Dendritic Polymer-Based Nanomedicines Remodel the Tumor Stroma: Improve Drug Penetration and Enhance Antitumor Immune Response.

The dense extracellular matrix (ECM) in solid tumors, contributed by cancer-associated fibroblasts (CAFs), hinders penetration of drugs and diminishes their therapeutic outcomes. A sequential treatment strategy of remodeling the ECM via a CAF modifier (dasatinib, DAS) is proposed to promote penetration of an immunogenic cell death (ICD) inducer (epirubicin, Epi) via apoptotic vesicles, ultimately enhancing the treatment efficacy against breast cancer. Dendritic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA)-based nanomedicines (poly[OEGMA-Dendron(G2)-Gly-Phe-Leu-Gly-DAS] (P-DAS) and poly[OEGMA-Dendron(G2)-hydrazone-Epi] (P-Epi)) are developed for sequential delivery of DAS and Epi, respectively. P-DAS reprograms CAFs to reduce collagen by downregulating collagen anabolism and energy metabolism, thereby reducing the ECM deposition. The regulated ECM can enhance tumor penetration of P-Epi to strengthen its ICD effect, leading to an amplified antitumor immune response. In breast cancer-bearing mice, this approach alleviates the ECM barrier, resulting in reduced tumor burden and increased cytotoxic T lymphocyte infiltration, and more encouragingly, synergizes effectively with anti-programmed cell death 1 (PD-1) therapy, significantly inhibiting tumor growth and preventing lung metastasis. Furthermore, systemic toxicity is barely detectable after sequential treatment with P-DAS and P-Epi. This approach opens a new avenue for treating desmoplastic tumors by metabolically targeting CAFs to overcome the ECM barrier.

Dendritic Nanomedicine with Boronate Bonds for Augmented Chemo-Immunotherapy via Synergistic Modulation of Tumor Immune Microenvironment.

Unsatisfied tumor accumulation of chemotherapeutic drugs and a complicated immunosuppressive microenvironment diminish the immune response rate and the therapeutic effect. Surface modification of these drugs with target ligands can promote their cellular internalization, but the modified drugs may be subjected to unexpected immune recognition and clearance. Herein, a phenylboronic acid (PBA) group-shieldable dendritic nanomedicine that integrates an immunogenic cell death (ICD)-inducing agent (epirubicin, Epi) and an indoleamine 2,3-dioxgenase 1 (IDO1) inhibitor (NLG919) is reported for tumor chemo-immunotherapy. This NLG919-loaded Epi-conjugated PEGylated dendrimers bridged with boronate bonds (NLG919@Epi-DBP) maintains a stable nanostructure during circulation. Under a moderate acidic condition, the PBA group exposes to the sialic acid residue on the tumor cell membrane to enhance the internalization and penetration of NLG919@Epi-DBP. At pH 5.0, NLG919@Epi-DBP rapidly disassembles to release the incorporated Epi and NLG919. Epi triggers robust ICD of tumor cells that evokes strong immune response. In addition, inhibition of the IDO1 activity downregulates the metabolism of L-tryptophan to kynurenine, leading to a reduction in the recruitment of immunosuppressive cells and modulation of the tumor immune microenvironment. Collectively, this promising strategy has been demonstrated to evoke robust immune response as well as remodel the immunosuppressive microenvironment for an enhanced chemo-immunotherapeutic effect.

Stimuli-responsive heparin-drug conjugates co-assembled into stable nanomedicines for cancer therapy.

The combination of chemotherapy and photodynamic therapy (PDT) has the potential to complement single-drug therapies, but chemotherapeutic agents and photosensitizers often have compromised therapeutic efficacies and strong toxic effects. In this study, we exploited nanotechnology to address this challenge by utilizing heparin as a carrier for co-delivery of chemotherapeutic drugs and photosensitizers for synergistic cancer therapy. Specifically, heparin-paclitaxel (HP-PTX) and heparin-pyropheophorbide-a (HP-Ppa) were synthesized by attaching paclitaxel (PTX), a small molecular chemotherapeutic drug, through a reactive oxygen species (ROS)-responsive linker and Ppa, a photosensitizer, to heparin, respectively. Two conjugates were co-assembled into a nanomedicine, HP-PP nanoparticles (NPs), for controllable co-delivery of Ppa and PTX into tumor cells. HP-PP NPs significantly enhanced the in vitro stability of HP-Ppa and the photostability of Ppa, and the synergistic actions of chemotherapy and PDT were confirmed by both in vitro and in vivo antitumor studies. Notably, HP-PP NPs enhanced tumor accumulation of Ppa up to 11-fold and the treatment of 4T1 tumor-bearing mice with HP-PP NPs resulted in a tumor growth inhibition of 98.1% without systemic toxicity. The strategy of co-assembly of heparin conjugates may offer great potential in enhancing the efficacy of combination therapy. STATEMENT OF SIGNIFICANCE: We proposed a nano-delivery system, HP-PP NPs, which was constructed by co-assembly of heparin-paclitaxel (HP-PTX) and heparin-pyropheophorbide-a (HP-Ppa), to co-deliver PTX and Ppa for synergistic cancer therapy. HP-PP NPs enhanced the photostability and the in vitro stability of Ppa and HP-Ppa, and induced greater cytotoxicity than HP-PTX NPs or HP-Ppa NPs. This co-delivery system displays enhanced tumor accumulation and has a remarkable synergistic antitumor effect with a tumor growth inhibition of 98.1%.