Abstract
Nanomedicine as a multimodality treatment of cancer utilizes the advantages of nanodelivery systems of drugs. They are superior to the clinical administration of different therapeutic agents in several aspects, including simultaneous delivery of drugs to the active site, precise ratio control of the loading drugs and overcoming multidrug resistance. The role of nanopolymer size and structural shape on the internalization process and subsequent intracellular toxicity is limited. Here, the size and shape dependent mechanism of a functionalized copolymer was investigated using folic acid (FA) covalently bonded to the copolymer poly (styrene-alt-maleic anhydride) (SMA) on its hydrophilic exterior via a biological linker 2,4-diaminobutyric acid (DABA) to target folic acid receptors (FR) overly expressed on cancer cells actively. We recently reported that unloaded FA-DABA-SMA copolymers significantly reduced cancer cell viability, suggesting a secondary therapeutic mechanism of action of the copolymer carrier post-internalization. Here, we investigated the size and shape dependent secondary mechanism of unloaded 350 kDa and 20 kDa FA-DABA-SMA. The 350 kDa and 20 kDa copolymers actively target folic acid receptors (FR) to initialize internationalization, but only the large size and sheet shaped copolymer disables cell division by intracellular disruptions of essential oncogenic proteins including p53, STAT-3 and c-Myc. Furthermore, the 350 kDa FA-DABA-SMA activates early and late apoptotic events in both PANC-1 and MDA-MB-231 cancer cells. These findings indicate that the large size and structural sheet shape of the 350 kDa FA-DABA-SMA copolymer facilitate multimodal tumor targeting mechanisms together with the ability to internalize hydrophobic chemotherapeutics to disable critical oncogenic proteins controlling cell division and to induce apoptosis. The significance of these novel findings reveals copolymer secondary cellular targets and therapeutic actions that extend beyond the direct delivery of chemotherapeutics. This report offers novel therapeutic insight into the intracellular activity of copolymers critically dependent on the size and structural shape of the nanopolymers.
Highlights
Targeting strategies of nanopolymers are formulated to enhance the specific distribution of the therapeutic macromolecules in the treatment of cancer
We reported on a biocompatible pH responsive, active targeting delivery system, fabricated using folic acid functionalized on an amphiphilic alternating copolymer poly via a biodegradable linker 2,4-diaminobutyric acid (FA-DABA-SMA) [1,2]
The DU-145 cells expressed minimal levels of folic acid receptors (FR). These different cell lines allowed for a better understanding of the behaviour of the nanopolymer interacting with the target FR receptor in a range from low to high FR expression levels to better evaluate the efficacy and targeting potential of FA-DABA-SMA
Summary
Targeting strategies of nanopolymers are formulated to enhance the specific distribution of the therapeutic macromolecules in the treatment of cancer. Active targeting mechanisms utilize tumor-specific receptor ligands to achieve a degree of specificity and are utilized as a promising complementary strategy to improve drug delivery. The self-assembly of the FA-DABA-SMA copolymeric template was designed to be pH responsive, forming amphiphilic nanostructures at pH 7, allowing for the encapsulation of hydrophobic drugs in its interior core This structure is stable at neutral pH, but collapses under acidic conditions consistent with the tumor microenvironment, thereby releasing the carrier drugs on-site from its core [4]. The size, shape and surface modifications, all of which alter the pharmacokinetics and intracellular mechanisms, can be chemically modified such that they can have a significant therapeutic impact in vivo [5]
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