Navy

Optimized cellular drug delivery with functionalized nanoparticles

Unique approach uses single dendritic wedge cell-penetrating peptides to facilitate drug delivery

Medical & Biotechnology

The Naval Research Laboratory has invented a novel pharmaceutical drug delivery technology representing a step towards theranostic disease treatments. The patented technology is available to businesses that would make, use, or sell it commercially.

A majority of current drug therapies are delivered systemically and treat the whole body even when a disease is confined to a specific organ or tissue type. This increases the required dosage while causing unwanted side effects such as offsite or systemic toxicity. Further, maintaining a therapeutic dose can be difficult when drugs are quickly metabolized or poorly soluble. Achieving a therapeutic dose with conventional medication over an appropriate time frame requires taking multiple doses, resulting in increased cost and often decreasing compliance from patients

Cellular uptake via endocytosis was confirmed and peptide delivery kinetics investigated as a function of QD–(Arg9)1–16 conjugate exposure time and QD assembly ratio where cellular viability assays reflected no overt cytotoxicity. The ability of single dendrimer conjugates to facilitate cellular uptake was confirmed for QD–(Arg9)2–16 repeats along with the ability to deliver >850 kDa of protein cargo per QD. Minimizing the number of CPPs required for cellular uptake is critical for expanding nanoparticle cargo carrying capacity and can allow for the inclusion of additional sensors, therapeutics and contrast agents on their surface. (Navy image)

Nanoparticle (NP)-mediated drug delivery has the potential to address many of these shortcomings. To date, cellular uptake of NPs has been facilitated by cell-penetrating peptides (CPPs). In addition to NPs, these polycationic peptides have enabled intracellular delivery of cargo such as drugs, small chemical molecules, and even large DNA fragments that would otherwise not enter the cell.

However, an important factor that is often not appreciated about CPP mediated cellular delivery of almost every type of NP material is that it requires a significant amount of CPP to be decorated around the NP surface for uptake to occur efficiently. Typical ratios utilized can range from 10 to 20 CPPs per NP or even higher. The net result is that a large portion of a given NP’s surface area and especially their cargo-carrying capacity may be given over to CPP attachment. This delivery system could be optimized with a strategy to utilize fewer CPPs.

Navy researchers have recently made a big step towards this optimization with a design that frees up space on the NP while retaining the delivery benefits of the CPPs. The new approach of delivering a nanoparticle to a cell includes contacting the cell with a nanoparticle bound to a single dendritic peptide. The dendritic peptide has a polyhistidine motif with a hinge and a spacer connecting the polyhistidine to a lysine-based dendritic wedge displaying at least two copies of a given peptide sequence (cell-penetrating peptide Arg9.) While minimizing the number of CPPs required for cellular uptake is critical for expanding nanoparticle cargo carrying capacity it can also allow for the inclusion of additional sensors, therapeutics and contrast agents on their surface.

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