Smart Assembled Human Serum Albumin Nanocarrier Enhanced Breast Cancer Treatment and Antitumor Immunity by Chemo- photothermal Therapy

High invasion and metastasis are the major obstacles to successful breast cancertherapy. Indocyanine green (ICG), a photosensitizer for photothermal therapy (PTT), shows potent anticancer efficacy when combined with the chemotherapeutic drug doxorubicin (DOX). Human serum albumin (HSA), a biocompatible carrier material, has been successfully used for the delivery of paclitaxel (Abraxane). In addition, there are ICG functional binding regions in HSA. Thus, a smart assembled nanoplatform (DI@HSA NPs) was constructed to achieve the synergistic effects of chemo- photothermal therapy against breast cancer. Compared to free ICG and free DOX, DI@HSA NPs showed satisfactory stability and exhibited an enhanced tumor targeting capacity. The mild hyperthermia generated by DI@HSA NPs can not only cause tumor photothermal ablation and promote the uptake of DI@HSA NPs by 4T1 cells, but also protect the healthy tissues nearby the tumor from overheating injury. More importantly, DI@HSA NPs greatly amplified the infiltration of CD4+ T cells and CD8+ T cells, resulting in inhibited tumor growth and metastasis. DI@HSA NPs, as a simple biocompatible nanoagent, showed excellent inhibition of breast cancer growth and metastasis by chemo-photothermal therapy, providing a potential strategy for the future therapy of breast cancer

Normalizing Tumor Blood Vessels to Improve Chemotherapy and Inhibit Breast Cancer Metastasis by Multifunctional Nanoparticles

The abnormal tumor blood vessels with high leakage can promote tumor cells to infiltrate into the systemic circulation and increase the risk of tumor metastasis. In addition, chemotherapy may destroy tumor blood vessels and further aggravate metastasis. Normalizing tumor blood vessels can reduce vascular leakage and increase vascular integrity. The simultaneous administration of vascular normalization drugs and chemotherapy drugs may resist the blood vessels’ destruction of chemotherapy. Here, multifunctional nanoparticles (CCM@LMSN/DOX&St), which combined chemotherapy with tumor blood vessel normalization, were prepared for the treatment of breast cancer. The results showed that CCM@LMSN/DOX&St-loaded sunitinib (St) promoted the expression of junction proteins Claudin-4 and VE-cadherin of endothelial cells, reversed the destruction of DOX to the endothelial cell layer, protected the integrity of the endothelial cell layer, and inhibited the migration of 4T1 tumor cells across the endothelial cell layer. In vivo experiments showed that CCM@LMSN/DOX&St effectively inhibited tumor growth in situ; what is exciting was that it also inhibited distal metastasis of breast cancer. CCM@LMSN/DOX&St encapsulated with St can normalize tumor blood vessels, reverse the damage of DOX to tumor blood vessels, increase the integrity of blood vessels, and prevent tumor cell invasion into blood vessels, which can inhibit breast cancer spontaneous metastasis and reduce chemotherapy-induced metastasis. This drug delivery platform effectively inhibited the progression of tumors and provided a promising solution for effective tumor treatment

GSH-Responsive Polymeric Micelles for Remodeling the Tumor Microenvironment to Improve Chemotherapy and Inhibit Metastasis in Breast Cancer

The tumor microenvironment (TME) of breast cancer is hypoxic, which can promote tumor progression, including invasion and metastasis, and limit the efficacy of anti-tumor treatment. Nitric oxide (NO) can dilate blood vessels, effectively alleviate hypoxia, and regulate the TME, which has the potential to improve the anti-tumor therapeutic efficacy. Here, chitosan (CO) and octadecylamine (ODA) were linked by the disulfide bond, and the LinTT1 peptide was linked onto CO–SS–ODA for targeting tumor cells and endothelial cells in tumors. The NO donor S-nitroso-N-acetylpenicillamine (SNAP) was connected to CO. Doxorubicin (DOX) was encapsulated, and GSH hierarchically responsive polymer micelles (TSCO–SS–ODA/DOX) were constructed for the treatment of breast cancer. The micelles had differently responsive drug release in different GSH concentrations. In endothelial cells, the micelles rapidly responded to release NO. In tumor cells, the disulfide bond rapidly broke and released DOX to effectively kill tumor cells. The disulfide bond was not sensitive to GSH concentration in endothelial cells, which had less release of DOX. The killing effect of the micelles to endothelial cells was much lower than that to tumor cells. The cell selective drug release of the drug delivery systems enabled safe and effective treatment of drugs. TSCO–SS–ODA/DOX, which had the excellent ability to target tumors, can alleviate tumor hypoxia, decrease the infiltration of M2 macrophages in tumors, increase the infiltration of M1 macrophages in tumors, and remodel the TME. Notably, TSCO–SS–ODA/DOX can significantly inhibit the growth of the primary tumor and effectively inhibit tumor metastasis. The drug delivery system provided a potential solution for effectively treating breast cancer

