In Vitro and In Vivo Evaluation of a Cyclic LyP-1-Modified Nanosystem for Targeted Endostatin Delivery in a KYSE-30 Cell Xenograft Athymic Nude Mice Model

Abstract

This work investigated the use of LyP-1 as a homing peptide for p32 receptor targeting on the surface of an endostatin (ENT)-loaded chitosan-grafted nanosystem intended for intracellular delivery of ENT and mitochondrial targeting in a squamous cell carcinoma (SCC) cell line (KYSE-30) model. The angiogenic factors for VEGF-C and MMP2 were assessed with in vivo evaluation of the nanosystem upon ENT release and tumor necrosis in nude mice with a KYSE-30 cell xenograft. The LyP-1-modified nanosystem revealed a three-fold decrease in proliferation at 1000 µg/mL compared with the control and facilitated receptor-mediated cellular uptake and internalization. In addition, targeting of the Lyp-1-functionalized nanosystem to mitochondrial and nuclear proteins in vitro and in vivo was achieved. Up to 60% inhibition of KYSE-30 cell migration was observed and the expressions of VEGF-C and MMP-2 as angiogenic markers were reduced 3- and 2-fold, respectively. A marked reduction in tumor mass was recorded (43.25%) with the control, a 41.36% decrease with the nanoparticles and a 61.01% reduction with the LyP-1-modified nanosystem following treatment in mice. The LyP-1-functionalized nanosystem targeted tumor lymphatics, instigated nuclear rupture and mitochondrial distortion, and decreased cell proliferation and migration with inhibition of VEGF-C and MMP2 expression.

Surface Immobilization of Anti-VEGF Peptide on SPIONs for Antiangiogenic and Targeted Delivery of Paclitaxel in Non-Small-Cell Lung Carcinoma

“…Interestingly, no significant loss was noted in the weight of mice treated with CLA-coated PTX-SPIONs@HRH, CLA-coated PTX-SPIONs, and Taxol, meanwhile mice that received only PBS showed a notable weight loss (>5%) due to the progression of cancer over the duration of the study (Figure d). A loss of weight in skeletal muscle and adipose tissue, known as cachexia, is fairly common in cancer and may also present as a side effect to chemotherapy. , As such, the results obtained indicated the potential of CLA-coated PTX-SPIONs@HRH and CLA-coated PTX-SPIONs to also retard cachexia, and further suggest that the dosage of Taxol administered could be tolerated, as no other side effects were observed.…”

“…Subcutaneous (SC) tumor Xenograft models are widely used in cancer research, and nude mice are the most commonly used rodents for the establishment of xenografts models owing to their compromised immune system. , In the present study, a lung tumor xenograft model was successfully established and used to evaluate in vivo antitumor activity of the formulated CLA-coated PTX-SPIONs@HRH. Accordingly, a rapid tumor growth was recorded in the PBS (placebo) group, with tumors reaching an average volume of 1484.7 mm 3 at day 20 (Figure a).…”

“…Moreover, 10E, 12Z CLA is an excellent coating agent, allowing maximal partitioning of PTX, a hydrophobic anticancer drug, owing to its poor aqueous solubility. , SPIONs coated with CLA have demonstrated enhanced antitumor activity against mouse breast cancer cells (4T1) . Meanwhile, peptides generally exhibit high selectivity and good efficacy for biomedical application. , This study reports on a holistic fabrication approach in achieving a targeted nanosystem that is safe by design, through the formulation of HRH-functionalized CLA-coated PTX-SPIONs (CLA-coated PTX-SPIONs@HRH) and its in vitro and in vivo evaluation. Subcutaneous injection of CLA-coated PTX-SPIONs@HRH in a lung tumor xenograft mouse model halted angiogenesis and restricted tumor growth.…”

Recombinant Endostatin as a Potential Radiosensitizer in the Treatment of Non-Small Cell Lung Cancer

“…RE-loaded nanoparticles have also shown anti-angiogenic effects in vivo; for example, a folic acid-decorated chitosan nanoparticle successfully targeting squamous cell carcinoma (SCC) [ 89 , 90 , 91 ]. VEGFR-2 was successfully targeted in the blood brain barrier by Lu et al, using a dual receptor peptide functionalized polyethyleneimine nanocomplex for secretory RE delivery to malignant glioma [ 92 ].…”

Short Antiangiogenic MMP-2 Peptide-Decorated Conjugated Linoleic Acid-Coated SPIONs for Targeted Paclitaxel Delivery in an A549 Cell Xenograft Mouse Tumor Model

“…Hence, the inhibition of tumor angiogenesis pathways is a prospective therapeutic approach for NSCLC. Synthetic and natural angiogenesis inhibitors which block new blood vessel formation have been explored for tumor therapy, and some peptide-based inhibitors have demonstrated promising antiangiogenic activity. − Matrix metalloproteinase 2 (MMP-2) has been shown to be implicated in lung cancer angiogenesis regulation and tumor metastasis. , MMP-2 expression is linked to tumor-induced angiogenesis, where it is responsible for degrading the extracellular matrix (ECM) and releasing stored angiogenic factors (i.e., basic fibroblast and/or vascular endothelial growth factors) which propel angiogenesis, tumor differentiation, and metastasis. , Thus, targeting MMP-2 and downregulating its expression could halt tumor angiogenesis and suppress proliferation and metastasis.…”