Authors: Alessia Felici
Source: CINECA IRIS Institutial Research Information System (University of Genoa) (article, 2021-05-12)
Field: Materials Science — Biomaterials

Development of discoidal polymeric nanoconstructs for the treatment of cancer disease High loading and specific release of therapeutic agents within the tumor microenvironment are key factors in the development of novel nano-based therapeutic systems against cancer. Although drug availability and preferential tumor accumulation improved with advanced drug delivery system for cancer therapy, they still faces challenge in drug encapsulation and retention. Here, Discoidal Polymeric Nanoconstructs (DPNs) were employed to load and systemically deliver both hydrophilic and hydrophobic therapeutic molecules. DPNs appear as disks, with a diameter of about 1 �m and a height of 400 nm, designed for vascular adhesion in a tortuous and low perfused vasculature as in the case of tumor. Moreover, soft DPNs presenting a stiffness of about few kPa, were shown to circulate longer, more effectively avoid the sequestration by hepatic and splenic immune cells and accumulate at higher doses in the tumor vasculature as compared to rigid DPNs. DPNs were synthetized by mixing together hydrophobic ? poly(lactic-co-glycolic acid) (PLGA) and hydrophilic ? polyethylene glycol diacrylate (PEG-diacrylate) using a top-down, template-based fabrication process. Improved performance in terms of encapsulation efficiency and drug retention have been achieved following two approaches; first, improving the fabrication process with a multi-passage strategy over the hydrophilic PVA template used for DPN production; Second, modulating the chemical proprieties of the selected drug Docetaxel by lipid or polymeric chains conjugation. In particular, two different prodrugs were realized, namely oleic-Docetaxel (O-DTXL) and PEG-Docetaxel (PEG-DTXL) incorporated in DPN via direct and absorption loading. On one side, the conjugation of Dtxl with PEG chains ensures an improved loading efficiency and retention capability of the drug within the soft polymeric net respect to the Docetaxel alone. In cell-line orthotopic brain cancer model, with only 1 mg/kg of drug administered intravenously every other days for 20 days post resection of the primary mass, DTXL-PEG550-DPNs increase the median overall survival (?30 days) as compared also to 10 chemotherapeutic cycles with temozolomide administered at a dose three times higher (3mg/Kg) (27 days).On the other side, multi-passage DTXL-DPNs efficiently accumulated in In orthotopic murine models of Triple negative breast cancer masses with a tumor-to-abdomen ratio of 1.3. With only 2 mg/kg of DTXL, intravenously administered every other day for 13 times, DTXL-DPNs induced tumor regression returning an 80% survival rate at 120 days as compared to 30% with free DTXL. Collectively, these results demonstrate that vascular targeting nanoconstructs with tunable pharmacological properties can be exploited to effectively treat multiples type of tumors. Cancer treatment ; Cancer ; Disease ; Nanotechnology ; Medicine ; Intensive care medicine ; Computer science ; Materials science ; Pathology Nanoparticle-Based Drug Delivery