Various
therapeutics exhibit unfavorable physicochemical properties or stability issues that reduce their in vivo efficacy. Therefore, carriers able to overcome such challenges and deliver
therapeutics to specific in vivo target sites are critically needed. For instance, anticancer drugs are hydrophobic and require carriers to solubilize them in aqueous environments, and gene-based
therapies (e.g.,
siRNA or pDNA) require carriers to protect the anionic genes from enzymatic degradation during systemic circulation. Polymeric
micelles, which are self-assemblies of amphiphilic
polymers (APs), constitute one delivery vehicle class that has been investigated for many biomedical applications. Having a hydrophobic core and a hydrophilic shell, polymeric
micelles have been used as
drug carriers. While traditional APs are typically comprised of nondegradable block copolymers,
sugar-based amphiphilic
polymers (SBAPs) synthesized by us are comprised of branched,
sugar-based hydrophobic segments and a hydrophilic poly(
ethylene glycol) chain. Similar to many amphiphilic
polymers, SBAPs self-assemble into polymeric
micelles. These nanoscale
micelles have extremely low critical
micelle concentrations offering stability against dilution, which occurs with systemic administration. In this Account, we illustrate applications of SBAPs for anticancer drug delivery via physical encapsulation within SBAP
micelles and chemical conjugation to form SBAP
prodrugs capable of micellization. Additionally, we show that SBAPs are excellent at stabilizing liposomal delivery systems. These SBAP-
lipid complexes were developed to deliver hydrophobic anticancer
therapeutics, achieving preferential uptake in
cancer cells over normal cells. Furthermore, these complexes can be designed to electrostatically complex with gene
therapies capable of transfection. Aside from serving as a nanocarrier, SBAPs have also demonstrated unique bioactivity in managing
atherosclerosis, a major cause of
cardiovascular disease. The atherosclerotic cascade is usually triggered by the unregulated uptake of
oxidized low-density lipoprotein, a
cholesterol carrier, in macrophages of the blood vessel wall; SBAPs can significantly inhibit
oxidized low-density lipoprotein uptake in macrophages and abrogate the atherosclerotic cascade. By modification of various functionalities (e.g., branching, stereochemistry, hydrophobicity, and charge) in the SBAP chemical structure, SBAP bioactivity was optimized, and influential structural components were identified. Despite the potential of SBAPs as atherosclerotic
therapies, blood stability of the SBAP
micelles was not ideal for in vivo applications, and means to stabilize them were pursued. Using kinetic entrapment via flash nanoprecipitation, SBAPs were formulated into nanoparticles with a hydrophobic solute core and SBAP shell. SBAP nanoparticles exhibited excellent physiological stability and enhanced bioactivity compared with SBAP
micelles. Further, this method enables encapsulation of additional hydrophobic drugs (e.g.,
vitamin E) to yield a stable formulation that releases two bioactives. Both as nanoscale carriers and
as polymer therapeutics, SBAPs are promising
biomaterials for medical applications.