Folic acid-conjugated amphiphilic alternating copolymer as a new active tumor targeting drug delivery platform

Abstract

Targeted drug delivery using polymeric nanostructures is an emerging cancer research area, engineered for safer, more efficient, and effective use of chemotherapeutic drugs. A pH-responsive, active targeting delivery system was designed using folic acid functionalized amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA). The polymeric template is pH responsive, forming amphiphilic nanostructures at pH 7, allowing the encapsulation of hydrophobic drugs on its interior. Moreover, the structure is stable only at neutral pH and collapses in the acidic tumor microenvironment, releasing drugs on-site from its core. The delivery vehicle is investigated using human pancreatic PANC-1 cancer cells and RAW-Blue™ mouse macrophage reporter cell line, both of which have overly expression of folic acid receptors. To trace the cellular uptake by both cell lines, curcumin was selected as a dye and drug mimic owing to its fluorescence nature and hydrophobic properties. Fluorescent microscopy of FA-DABA-SMA loaded with curcumin revealed a significant internalization of the dye by human pancreatic PANC-1 cancer cells compared to those with unfunctionalized polymers (SMA). Moreover, the FA-DABA-SMA polymers exhibit rodlike association specific to the cells. Both empty SMA and FA-DABA-SMA show little toxicity to PANC-1 cells as characterized by WST-1 cell proliferation assay. These results clearly indicate that FA-DABA-SMA polymers show potential as an active tumor targeting drug delivery system with the ability to internalize hydrophobic chemotherapeutics after they specifically attach to cancer cells.

Recent advances in "smart" delivery systems for extended drug release in cancer therapy

“…NP drug-delivery systems that can release the drug in response to specific physiological triggers, at the appropriate time, and at the correct target site are referred to as smart NPs. 11 For this review, smart NPs refer to those incorporating all three delivery strategies: passive, active, and stimuli-responsive targeting, 6 as summarized in Figure 1.…”

“…Recent trends in NP design suggest that there is a focus on multifunctional targeting or "smart" delivery, which incorporates multiple complementary targeting strategies, including passive, active, and stimuli-responsive targeting. 6,7 The addition of extended drug-release properties could further improve multifunctional targeting, whereby smart extendedrelease NPs (SER NPs) can provide additional physiological and clinical benefits, particularly in the treatment of cancer, where drug delivery poses significant challenges. 8 SER NPs can be modified with active and stimuli-responsive targeting to take into account the pathophysiological characteristics of the tumor, and can be matched to the patient's lifestyle by modifying the desired length and duration of extended release.…”

Advancements in Polymer Science: ‘Smart’ Drug Delivery Systems for the Treatment of Cancer

“…In contrast, FA-DABA-SMA was internalized through folic acidmediated receptor endocytosis and curcumin was found to have been internalized and localized to the nucleus through fluorescence analysis (Figure 3). 29 In addition, the study showed no adverse effects of the functionalized polymer on cell viability. However, the cell viability study of the curcumin loaded FA-DABA-SMA revealed a significant decrease in the number of cancerous cells.…”

“…28 This property allows for this delivery system to take advantage of the characteristics of the human body such that the intact cylinder can travel through the body, and release the drugs following internalization by malignant cells where the pH changes. 29 Following folate binding to its receptor, the nanoparticle is internalized in an endocytic pathway into the cytosol, where the pH drops further to pH 5. 30 Due to the amphiphilic nature of this conjugated nanoparticle, this pH drop will result in a conformational change that will release the therapeutic load directly into the malignant cell ( Figure 2).…”

“…Therefore, one possible avenue to further explore would be to encapsulate hydrophobic chemotherapeutic drugs and determine whether there is an increase in cell death when compared with conventional methods of treatment. Taken in part from: © Li et al 29 Publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted non-commercial use, provided the original work is properly cited.…”