Cancer-targeted Delivery System Research Articles

A Multiple Targeting Genome Editing System for Remodulation of Circulating Malignant Cells to Eliminate Cancer Immunosuppression and Restore Immune Responses.

Cancer immunotherapy, which aims to eliminate cancer immunosuppression and reactivate anticancer immunity, holds great promise in oncology treatments. However, it is challenging to accurately study the efficacy of immunotherapy based on human-derived cells through animal experiments due to xenogeneic immune rejection. Herein, a personalized and precise strategy to evaluate the effectiveness of immunotherapy using the blood samples of cancer patients is presented. Through the utilization of multiple cancer-targeting delivery system decorated with the epidermal growth factor receptor (EGFR)-specific aptamer CL4 and the AXL-specific aptamer GL21.T to achieve superior efficiency in delivering the genome editing plasmid for MUC1 knockout, effective modulation on the behavior of circulating malignant cells (CMCs) is realized. After genome editing, both mucin 1 (MUC1) and programmed death-ligand 1 (PD-L1) are significantly downregulated in CMCs. The elimination of immunosuppression results in markedly enhanced secretion of pro-inflammatory anticancer cytokines encompassing interleukins 2, 12, and 15 and interferon-γ by immune cells. The study not only provides a strategy to overcome immunosuppression but also yields critical insights for personalized immunotherapy approaches.

Multifunctional Lipid-Based Nanoparticles for Codelivery of Anticancer Drugs and siRNA for Treatment of Non-Small Cell Lung Cancer with Different Level of Resistance and EGFR Mutations

Resistance to chemotherapy, enhanced proliferation, invasion, angiogenesis, and metastasis (RPIAM) represent major obstacles that limit the efficacy of cancer treatment especially in advanced stages of cancer. Overcoming or suppressing RPIAM can dramatically improve the treatment outcome. Non-small cell lung cancer (NSCLC) is frequently diagnosed in an advanced stage and often possesses intrinsic resistance to chemotherapy accompanied by the fast development of acquired resistance during the treatment. Oncogenic receptor tyrosine kinases (TKs), specifically epidermal growth factor (EGF) TKs, play an important role in the activation of MAPK/PI3K/Akt/STAT pathways, finally leading to the development of RPIAM. However, the suppression of EGF-TK by different drugs is limited by various defensive mechanisms and mutations. In order to effectively prevent the development of RPIAM in NSCLC, we formulated and tested a multicomponent and multifunctional cancer targeted delivery system containing Nanostructured Lipid Carriers (NLCs) as vehicles, luteinizing hormone release hormone (LHRH) as a cancer targeting moiety, EFG-TK inhibitor gefitinib and/or paclitaxel as anticancer drug(s), siRNA targeted to EGF receptor (EGFR) mRNA as a suppressor of EGF receptors, and an imaging agent (rhodamine) for the visualization of cancer cells. Experimental data obtained show that this complex delivery system possesses significantly enhanced anticancer activity that cannot be achieved by individual components applied separately.

Alginate-Based Platforms for Cancer-Targeted Drug Delivery.

As an acidic, ocean colloid polysaccharide, alginate is both a biopolymer and a polyelectrolyte that is considered to be biocompatible, nontoxic, nonimmunogenic, and biodegradable. A significant number of studies have confirmed the potential use of alginate-based platforms as effective vehicles for drug delivery for cancer-targeted treatment. In this review, the focus is on the formation of alginate-based cancer-targeted delivery systems. Specifically, some general chemical and physical properties of alginate and different types of alginate-based delivery systems are discussed, and various kinds of alginate-based carriers are introduced. Finally, recent innovative strategies to functionalize alginate-based vehicles for cancer targeting are described to highlight research towards the optimization of alginate.

