapy has changed the standards of care for some cancer patients. However, current chemo-immunotherapy strategies do not benefit most colorectal cancer patients and many triple-negative breast cancer patients. Here, the design of a three-in-one nanoscale coordination polymer (NCP), OX/GC/CQ, comprising prodrugs of oxaliplatin (OX), gemcitabine (GC), and 5-carboxy-8-hydroxyquinoline (CQ) for triple-modality chemo-immunotherapy is reported. OX/GC/CQ exhibits optimal pharmacokinetics and enhanced particle accumulation and drug release in acidic tumor tissues, wherein CQ greatly enhances immunogenic cell death induced by OX/GC and downregulates programmed cell death-ligand 1  expression in cancer cells. Consequently, OX/GC/CQ efficiently promotes infiltration and activity of cytotoxic T lymphocytes, while decreasing the proportion of immunosuppressive regulatory T cells. Intravenous injection of OX/GC/CQ reduces the growth of colorectal carcinoma and triple-negative breast cancer, prevents metastasis to lungs, and extends mouse survival by 30-40 days compared to free drugs. This work highlights the potential of NCPs in co-delivering synergistic chemo-immunotherapeutics for the treatment of advanced and aggressive cancers.

TLR3 agonist nanoscale coordination polymer synergizes with immune checkpoint blockade for immunotherapy of cancer.

Immunotherapies including immune checkpoint blockade (ICB) have become integral to treatments for immunogenic tumors by reinvigorating host immune functions to attack tumor cells. However, the clinical applications of ICB are limited by relatively low response rates as well as inherent and acquired resistance in many types of cancer. A potential solution is to selectively deliver immune modulators to tumors to activate the tumor microenvironment (TME) and enhance the therapeutic effect of ICB. Here we report the design of polyinosinic: polycytidylic acid (pIC) nanoscale coordination polymer (NCP), pIC@NCP, and its ability to activate tumor-specific immune responses and synergize with ICB for potent antitumor effects. With prolonged blood circulation, facile cell uptake, and triggered release of pIC in acidic TMEs, pIC@NCP shows robust tumor growth inhibition via activation of the endosomal toll-like receptor 3 signaling pathway. The synergistic combination of pIC@NCP and ICB further controls tumor growth in syngeneic mouse models of colorectal cancer and a spontaneous mouse model of prostate cancer. This study highlights the potential of NCP delivery of nucleic acid therapeutics for immune activation and cancer therapy.

Tumor-Activatable Nanoparticles Target Low-Density Lipoprotein Receptor to Enhance Drug Delivery and Antitumor Efficacy.

The binding of plasma proteins to nanomedicines is widely considered detrimental to their delivery to tumors. Here, the design of OxPt/SN38 nanoparticle containing a hydrophilic oxaliplatin (OxPt) prodrug in a coordination polymer core and a hydrophobic cholesterol-conjugated SN38 prodrug on the lipid shell for active tumor targeting is reported. OxPt/SN38 hitchhikes on low-density lipoprotein (LDL) particles, concentrates in tumors via LDL receptor-mediated endocytosis, and selectively releases SN38 and OxPt in acidic, esterase-rich, and reducing tumor microenvironments, leading to 6.0- and 4.9-times higher accumulations in tumors over free drugs. By simultaneously crosslinking DNA and inhibiting topoisomerase I, OxPt/SN38 achieved 92-98% tumor growth inhibition in five colorectal cancer tumor models and prolonged mouse survival by 58-80 days compared to free drug controls in three human colorectal cancer tumor models without causing serious side effects. The study has uncovered a novel nanomedicine strategy to co-deliver combination chemotherapies to tumors via active targeting of the LDL receptor.