The malignant brain cancer, glioblastoma multiforme (GBM), is heterogeneous, infiltrative, and associated with chemo-and radioresistance. Despite pharmacological advances, prognosis is poor. Delivery into the brain is hampered by the blood-brain barrier (BBB), which limits the efficacy of both conventional and novel therapies at the target site. Current treatments for GBM remain palliative rather than curative; therefore, innovative delivery strategies are required and nanoparticles (NPs) are at the forefront of future solutions. Since the FDA approval of Doxil® (1995) and Abraxane (2005), the first generation of nanomedicines, development of nano-based therapies as anti-cancer treatments has escalated. A new generation of NPs has been investigated to efficiently deliver therapeutic agents to the brain, overcoming the restrictive properties of the BBB. This review discusses obstacles encountered with systemic administration along with integration of NPs incorporated with conventional and emerging treatments. Barriers to brain drug delivery, NP transport mechanisms across the BBB, effect of opsonisation on NPs administered systemically, and peptides as NP systems are addressed. Keywords BBB. Cell penetrating peptides. Drug delivery. GBM. Nanoparticle. RALA Abbreviations Au PENP P o l y e t h y l e n e i m i n e-e n t r a p p e d g o l d nanoparticles Au Gold BBB Blood-brain barrier Bcl-2 B cell lymphoma-2 BCRP Breast cancer resistance protein BMEC Brain microvascular endothelial cell c(RGD) Cyclic (arginine-glycine-aspartic acid) peptide C h o l-P C L-LNP PEGylated cleavage lipopeptide CNS Central nervous system CPP Cell penetrating peptide D M-P C L-LNP Dimyristoyl anchored PEGylated MMPcleavable lipopeptide DSPE 1 , 2-D i s t e a r o y l-s n-g l y c e r o-3phosphoethanolamine DTC Dithiolane-functionalized trimethylene carbonate EB

, H. O. (2019). DNA vaccination via RALA nanoparticles in a microneedle delivery system induces a potent immune response against the endogenous prostate cancer stem cell antigen. Acta Biomaterialia.

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Bisphosphonates (BPs) are a class of bone resorptive drug with a high affinity for the hydroxyapatite structure of bone matrices that are used for the treatment of osteoporosis. However, clinical application is limited by a common toxicity, BP-related osteonecrosis of the jaw. There is emerging evidence that BPs possess anticancer potential, but exploitation of these antiproliferative properties is limited by their toxicities. We previously reported the utility of a cationic amphipathic fusogenic peptide, RALA, to traffic anionic nucleic acids into various cell types in the form of cationic nanoparticles. We hypothesized that complexation with RALA could similarly be used to conceal a BP's hydroxyapatite affinity, and to enhance bioavailability, thereby improving anticancer efficacy. Incubation of RALA with alendronate, etidronate, risedronate, or zoledronate provoked spontaneous electrostatic formation of cationic nanoparticles that did not exceed 100 nm in diameter and that were stable over a range of temperatures and for up to 6 h. The nanoparticles demonstrated a pH responsiveness, possibly indicative of a conformational change, that could facilitate release of the BP cargo in the endosomal environment. RALA/BP nanoparticles were more potent anticancer agents than their free BP counterparts in assays investigating the viability of PC3 prostate cancer and MDA-MB-231 breast cancer cells. Moreover, RALA complexation potentiated the tumor growth delay activity of alendronate in a PC3 xenograft model of prostate cancer. Taken together, these findings further validate the use of BPs as repurposed anticancer agents.

Thermoresponsive hydrogels demonstrate tremendous potential as sustained drug delivery systems. However, progress has been limited as formulation of a stable biodegradable thermosensitive hydrogel remains a significant challenge. In this study, free radical polymerization was exploited to formulate a biodegradable thermosensitive hydrogel characterized by sustained drug release. Highly deacetylated chitosan and N-isopropylacrylamide with distinctive physical properties were employed to achieve a stable, hydrogel network at body temperature. The percentage of chitosan was altered within the copolymer formulations and the subsequent physical properties were characterized using 1H-NMR, FTIR, and TGA. Viscoelastic, swelling, and degradation properties were also interrogated. The thermoresponsive hydrogels were loaded with RALA/pEGFP-N1 nanoparticles and release was examined. There was sustained release of nanoparticles over three weeks and, more importantly, the nucleic acid cargo remained functional and this was confirmed by successful transfection of the NCTC-929 fibroblast cell line. This tailored thermoresponsive hydrogel offers an option for sustained delivery of macromolecules over a prolonged considerable period.