Dual-responsive nanoparticles loading bevacizumab and gefitinib for molecular targeted therapy against non-small cell lung cancer.

The combination of vascular endothelial growth factor (VEGF) inhibitors and tyrosine kinase inhibitors (TKIs) is newly available for molecular targeted therapy against non-small cell lung cancer (NSCLC) in clinic. However, the therapeutic benefits remain unsatisfying due to the poor drug delivery to targets of interest. In this study, we developed bevacizumab-coated gefitinib-loaded nanoparticles (BCGN) with dual-responsive drug release for inhibiting tumor angiogenesis and phosphorylation of epidermal growth factor receptor (EGFR). Through an exogenous corona strategy, bevacizumab is easily coated on gefitinib-loaded nanoparticles via electrostatic interaction. After intravenous injection, BCGN are efficiently accumulated in NSCLC tumors as confirmed by dual-model imaging. Bevacizumab is released from BCGN upon oxidation in tumor microenvironment, whereas gefitinib is released after being internalized by tumor cells and disassembled in reduction cytoplasm. The dual-responsive release of bevacizumab and gefitinib significantly inhibits tumor growth in both A549 and HCC827 human NSCLC models. Our approach provides a promising strategy to improve combinational molecular targeted therapy of NSCLC with precisely controlled drug release.

ROS-Responsive Nanocomplex of aPD-L1 and Cabazitaxel Improves Intratumor Delivery and Potentiates Radiation-Mediated Antitumor Immunity.

Despite the promising benefits of immune checkpoint inhibitors (ICIs) in clinical cancer treatments, the therapeutic efficacy is largely restricted by low antitumor immunity and limited intratumor delivery in solid tumors. Herein, we designed a reactive oxygen species (ROS)-responsive albumin nanocomplex of antiprogrammed cell death receptor ligand 1 (aPD-L1) and cabazitaxel (RAN-PC), which exhibited prominent tumor accumulation and intratumor permeation in 4T1 tumors. Compared with the negative control, the RAN-PC + radiation treatment (RAN-PC+X) produced a 3.61- and 5.10-fold enhancement in CD3+CD8+ T cells and the interferon (IFN)-γ-expressing subtype, respectively, and notably reduced versatile immunosuppressive cells. Moreover, RAN-PC+X treatment resulted in notable retardation of tumor growth, with a 78.97% inhibition in a 4T1 breast tumor model and a 90.30% suppression in a CT-26 colon tumor model. Therefore, the ROS-responsive albumin nanocomplex offers an encouraging platform for ICIs with prominent intratumor delivery capacity for cancer immunotherapy.

Poly(maleic anhydride-alt-1-octadecene)-based bioadhesive nanovehicles improve oral bioavailability of poor water-soluble gefitinib.

The poor water solubility and inadequate oral bioavailability of gefitinib (Gef) remain a critical issue to achieve the therapeutic outcomes. Herein, we designed a poly(maleic anhydride-alt-1-octadecene) (PMA/C18) based lipid nanovehicle (PLN) to improve the intestinal absorption and oral bioavailability of poorly water-soluble Gef. PLN was nanometer-sized particles, and Gef was dispersed in the PLN formulation as amorphous or molecular state. At 4 h of oral administration, the tissue concentration of Gef in duodenum, jejunum, and ileum was profoundly enhanced 3.37-, 8.94-, and 8.09-fold by PLN when comparing to the counterpart lipid nanovehicle. Moreover, the oral bioavailability of Gef was significantly enhanced 2.48-fold by the PLN formulation when comparing to the free drug suspension. Therefore, this study provides an encouraging bioadhesive delivery platform to improve the oral delivery of poorly water-soluble drugs.

Spatial-Drug-Laden Protease-Activatable M1 Macrophage System Targets Lung Metastasis and Potentiates Antitumor Immunity.

Lung metastasis is a critical cause of cancer mortality and its therapy is largely challenged by the limited drug delivery efficiency and robust immunosuppression in metastatic tumors. Herein, we designed a spatial-drug-laden M1 macrophage system with liposomal R848 inside and fibroblast activation protein protease (FAP)-sensitive phospholipid-DM4 conjugate on the membrane of M1 macrophage (RDM). RDM could preferentially accumulate at the metastatic lesions in lungs and responsively release the therapeutic agents as free drug molecules or drug-loaded nanovesicles. RDM treatment notably enhanced the infiltration of CD3+CD8+ T cells to lung metastasis and, respectively, caused an 8.54-, 12.87- and 2.85-fold improvement of the granzyme-B-, interferon-γ-, and Ki67-positive subtypes versus negative control. Moreover, RDM treatment produced a 90.99% inhibition of lung metastasis in 4T1 models and significant prolongation of survival in three murine lung metastatic models. Therefore, the drug-laden FAP-sensitive M1 macrophage system represents a feasible strategy to target lung metastasis and boost antitumor immunity for antimetastasis therapy.