A54 Peptide Modified and Redox-Responsive Glucolipid Conjugate Micelles for Intracellular Delivery of Doxorubicin in Hepatocarcinoma Therapy

Redox-responsive nanomaterials applied in drug delivery systems (DDS) have attracted an increasing attention in pharmaceutical research as a carrier for antitumor therapy. However, there would be unwanted drug release from a redox-responsive DDS with no selection at nontarget sites, leading to undesirable toxicities in normal tissues and cells. Here, an A54 peptide modified and PEGylated reduction cleavable glucolipid conjugate (A54-PEG-CSO-ss-SA, abbreviated to APCssA) was designed for intracellular delivery of doxorubicin (DOX). The synthesized APCssA could be assembled via micellization self-assembly in aqueous water above the critical micelle concentration (54.9 μg/mL) and exhibited a high drug encapsulation efficiency (77.92%). The APCssA micelles showed an enhanced redox sensitivity in that the disulfide bond could be degraded quickly and the drug would be released from micelles in 10 mM levels of glutathione (GSH). The cellular uptake studies highlighted the affinity of APCssA micelles toward the hepatoma cells (BEL-7402) compared to that toward HepG2 cells. In contrast with the nonresponsive conjugate, the drug was released from APCssA micelles more quickly in 10 mM level of GSH concentration (tumor cells). Moreover, the DOX-loaded APCssA micelles displayed an increased cytotoxicity which was 1.6- to 2.0-fold that of unmodified and nonresponsive micelles. In vivo, the APCssA micelles had stronger distribution to liver and hepatoma tissue and prolonged the circulation and retention time, while the drug release only occurred in the tumor tissue. The APCssA/DOX showed the tumor inhibition rate equal to that of commercial doxorubicin hydrochloric without negative consequence. This study suggested that the APCssA/DOX showed promising potential to treat the tumor for its special tumor targeting, selective intracellular drug release, enhanced antitumor activity, and reduced toxicity on normal tissues

Redox-Responsive Polymer–Drug Conjugates Based on Doxorubicin and Chitosan Oligosaccharide‑<i>g</i>‑stearic Acid for Cancer Therapy

Here, a biodegradable polymer–drug conjugate of doxorubicin (DOX) conjugated with a stearic acid-grafted chitosan oligosaccharide (CSO-SA) was synthesized via disulfide linkers. The obtained polymer–drug conjugate DOX-SS-CSO-SA could self-assemble into nanosized micelles in aqueous medium with a low critical micelle concentration. The size of the micelles was 62.8 nm with a narrow size distribution. In reducing environments, the DOX-SS-CSO-SA could rapidly disassemble result from the cleavage of the disulfide linkers and release the DOX. DOX-SS-CSO-SA had high efficiency for cellular uptake and rapidly released DOX in reductive intracellular environments. <i>In vitro</i> antitumor activity tests showed that the DOX-SS-CSO-SA had higher cytotoxicity against DOX-resistant cells than free DOX, with reversal ability up to 34.8-fold. DOX-SS-CSO-SA altered the drug distribution <i>in vivo</i>, which showed selectively accumulation in tumor and reduced nonspecific accumulation in hearts. <i>In vivo</i> antitumor studies demonstrated that DOX-SS-CSO-SA showed efficient suppression on tumor growth and relieved the DOX-induced cardiac injury. Therefore, DOX-SS-CSO-SA is a potential drug delivery system for safe and effective cancer therapy

Poly(ethyleneglycol)‑<i>b</i>‑Poly(ε-caprolactone-<i>co</i>-γ-hydroxyl-ε- caprolactone) Bearing Pendant Hydroxyl Groups as Nanocarriers for Doxorubicin Delivery

A novel biodegradable amphiphilic diblock copolymer methoxy poly­(ethylene glycol)-<i>b</i>-poly­(ε-caprolactone-<i>co-γ</i>-hydroxyl-ε-caprolactone) (mPEG-<i>b</i>-P­(CL-<i>co</i>-HCL)) bearing pendant hydroxyl groups on the PCL block was prepared. The hydroxyl groups were formed through the reduction of ketones by sodium borohydride without protection and deprotection. The obtained polymers were well characterized by ¹H NMR, Fourier transform infrared (FT-IR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and contact angle measurement. mPEG-<i>b</i>-P­(CL-<i>co</i>-HCL) could self-assemble into stable nanoparticles (NPs) with critical micellar concentrations (CMC) of 6.3 <b></b>× 10^–4 ∼ 8.1 <b> × </b> 10^–4 mg/mL. The NPs prepared from mPEG-<i>b</i>-P­(CL-<i>co</i>-HCL) were spherical in shape with diameters about 100 to 140 nm. The hydrophobic doxorubicin (DOX) was chosen as a drug model and successfully encapsulated into the NPs. The encapsulation efficiency and release kinetics of DOX were investigated. The results indicated that the introduction of hydroxyl groups onto the core-forming block could decrease the hydrophobicity of copolymers, thus improving the storage stability of NPs in aqueous solution. Moreover, higher loading capacity and slower <i>in vitro</i> release of DOX were observed, which was due to the hydrogen-bonding formation between DOX and hydroxyl groups. Meanwhile, the MTT assay demonstrated that the blank NPs were biocompatible to HepG2 cell,s while free DOX and DOX-loaded NPs showed significant cytotoxicity against the cells. Moreover, Compared to the free DOX, the DOX-loaded NPs were more efficiently internalized by HepG2 cells. In sum, the introduction of hydroxyl groups on the polyester block in mPEG-<i>b</i>-P­(CL-<i>co</i>-HCL) exhibited great potentials for modifications in the stability, drug solubilization, and release properties of NPs

