PLGA from PolySciTech used as part of development of pH responsive nanoparticles for cancer treatment

One of the fundamental problems with treatment of cancer is that the disease itself is still “part” of the human body. Cancer is simply a portion of the tissue and cells which are growing/proliferating at the wrong rate or in a manner which is damaging other tissues. For most diseases caused by an external pathogen, designing a medicinal treatment is simply a matter of finding an agent which affects the pathogen and not the patient. For example, the antibiotic penicillin prevents synthesis of cell-walls, which are key components of bacteria but not found in human cells. For this reason, penicillin can be easily administered to patients at high systemic doses with minimal concern for side effects. Unfortunately, for cancer, the situation is not so simple. Most agents which act to kill or prevent growth of cancer cells also have similar action on healthy cells, due to the fact both that the disease and the patient are of the same cell-type. For this reason, the few differences between cancer cells and normal cells that do exist are ideal targets to improve the action of therapeutics against cancer while maintaining minimal activity against normal cells. One difference between normal tissues and cancer is that, due to differences in tumor metabolism, the tumor tissues become acidic with pH ~6.5-7 (typical cellular pH is 7.4). This has led to rumors that acidity causes the tumor to grow and that cancer can be prevented, or even cured, simply by consuming pH basic (or so-called “alkaline”) foods. If this was true, then cancer could be cured by simply eating Rolaids or TUMS, which is not the case. It is the growing cancer which generates the acidic environment, not the other way around. This pH variability is one difference between normal tissue and cancerous tissues which can be used for optimizing targeted drug strategies. Recently, researchers working jointly at Purdue University, Fudan University (China), Shenyang Pharmaceutical University (China), and Eli Lilly, utilized PLGA from PolySciTech (www.polyscitech.com) (PolyVivo AP081) to create drug-loaded nanoparticles. These were surface modified to render them pH sensitive for preferential release at low pH. Although they worked well during in-vitro testing, there were problems with components of blood interacting with the coating and altering it preventing the pH effect from being fully utilized during in-vivo research. This is an important aspect of real science. Often, during development, there are setbacks to overcome which are discovered over the course of the research. This research holds promise for development of improved chemotherapeutics. Read more: Han, Ning, Jun Xu, Liang Pang, Hyesun Hyun, Jinho Park, and Yoon Yeo. “Development of surface-variable polymeric nanoparticles for drug delivery to tumors.” Molecular Pharmaceutics (2017). http://pubs.acs.org/doi/abs/10.1021/acs.molpharmaceut.7b00050

“Abstract: To develop nanoparticle drug carriers that interact with cells specifically in the mildly acidic tumor microenvironment, we produced polymeric nanoparticles modified with amidated TAT peptide via a simple surface modification method. Two types of core poly(lactic-co-glycolic acid) nanoparticles (NL and NP) were prepared with a phospholipid shell as an optional feature and covered with polydopamine that enabled the conjugation of TAT peptide on the surface. Subsequent treatment with acid anhydrides such as cis-aconitic anhydride (CA) and succinic anhydride (SA) converted amines of lysine residues in TAT peptide to β-carboxylic amides, introducing carboxylic groups that undergo pH-dependent protonation and deprotonation. The nanoparticles modified with amidated TAT peptide (NLpT-CA and NPpT-CA) avoided interactions with LS174T colon cancer cells and J774A.1 macrophages at pH 7.4 but restored the ability to interact with LS174T cells at pH 6.5, delivering paclitaxel efficiently to the cells following a brief contact time. In LS174T tumor-bearing nude mice, NPpT-CA showed less accumulation in the lung than NPpT, reflecting the shielding effect of amidation, but tumor accumulation of NPpT and NPpT-CA was equally minimal. Comparison of particle stability and protein corona formation in media containing sera from different species suggests that NPpT-CA has been activated and opsonized in mouse blood to a greater extent than those in bovine serum-containing medium, thus losing the benefits of pH-sensitivity expected from in vitro experiments. Keywords: acid anhydrides; drug delivery; pH sensitive; PLGA nanoparticles; TAT peptide”

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