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

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

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

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

Incubation with CSO-SA/PEDF (24 µl/ml) induced fluorescent TUNEL-positive changes in ECSC nuclei after 48 h and 72 h of treatment.

<p>It shows that apoptotic cells in ECSC (d) increases significantly after 48 h (b) and 72 h (c) of treatment comapred to controls (a). (original magnification ×200).</p

The expression of VEGF (a–c) and PEDF (d–f) in implants of control, PEDF-1 and PEDF-5 groups in nude mice.

<p>It shows that CSO-SA/PEDF treatment increases the PEDF expression both in PEDF-1 (b) and PEDF-5 (c) groups significantly compared to controls (a), while decreases the VEGF expression in PEDF-1 (e) group significantly compared to controls (d). (Original magnification ×400).</p

The mean of volumes of the endometriosis foci in each group (PEDF-1: CSO-SA/PEDF group when treatment was initiated on postoperative day 1; PEDF-5: CSO-SA/PEDF group when treatment was initiated on postoperative day 5).

<p>The mean of volumes of the endometriosis foci in each group (PEDF-1: CSO-SA/PEDF group when treatment was initiated on postoperative day 1; PEDF-5: CSO-SA/PEDF group when treatment was initiated on postoperative day 5).</p

PEDF and VEGF expressions in endometriotic lesions in the treated and control groups.

#<p>PEDF-1 and 5: Mice treated with PEDF gene on day 1 and 5 after transplantation.</p>*<p>Indicate significant difference (p<i><</i>0.05, versus control).</p

Histopathologic examination of endometriosis lesions (stain: hematoxylin and eosin; magnification × 200).

<p>It shows abundant glands and stroma in the control group (a). Gland and stromal structure in PEDF-1(c) and PEDF-5 groups (b) are smaller than that in control group.</p

Histopathologic scores, microvessel density and cell apoptosis in endometriotic lesions in the treated and control groups.

#<p>PEDF-1 and 5: Mice treated with PEDF gene on day 1 and 5 after transplantation.</p>##<p>HS = histopathologic score.</p>*<p>Indicate significant difference (p<i><</i>0.05, versus control).</p