Drug delivery systems involving polymer therapeutics enhance drug potency by improved solubility and specificity and may assist in circumventing chemoresistance in pancreatic cancer (PC). We compared the effectiveness of the naturally occurring drug, betulinic acid (BA), alone and in a polymer conjugate construct of polyethylene glycol (PEG), (PEG–BA), on PC cells (MIA PaCa-2), a normal cell line (Vero) and on peripheral blood mononuclear cells (PBMCs). PEG–BA, was tested for its effect on cell death, immunomodulation and chemoresistance-linked signalling pathways. The conjugate was significantly more toxic to PC cells (p < 0.001, IC50 of 1.35 ± 0.11 µM) compared to BA (IC50 of 12.70 ± 0.34 µM), with a selectivity index (SI) of 7.28 compared to 1.4 in Vero cells. Cytotoxicity was confirmed by increased apoptotic cell death. PEG–BA inhibited the production of IL-6 by 4–5.5 fold compared to BA-treated cells. Furthermore, PEG–BA treatment of MIA PaCa-2 cells resulted in the dysregulation of crucial chemoresistance genes such as WNT3A, TXNRD1, SLC2A1 and GATA3. The dysregulation of chemoresistance-associated genes and the inhibition of cytokines such as IL-6 by the model polymer construct, PEG–BA, holds promise for further exploration in PC treatment.
: Synthetic chemotherapeutics have played a crucial role in minimizing mostly palliative symptoms associated with cancer; however, they have also created other problems such as system toxicity due to a lack of specificity. This has led to the development of polymer-drug conjugates amongst other novel drug delivery systems. Most of the formulations designed using delivery systems consist of synthetic drugs and face issues such as drug resistance, which has already rendered drugs such as antibiotics ineffective. This is further exacerbated by toxicity due to long term use. Given these problems and the fact that conjugation of synthetic compounds to polymers has been relatively slow with no formulation on the market after a decade of extensive studies, the focus has shifted to using this platform with medicinal plant extracts to improve solubility, specificity and increase drug release of medicinal and herbal bioactives. In recent years, various plant extracts such as flavonoids, tannins and terpenoids have been studied extensively using this approach. The success of formulations developed using novel drug-delivery systems is highly dependent on the tumour microenvironment especially on the enhanced permeability and retention effect. As a result, the compromised lymphatic network and ‘leaky’ vasculature exhibited by tumour cells act as a guiding principle in the delivering of these formulations. This review focuses on the state of the polymer-drug conjugates and their exploration with natural compounds, the progress and difficulties thus far, and future directions concerning cancer treatment.
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