RGD-modified PEGylated paclitaxel nanocrystals with enhanced stability and tumor-targeting capability

Nanocrystals has been constructed for insoluble drugs as a novel type of nanoscale drug delivery systems with high drug loading. How to prepare nanocrystals with good stability and tumor targeting capability is still challenging. This study was to modify paclitaxel nanocrystals with polyethylene glycol (PEG) for stabilization and RGD peptide for tumor targeting. Inspired by the structure of mussel's foot protein, polydopamine (PDA) was introduced to the drug delivery system for the modification of nanocrystals. Briefly, PDA was coated on the surface of nanocrystals to form a reaction platform for further PEGylation and RGD peptide conjugation. PEGylated nanocrystals with RGD peptide modification (NC@PDA-PEG-RGD) were prepared with near-spheroid shape, drug loading 45.12 ± 1.81% and a hydrodynamic diameter 419.9 ± 80.9 nm. The size of NC@PDA-PEG-RGD remained basically unchanged for at least 72 h in the presence of plasma while the size of unmodified nanocrystals (NC) increased and exceeded 1000 nm in 12 h. Cellular uptake and cellular growth inhibition experiments using the lung cancer cell line A549 demonstrated the superiority of NC@PDA-PEG-RGD over NC or PEGylated nanocrystals without RGD modification (NC@PDA-PEG). In A549 model tumor bearing-mice, NC@PDA-PEG-RGD showed significantly higher intratumor accumulation and slower tumor growth than NC@PDA-PEG or free paclitaxel. In summary, our study suggested the superiority of RGDmodified PEGylated paclitaxel nanocrystals as a lung cancer-targeted delivery system and the potential of PDA coating technique for targeting functionalization of nanocrystals.

Cancer-targeted delivery systems based on peptides.

There is a growing interest for the discovery of new cancer-targeted delivery systems for drug delivery and diagnosis. A synopsis of the bibliographic data will be presented on bombesin, neurotensin, octreotide, Arg-Gly-Asp, luteinizing hormone-releasing hormone and other peptides. Many of them have reached the clinics for therapeutic or diagnostic purposes, and have been utilized as carriers of known cytotoxic agents such as doxorubicin, paclitaxel, cisplatin, methotrexate or dyes and radioisotopes. In our article, recent advances in the development of peptides as carriers of cytotoxic drugs or radiometals will be analyzed.

An investigation of antitumor efficiency of novel sustained and targeted 5-fluorouracil nanoparticles.

Traditional chemotherapeutic drugs remain the major treatment for advanced colorectal cancer. However, due to the lack of tumor specificity these drug also destroy healthy tissue and organs, which has been the main reason for treatment failure and mortality. Folate-based drug delivery systems for improving nanoparticle endocytosis have been used to address these problems. Here, folic acid (FA) conjugated mPEG-b-P(CABCL-co-ACL) diblock copolymers were synthesized and characterized by TEM and NMR. Drug loaded nanoparticles were prepared using dialysis method and was obtained with a mean diameter of 45.2nm with sustained invitro release profile. Invitro cytotoxicity assay indicated that the cytotoxicity of folate modified nanoparticles were significantly increased compared to free drug and non-folate nanoparticles. In addition, results of hemolytic and histopathologic study suggested that the non-loaded nanoparticle (NL/NP) was non-toxic and biocompatible at the testing concentration. Moreover, invivo results showed that FA/5-FU/NP effectively inhibited growth of HCT-8 cell-based xenograft tumors in BALB/c mice and revealed stronger antitumor efficacy than other treated groups. Thus, both invitro and invivo results exhibited that the folate conjugated mPEG-b-P(CABCL-co-ACL) copolymers have great potential to be used as sustainable and specific colon cancer targeting delivery system for anticancer agents.

