Boosting the therapeutic efficacy of discoidal nanoconstructs against glioblastoma with rationally designed PEG-Docetaxel conjugates.

Maximizing loading while modulating the release of therapeutic molecules from nanoparticles and implantable drug delivery systems is the key to successfully address deadly diseases like brain cancer. Here, four different conjugates of the potent chemotherapeutic molecule docetaxel (DTXL)were realized to optimize the pharmacological properties of 1,000 × 400 nmDiscoidal PolymericNanoconstructs(DPNs). DTXL was covalently linked to poly-(ethylene) glycol(PEG)chains of different molecular weights, namely 350, 550 and 1,000 Da, and oleic acid (OA). After extensive physico-chemical and pharmacological characterizations, the conjugate PEG-DTXL showedan optimal compromise between loading and sustained release out of DPNs, as opposed to the insufficient loading of PEG-DTXL and PEG-DTXL and the excessively slow release of OA-DTXL. Not surprisingly, viability tests conducted on U87-MG cells showed a delay in cytotoxic activity for the DTXL conjugates compared to free DTXL within the first 48 h. However, PEG-DTXL returned an IC value of ∼ 10 nMat 72 h, which is comparable to free DTXL.In mice bearing orthotopically implanted U87-MG cells, the intravenous administration of PEG-DTXL loaded DPNs doubled the overall animal survival (52.5 days) as compared to temozolomide (27 days) and the untreated controls (32 days). Collectively, these results continue to demonstrate that the therapeutic efficacy of nanoparticles can be boosted by rationally designing drug conjugates-particle complexes for optimal loading and release profiles.