Bioinspired nanovehicle of furoxans-oxaliplatin improves tumoral distribution for chemo-radiotherapy.

The spatiotemporal distribution of therapeutic agents in tumors remains an essential challenge of radiation-mediated therapy. Herein, we rationally designed a macrophage microvesicle-inspired nanovehicle of nitric oxide donor-oxaliplatin (FO) conjugate (M-PFO), aiming to promote intratumor permeation and distribution profiles for chemo-radiotherapy. FO was responsively released from M-PFO in intracellular acidic environments, and then be activated by glutathione (GSH) into active oxaliplatin and NO molecules in a programmed manner. M-PFO exhibited notable accumulation, permeation and cancer cell accessibility in tumor tissues. Upon radiation, the reactive peroxynitrite species (ONOO-) were largely produced, which could diffuse into regions over 400 µm away from the tumor vessels and be detectable after 24 h of radiation, thereby exhibiting superior efficacy in improving the spatiotemporal distribution in tumors versus common reactive oxygen species (ROS). Moreover, M-PFO mediated chemo-radiotherapy caused notable inhibition of tumor growth, with an 89.45% inhibition in HT-29 tumor models and a 92.69% suppression in CT-26 tumor models. Therefore, this bioinspired design provides an encouraging platform to improve intratumor spatiotemporal distribution to synergize chemo-radiotherapy.

Nanomedicine Strategies to Circumvent Intratumor Extracellular Matrix Barriers for Cancer Therapy.

The dense and heterogeneous physical network of the extracellular matrix (ECM) in tumors represents a formidable barrier that limits intratumor drug delivery and the therapeutic efficacy of many anticancer therapies. Here, the two major nanomedicine strategies to circumvent intratumor ECM barriers: regulating the physiochemical properties of nanomedicines and remodeling the components and structure of the ECM are summarized. Nanomedicines can be rationally regulated by optimizing physiochemical properties or designed with biomimetic features to promote ECM permeation capability. Meanwhile, they can also be designed to remodel the ECM by modulating signaling pathways or destroying the components and architecture of the ECM via chemical, biological, or physical treatments. These efforts produce profound improvements in intratumor drug delivery and anticancer efficacy. Moreover, to aid in their anticancer efficacy, feasible approaches for improving ECM-circumventing nanomedicines are proposed.

Strategies of engineering nanomedicines for tumor retention.

The retention of therapeutic agents in solid tumors at sufficient concentration and duration is crucial for their antitumor effects. Given the important contribution of nanomedicines to oncology, we herein summarized two major strategies of nanomedicines for tumor retention, such as transformation- and interactions-mediated strategies. The transformation-mediated retention strategy was achieved by enlarging particle size of nanomedicines or modulating the morphology into fibrous structures, while the interactions-mediated retention strategy was accomplished by modulating nanomedicines to promote their interactions with versatile cells or components in tumors. Moreover, we provide some considerations and perspectives of tumor-retaining nanomedicines for effective cancer therapy.

Microvesicle-inspired oxygen-delivering nanosystem potentiates radiotherapy-mediated modulation of tumor stroma and antitumor immunity.

The efficacy of radiotherapy is greatly challenged by intense hypoxia, intricate stroma and suppressive immune microenvironments in tumors. Herein, we rationally designed a microvesicle-inspired oxygen-delivering polyfluorocarbon nanosystem loading DiIC18(5) and halofuginone (M-FDH) with prominent capacity of improving tumor oxygenation and intratumor distribution, synergizing radiation to disrupt tumor stroma and boost antitumor immunity for combinational cancer therapy. M-FDH produced a 10.98-fold enhancement of tumor oxygenation and caused efficient production of reactive oxygen species (ROS) upon radiation. M-FDH + X ray treatment resulted in notable DNA damages, over 90% elimination of cancer-associated fibroblasts (CAFs) and major components of extracellular matrix, significant enhancement of tumoricidal CD3+CD8+ T cells, and profound elimination of suppressive immune cells in 4T1 tumors. The therapeutic benefits of M-FDH + X ray on suppressing tumor growth were confirmed in two murine tumor models. Therefore, this study provides an encouraging microvesicle-inspired strategy to target cancer cells and CAFs in tumors and synergize radiotherapy for effective cancer treatment.