Enzyme-Sensitive and Amphiphilic PEGylated Dendrimer-Paclitaxel Prodrug-Based Nanoparticles for Enhanced Stability and Anticancer Efficacy

Abstract

In this study, we prepared a smart polymeric vehicle for the hydrophobic drug paclitaxel (PTX) that allowed a maximum steady-state circulation and a fast intracellular release in tumors. PTX was linked to the Janus PEGylated (PEG = poly(ethylene glycol)) peptide dendrimer via an enzyme-sensitive linker glycylphenylalanylleucylglycine tetrapeptide by efficient click reaction, resulting in Janus dendritic prodrug with 20.9% PTX content. The prodrug self-assembled into nanoscale particles with appropriate nanosizes, compact morphology, and negative surface charge. In addition to high stability during circulation, as demonstrated by protein adsorption assays and drug release studies in the cancer's intracellular environment, the nanoparticles were able to quickly release the drug intact in its original molecular structure, as verified via high-performance liquid chromatography and mass spectrometry analyses. Compared to free PTX, the enzyme-responsive feature of nanoparticles promoted higher cytotoxicity against 4T1 cancer cells and much lower cytotoxicity against normal cells. The nanoparticles accumulated in the tumor and were retained for an extended period of time, as confirmed by fluorescence imaging. Therefore, these nanoparticles exhibited significantly enhanced antitumor efficiency in the 4T1 breast cancer model as indicated by the observed inhibition of angiogenesis and proliferation as well as induction of apoptosis. Moreover, the nanoparticles reduced the occurrence of side effects, particularly dose-limited toxicities, as monitored by body weight and hematological features. Hence, our Janus PEGylated dendrimer-PTX prodrug-based nanoparticles may potentially serve as nanoscale vehicles for breast cancer therapy.

Preparation and characterization of silicone rubber through the reaction between γ‐chloropropyl and amino groups with siloxane polyamidoamine dendrimers as cross‐linkers

“…Owing to their superior characteristics, such as high symmetry, nanoscopic scale, well‐controlled molecular shape, unique monodispersity, and multi‐functionality, they have been widely developed in recent years . Especially, a large number of chemically reactive sites at the termini or in the cavities offers many opportunities for potential applications in many fields, such as biomedicine, surface chemistry, luminescence, and catalysis . Dendrimers have also been explored as cross‐linkers into polymer to achieve novel technological applications .…”

Enzyme/pH-sensitive dendritic polymer-DOX conjugate for cancer treatment

“…. . results confirmed that the dendritic conjugate carried the drugs into cancer cells through endocytosis, was trafficked through the endolysosomal pathways [44], and finally released the drug in the acidic organelles for its therapeutic function.…”

Two-step polymer- and liposome-enzyme prodrug therapies for cancer: PDEPT and PELT concepts and future perspectives

“…Recently, Lin et al presented hyaluronic acid (HA) legumain-sensitive nanogel, based on the same AAN peptide, for the delivery of Doxorubicin with a high targeting efficiency, both in vitro and in vivo [132]. Gly-Phe-Leu-Gly PEGylated dendrimers Doxorubicin [95] Val-Cit PEG-based micelles Doxorubicin [99] Val-Cit PEG Camptothecin [100] Val-Cit PEG Paclitaxel [105] Gly-Phe-Leu-Gly PEG Gemcitabine [101] Gly-Phe-Leu-Gly HPMA copolymer Gemcitabine [103] Gly-Phe-Leu-Gly HPMA copolymer Gemcitabine Paclitaxel [102] PAMAM dendrimers encapsulated in liposomes Paclitaxel [104] Gly-Phe-Leu-Gly PEG-Janus dendrimers Paclitaxel [106] Gly-Phe-Leu-Gly Dendrimers (NTN1956) Doxorubicin [94] Peptidic bond in the polymeric backbone PGA Paclitaxel (PolyGlumex ®)…”