Targeting prostate cancer with docetaxel-loaded peptide 563-conjugated PEtOx-co-PEI30%-b-PCL polymeric micelle nanocarriers.

Prostate cancer is a global disease that negatively affects the quality of life. Although various strategies against prostate cancer have been developed, only a few achieved tumor-specific targeting. Therefore, a special emphasis has been placed on the treatment of cancer using nano-carrier-encapsulated chemotherapeutic agents conjugated with tumor-homing peptides. The targeting strategy coupling the drugs with nanotechnology helps to overcome the most common barriers, such as high toxicity and side effects. Prostate-specific membrane antigen has emerged as a promising target molecule for prostate cancer and shown to be targeted with high affinity by GRFLTGGTGRLLRIS peptide known as peptide 563 (P563). Here, we aimed to assess the in vitro and in vivo targeting efficiency, safety, and efficacy of P563-conjugated, docetaxel (DTX)-loaded polymeric micelle nanoparticles (P563-PEtOx-co-PEI30%-b-PCL-DTX) against prostate cancer. To this end, we analyzed the cytotoxic activity of P563-PEtOx-co-PEI30%-b-PCL and P563-PEtOx-co-PEI30%-b-PCL-DTX by a cell proliferation assay using PNT1A and 22Rv1 cells. We have also determined the targeting selectivity of P563-PEtOx-co-PEI30%-b-PCL-FITC by flow cytometry and assessed the induction of cell death by western blot and TUNEL assays for P563-PEtOx-co-PEI30%-b-PCL-DTX in 22Rv1 cells. To investigate the in vivo efficacy, we administered DTX in the free form or in polymeric micelle nanoparticles to athymic CD-1 nu/nu mice 22Rv1 xenograft models and performed histopathological analyses. Our study showed that targeting prostate cancer with P563-conjugated PEtOx-co-PEI30%-b-PCL polymeric micelles could exert a potent anti-cancer activity with low side effects.

Delivery of doxorubicin loaded P18 conjugated-poly(2-ethyl-oxazoline)-DOPE nanoliposomes for targeted therapy of breast cancer.

Breast cancer, a heterogeneous disease, has the highest incidence rate and is a major cause of death in females worldwide. Drug delivery by using nanotechnology has shown great promise for improving cancer treatment. Nanoliposomes are known to have enhanced accumulation ability in tumors due to prolonged systemic circulation. Peptide 18 (P18), a tumor homing peptide targeting keratin-1 (KRT-1), was previously shown to have high binding affinity towards breast cancer cells. In this study, we investigate the ability of P18 conjugated PEtOx-DOPE nanoliposomes (P18-PEtOx-DOPE) for the targeted delivery of doxorubicin to AU565 breast cancer model. Toxicology studies of PEtOx-DOPE nanoliposomes performed on normal breast epithelial cells (MCF10A), showed minimal toxicity. Doxorubicin delivery by P18-PEtOx-DOPE to AU565 cells induces cytotoxicity in a dose and time dependent manner causing mitotic arrest in G2/M phase at 24 h. Anti-cancer activity of P18-PEtOx-DOPE-DOX nanoliposomes on AU565 cells was detected by Annexin V/PI apoptosis assay. In terms of in vivo antitumor efficacy, P18-PEtOx-DOPE-DOX nanoliposomes administration to AU565 CD-1 nu/nu mice model showed significant decrease in tumor volume suggesting that DOX delivered by these nanoliposomes elicited a strong antitumor response comparable to the free delivery of doxorubicin. Overall, our results offered preclinical proof for the use of P18-PEtOx-DOPE-DOX nanoliposomes in KRT-1+ breast cancer therapy.

Synthesis and evaluation of tumor-homing peptides for targeting prostate cancer.

High toxicity caused by chemotherapeutic drugs and the acquisition of drug resistance by cancer cells are the major drawbacks in cancer therapy. A promising approach to overcome the posed barriers is conjugating tumor-homing peptides to drugs or nanocarriers. Such high-affinity peptides can specifically target surface markers overexpressed by cancer cells, ensuring a rapid and cancer-specific uptake of the drugs. Since prostate-specific membrane antigen (PSMA) is overexpressed by aggressive prostate cancer cells, targeting this surface protein with peptide conjugates can lead to the development of effective strategies against prostate cancer. In this study, we aimed to determine which PSMA-binding peptide among peptides 563, 562 and 9-mer, show the highest selectivity towards PSMA using 22Rv1 prostate cancer cells, a cell line with moderate PSMA levels. Tumor-homing peptides were synthesized by fluorenylmethoxycarbonyl-based solid-phase peptide synthesis (Fmoc-SPPS) strategy, and evaluated for their prostate cancer cell-specific targeting efficiencies by flow cytometry. Our results showed that the PSMA-binding capacity of peptide 563 was superior to those of 562, 9-mer, and 5-mer; therefore, can be utilized as a potent-targeting agent not only in the treatment of high PSMA positive but also moderate PSMA positive prostate cancer tumors.

Transglutaminase 2: The Maestro of the Oncogenic Mediators in Renal Cell Carcinoma.

Transglutaminase 2 (TG2) is a multifunctional crosslinking enzyme that displays transamidation, protein disulfide isomerase, protein kinase, as well as GTPase and ATPase activities. TG2 can also act as an adhesion molecule involved in the syndecan and integrin receptor signaling. In recent years, TG2 was implicated in cancer progression, survival, invasion, migration, and stemness of many cancer types, including renal cell carcinoma (RCC). Von Hippel-Lindau mutations leading to the subsequent activation of Hypoxia Inducible Factor (HIF)-1-mediated signaling pathways, survival signaling via the PI3K/Akt pathway resulting in Epithelial Mesenchymal Transition (EMT) metastasis and angiogenesis are the main factors in RCC progression. A number of studies have shown that TG2 was important in HIF-1- and PI3K-mediated signaling, VHL and p53 stabilization, glycolytic metabolism and migratory phenotype in RCC. This review focuses on the role of TG2 in the regulation of molecular pathways nurturing not only the development and propagation of RCC, but also drug-resistance and metastatic potential.