Albumin–Polymer–Drug Conjugates: Long Circulating, High Payload Drug Delivery Vehicles

Abstract

Albumin is an exquisite tool of nature used in biomedicine to achieve long blood residence time for drugs, but the payload it can carry is typically limited to one molecule per protein. In contrast, synthetic macromolecular prodrugs contain multiple copies of drugs per polymer chain but offer only a marginal increase in the circulation lifetime of the drugs. We combine the benefits of the two platforms and at the same time overcome their respective limitations. Specifically, we develop the synthesis of albumin–polymer–drug conjugates to obtain long circulating, high payload drug delivery vehicles. In vivo data validate that albumin endows the conjugate with a blood residence time similar to that of the protein and well exceeding that of the polymer. Therapeutic activity of the conjugates is validated using prodrugs of panobinostat, an HIV latency reversal agent, in which case the conjugates matched the drug in terms of efficacy of treatment.

Strategies for Preparing Albumin-based Nanoparticles for Multifunctional Bioimaging and Drug Delivery

“…The DOX was released from the nanoparticle with a two-step drug release mechanism based on pH and protease responses. The drug could also be loaded in the albumin-polymer-based nanoparticle through a cleavable disulphide bond 254 .…”

The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

“…LRAs, like ARVs, are a group of mostly small molecule compounds (<1000 Da), and but diverse physicochemical properties and biological targets, and could thus similarly benefit from novel formulations strategies. Our group and others have attempted to synthetize LRAs in nanoparticles [86,87]. Following polymer linking of panobinostat (an LRA), we observed HIV-latency reversal in two latently infected cell lines, ACH2 (T cells) and U1 (monocytes).…”

“…Combined with novel linker chemistry, for example self-immolative linkers (SIL), both polymer size and complexity as well as triggered release of drug can be controlled, yielding a very attractive drug-delivery strategy [81]. Some of the most commonly used polymer systems are poly(hydroxypropyl methacrylamide) (PHPMA) [82][83][84][85][86][87], poly(lactic-co-glycolic acid) (PLGA) [88], poly(methacrylates) (PMA) [89,90] and poly(ethylene glycol) (PEG) [91]. The benefit of combining direct conjugation to a polymer via linker chemistry is the possibility to co-deliver different pharmaceutical drugs on the same polymer scaffold.…”

“…Our group sought to develop and utilize these features of polymers. We have focused on combining antiviral small molecule drugs with synthetic polymers in combination with lipids such as DSPE or endogenous proteins like albumin to develop long-acting drug-delivery platforms [81][82][83][84][85][86][87]92]. Because albumin has an incredible long circulation time in vivo in humans (i.e., 19-21 days [93]), it can be used to traffic compounds through circulation.…”

Recent trends in protein and peptide-based biomaterials for advanced drug delivery

“…Drug-containing monomer (drug: panobinostat, dark blue) was copolymerized with HPMA using RAFT agents, which allow one-step conjugation of albumin. Adapted with permission from [ 59 ] (A) and [ 172 ] (B). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)…”