Targeted Nanomedicine for Suppression of CD44 and Simultaneous Cell Death Induction in Ovarian Cancer: An Optimal Delivery of siRNA and Anticancer Drug

The proposed project is aimed at enhancing the efficiency of epithelial ovarian cancer treatment and reducing adverse side effects of chemotherapy using nanotechnology. Overexpression of the CD44 membrane receptor results in tumor initiation, growth, cancer stem cells' specific behavior, development of drug resistance, and metastases. We hypothesize that a developed cancer-targeted delivery system that combines CD44 siRNA with paclitaxel would successfully deliver its payload inside cancer cells, effectively induce cell death, and prevent metastases. We synthesized, characterized, and tested a nanoscale-based drug delivery system (DDS) containing a modified polypropylenimine (PPI) dendrimer as a carrier; anticancer drug paclitaxel as a cell death inducer; a synthetic analog of luteinizing hormone-releasing hormone (LHRH) peptide as a tumor-targeting moiety; and siRNA targeted to CD44 mRNA. The proposed DDS was tested in vitro and in vivo using metastatic ovarian cancer cells isolated from patients with malignant ascites. We found that in contrast with cells isolated from primary tumors, CD44 was highly overexpressed in metastatic cancer cells. Treatment with the proposed tumor-targeted nanoscale-based nucleic acid and DDS led to the suppression of CD44 mRNA and protein, efficient induction of cell death, effective tumor shrinkage, and prevention of adverse side effects on healthy organs. We show a high therapeutic potential for combinatorial treatment of ovarian carcinoma with a novel DDS that effectively transports siRNA targeting to CD44 mRNA simultaneously with cytotoxic agents. Clin Cancer Res; 19(22); 6193-204. ©2013 AACR.

Characterization and anti-tumor activity of chemical conjugation of doxorubicin in polymeric micelles (DOX-P) in vitro

Characterization and anti-tumor activity of chemical conjugation of doxorubicin (DOX) in polymeric micelles were investigated. Polymeric micelles with chemical conjugation of doxorubicin (DOX-P) were prepared. Succinic anhydride activated pluronic F68 was first synthesized and the primary amine group in doxorubicin was conjugated to the terminal carboxyl of pluronic F68 via a amide. The resulting polymeric micelles in aqueous solution were characterized by measurement of size, ξ-potential, drug loading and critical micelle concentration. From characterization results, DOX-P micelles had superiorities over physically-loaded DOX micelles in loading efficiency, diameter and CMC value. From drug release experiment in vitro, DOX-P micelles reached a sustained release profile for DOX. The cytotoxic activity of the micelles against A549/DOX cells was greater than free DOX. Fluorescence microscope observation and flow cytometry analysis supported the enhanced cellular uptake of the micelles. From A549/DOX cells experiments, DOX-P micelles could enhance DOX anti-tumor activity and circumvent the multi-drug resistance (MDR) of A549/DOX cells. With low CMC value, high loading efficiency, nanometer diameter, good penetration ability and controlled release behaviour, DOX-P micelles might be developed as a new cancer targeted delivery system.

Enhanced Cancer-Targeted Delivery Using Engineered High-Density Lipoprotein-Based Nanocarriers

One of the greatest obstacles nanoscale drug delivery systems face is the high nonspecific uptake by the reticular endothelial system (RES). Currently, PEGylation is the method of choice to address this problem. Herein we introduce an engineered high density lipoprotein-based nanocarrier (eHDL) as an enhanced cancer-targeted delivery system. eHDLs are high-density lipoprotein (HDL)-like nanoparticles consisting of a tumor ligand-conjugated apoA-I scaffold capable of carrying versatile payloads of cancer diagnostics and therapeutics. Similar to native HDL, eHDLs are biocompatible, precisely controlled ultra small particles (∼10 nm) with RES mitigating properties. In this study, we describe the preparation and characterization of eHDL and confirm that incorporation of exogenous agents do not compromise the structural or functional integrity of the particle. We further demonstrate both in vitro and in vivo that eHDL can be efficiently targeted to cancer cells. Proof of the efficacy of this procedure was demonstrated using a proto-type near-infrared (NIR) fluorescentlabeled folate receptor-targeted eHDL. This eHDL displayed exceptional in vivo performance in tumor-bearing mice. High levels of the particles were selectively localized within the targeted tumor while minimal uptake by RES was detected. This study demonstrates that eHDL particles are highly efficient carriers that provide a viable non-PEGylated approach for addressing the non-specific uptake of most nanoparticle-based delivery systems.