Preclinical development of carrier-free prodrug nanoparticles for enhanced antitumor therapeutic potential with less toxicity

Abstract

Background Nanomedicine has emerged as a promising strategy for cancer treatment. The most representative nanomedicine used in clinic is PEGylated liposomal doxorubicin DOXIL®, which is first FDA-approved nanomedicine. However, several shortcomings, such as low drug loading capacity, low tumor targeting, difficulty in mass production and potential toxicity of carrier materials, have hindered the successful clinical translation of nanomedicines. In this study, we report a preclinical development process of the carrier-free prodrug nanoparticles designed as an alternative formulation to overcome limitations of conventional nanomedicines in the terms of technical- and industrial-aspects. Results The carrier-free prodrug nanoparticles (F68-FDOX) are prepared by self-assembly of cathepsin B-specific cleavable peptide (FRRG) and doxorubicin (DOX) conjugates without any additional carrier materials, and further stabilized with Pluronic F68, resulting in high drug loading (> 50%). The precise and concise structure allow mass production with easily controllable quality control (QC), and its lyophilized powder form has a great long-term storage stability at different temperatures (− 4, 37 and 60 °C). With high cathepsin B-specificity, F68-FDOX induce a potent cytotoxicity preferentially in cancer cells, whereas their cytotoxicity is greatly minimized in normal cells with innately low cathepsin B expression. In tumor models, F68-FDOX efficiently accumulates within tumor tissues owing to enhanced permeability and retention (EPR) effect and subsequently release toxic DOX molecules by cathepsin B-specific cleavage mechanism, showing a broad therapeutic spectrum with significant antitumor activity in three types of colon, breast and pancreatic cancers. Finally, the safety of F68-FDOX treatment is investigated after single-/multi-dosage into mice, showing greatly minimized DOX-related toxicity, compared to free DOX in normal mice. Conclusions Collectively, these results provide potential preclinical development process of an alternative approach, new formulation of carrier-free prodrug nanoparticles, for clinical translation of nanomedicines.

Pluronic F-68 and F-127 Based Nanomedicines for Advancing Combination Cancer Therapy

“…Similarly, the plasma half-life (t 1/2 ) values of free DOX, FRRG-DOX, and Pluronic F-68-FDOX were 1.33 ± 0.23 h, 7.96 ± 4.59 h, and 25.83 ± 0.80 h, respectively. The longest plasma t 1/2 of Pluronic F-68-FDOX was due to the surface modification of Pluronic F-68 [ 97 ].…”

Impact of doxorubicin-loaded ferritin nanocages (FerOX) vs. free doxorubicin on T lymphocytes: a translational clinical study on breast cancer patients undergoing neoadjuvant chemotherapy

“…This intricate scenario prompts further investigation into the impact of an anthracyclines regimen on dividing T cells to improve DOX immune-mediated antitumor activity [ 12 ]. Simultaneously, there is growing interest in developing refined DOX formulations to mitigate detrimental effects such as severe cardiotoxicity resulting from unfavorable pharmacokinetics and inadequate targeting of tumors [ 13 ].…”

Breaking Barriers: Nanomedicine-Based Drug Delivery for Cataract Treatment

“…67 To improve the bioavailability and therapeutic effectiveness of topically administered drugs for treating cataracts, researchers are developing more bioavailable prodrugs and applying nanotechnology to protect the active molecules and maintain drug delivery. 68 These strategies aim to decrease the frequency of drug administration, minimize systemic toxicity, and enhance drug penetration into ocular tissues while improving the retention time of the anterior corneal surface. Drug delivery systems, such as prodrugs, microemulsions, nanocrystals, nanosuspensions, nanomicelles, nanoparticles, and nanozymes, have gained substantial attention owing to their better eminent functionality (Figure 4).…”