Azobenzene-Containing Block Copolymer Templates for Robust Au@TiO₂ Nanoporous Network Films toward Hot-Electron-Mediated Efficient Visible-Light Photocatalysis

Robust metallic doped semiconducting networks of precise organization, over large scales and small dimensionality, hold great application potential in the basis of photocatalytic materials. Herein, a facile method to fabricate robust Au@TiO2 hierarchical nanoporous network films is reported, which is templated by thermally stable poly(4-vinylpyridine)-block-poly{11-[4-(4-butylphenylazo)phenoxy]undecyl methacrylate} (P4VP-b-PMA(11C)Az) liquid crystalline (LC) block copolymers (BCPs). A P4VP100-b-PMA(11C)Az15 thin film can self-assemble to form ∼50 nm orderly packed PMA(11C)Az periodic spheres in the P4VP matrix via a solvent-annealing process. When these spherical P4VP100-b-PMA(11C)Az15 films with different thicknesses were exposed to the sol–gel titania precursors alcohol solutions with titanium(IV) isopropoxide (TIPT) and titanium tetrachloride (TiCl4; mass ratio, 3:1), titania was well-formed in the P4VP phase during the calcination process. After a further deposition–precipitation (DP) process, ∼10 nm Au nanoparticles were homogeneously doped in robust TiO2 nanoporous network films. The photocatalytic performance of the obtained robust Au@TiO2 films was studied in detail. It displays significantly enhanced visible light photocatalytic activity. The enhancement mechanism was ascribed to the injection of hot electrons of photoexcited Au nanoparticles to robust porous TiO2 films, which was confirmed by 420 nm Xe laser-induced fast photodegradation of rhodamine B

Polymer-Modified Lipid Nanoparticles with Microenvironment-Responsive Graded Release for Amplified Photodynamic Therapy Through Tumor Vascular Normalization

Photodynamic therapy (PDT) is a promising approach to cancer treatment, but the heterogeneity of the tumor microenvironment (TME) limits its application. Tumor vasculature is thought to be involved in abnormal TME. Therefore, tumor vascular normalization (TVN) is expected to be a strategy to reshape TME. We prepared a graded-release nanodrug combining TVN and PDT, named as PEVM, with the core of lipid nanoparticles for sustained release of anti-angiogenic drugs and the shell of a pH-sensitive polymer linked to a photosensitizer, and evaluated its therapeutic effect on a breast cancer model. We found that PEVM could achieve mutual benefits in both therapeutic effects. TVN not only increased the intratumoral oxygen level as a raw material for PDT, but also activated the anti-tumor immune response, further improving the efficacy of PDT. PEVM showed favorable anti-tumor efficiency and exhibited the potential of combining TVN and PDT

Targeting High Expressed α₅β₁ Integrin in Liver Metastatic Lesions To Resist Metastasis of Colorectal Cancer by RPM Peptide-Modified Chitosan-Stearic Micelles

Liver metastasis is a leading death cause in colorectal cancer. The pathological differences between orthotopic tumors and metastatic lesions increased the therapeutic difficulty of metastasis. Herein, the α₅β₁ integrin receptor expression on metastatic cells was first measured, the result showed that metastatic cells expressed the α₅β₁ integrin higher than that of the original cells from orthotopic tumors. Afterward, RPM peptide-modified chitosan-stearic (RPM-CSOSA) was designed based on α₅β₁ integrin expression. The cytotoxicity and resistance to migration and the invasion ability of the targeting drug delivery system loading doxorubicin (DOX) and curcumin (CUR) were evaluated in vitro. The metastatic inhibition of the targeting drug delivery system was also investigated in HT29 liver metastatic models. The modified RPM peptide could increase the cellular internalization of CSOSA micelles in metastatic tumor cells and endothelial cells mediated by α₅β₁ integrin. The synergistic effects of RPM-CSOSA/DOX and RPM-CSOSA/CUR could obviously inhibit migratory and invasive abilities of HT29 cells and endothelial cells. Moreover, the RPM-CSOSA/DOX&RPM-CSOSA/CUR could obviously decrease the number of metastatic sites by 86.96%, while CSOSA/DOX&CSOSA/CUR decreased liver metastasis by 66.58% compared with that in the saline group. In conclusion, the RPM peptide-modified drug delivery system may provide insights into targeting the metastatic cells overexpressing the α₅β₁ integrin, and it has the potential to inhibit liver metastasis of colorectal cancer