Abstract
Although selective tumor delivery of anticancer drugs has been sought by exploiting either passive targeting or by ligand-mediated targeting, a selective anticancer therapy remains an unmet medical need. Despite the advances which have been achieved by nanomedicines, nanosystems such as polymer-drug conjugates still miss the goal of clinical efficacy. In this study, we demonstrated that polymer-drug conjugates require a thoroughly chemical design and the right targeting agent/polymer ratio to be selective and effective towards cancer cells. In particular, two PEG conjugates carrying paclitaxel and targeted with different folic acid (FA)/PEG ratios (one or three) were investigated. The cytotoxicity study in positive (HT-29) and negative (HCT-15) FA receptor (FR)-cell lines demonstrated that the conjugates with one or three FAs were 4- or 28-fold more active in HT-29 cells, respectively. The higher activity of the 3-FA conjugate was confirmed by its strong impact on cell cycle arrest. Furthermore, FA targeting had a clear effect on migration and invasiveness of HT-29 cells, which were significantly reduced by both conjugates. Interestingly, the 3-FA conjugate showed also an improved pharmacokinetic profile in mice. The results of this study indicate that thorough investigations are needed to optimize and tune drug delivery and achieve the desired selectivity and activity towards cancer cells.
Highlights
Published: 23 June 2021A variety of cytotoxic drugs have long been used in cancer chemotherapy, in single or combined protocols, with the aim of hitting and killing tumor cells while sparing healthy cells
Heterobifuctional Poly(ethylene glycol) (PEG), eventually modified with a dendron structure, have the advantage to be suited for a defined structure design of the conjugates in which the targeting moiety is spatially separated from the drug moiety, generating a homogeneous structure that can overcome some limitations of random conjugates, as we have shown in other studies [6,7,8,9]
Two PEG conjugates carrying PTX and a different loading of folic acid (FA) were prepared starting from Boc-NH-PEG5k-NHS
Summary
Published: 23 June 2021A variety of cytotoxic drugs have long been used in cancer chemotherapy, in single or combined protocols, with the aim of hitting and killing tumor cells while sparing healthy cells. Tumor selectivity with most of these drugs has been sought through preferential cytotoxicity against cells with higher proliferation or metabolic rates. The selective delivery of cytotoxic drugs to tumor cells have been extensively studied in an attempt to accumulate the payload preferentially in tumor tissues by exploiting the conjugation of targeting agents directly to these drugs or to the delivery systems carrying the drugs. This approach of ligand-mediated targeting is intended for improving the internalization of targeted nanomedicines by cells overexpressing a specific receptor. It is important to increase the fraction of an administered nanomedicine that reaches the target site by exploiting the enhanced permeability and retention (EPR)
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