2021 Annual Meeting
Exploring Intermolecular Drug-Nanocarrier Interactions for High Drug Loading
Introduction: Nanomedicines offer distinct advantages over traditional small-molecular drugs such as improved
tropism and reduced side-effects. Despite this, nanomedicines have not lived up to expectations, with relatively few
clinical approvals. One contributing factor for this is carrier immunogenicity, which limits the total dose. It has
become recently appreciated that higher drug-loading (wt% drug in NP) leads to higher maximum tolerated doses,
and improved outcomes. Here, we have developed a polymeric nanocarrier library where the hydrophobic âcoreâ
contains varied proportions of H-bonding (monomer A) and Ï-interacting (monomer B) moieties so to optimize
drug-nanocarrier interactions.
Materials and Methods: Hydrophobic polymer âcoresâ were synthesized via anionic ring-opening
polymerization of monomer A and monomer B at 100, 90, 80, 60, 50 40 and 30 wt.% of B and end-capped with an
alkyne moiety. The core polymers were conjugated to hydrophilic stealth corona block, (poly(dimethylacrylamide)
(PDMA)-azide) via the copper-catalyzed Huisgen click-reaction and purified by dialysis. Difficult to load drugs, containing a mixture of H-bond acceptors/donors and Ï-interacting groups, were chosen. Polymer and drug were dissolved at a 1:1 ratio and solvent was removedby nitrogen-flow, followed by high vacuum. Films were rehyd rated at 10 mg/mL drug in DI water (stirred at 1200
rpm / 50°C) then centrifuged for 4 minutes at 7000 rpm; the supernatant was separated from pellet and
loaded drug was determined by HPLC analysis. The resulting concentration was used to calculate loading efficiency
(LE) and load capacity (LC); the latter was determined gravimetrically after supernatant lyophilization.
Results and Discussion: Drugs that have proportionally large potential for both H-bond and Ï-Ï interactions were
expected to load well into polymeric cores with complimentary interactions. Paclitaxel, which contains both H-bonding and Ï-interacting moieties displayed a loading maximum at 90%B (i.e., high Ï-interactions + low H-bond).
In contrast, etoposide displayed significantly higher (>2x) LE+LC in the absence of any H-bonding groups in the
core (100%B), whereas bortezomib and cyclosporin A (two drugs with a predominance of strong H-bond accepting
amide groups) had an increased loading with increasing H-bonding.
Conclusions: Highest drug loading occurs when the H-bond and Ï-Ï interactions between the core polymer and the
drug are maximized; for every drug this likely needs to be tailored. âUltraâ-high loading (>35% LC) of paclitaxel
and etoposide was achieved after core optimization, significantly higher than benchmark controls. Future works will evaluate additional
drugs as well as new core and corona chemistries to gain better understanding of the structure function relationships
of drug-loading.
tropism and reduced side-effects. Despite this, nanomedicines have not lived up to expectations, with relatively few
clinical approvals. One contributing factor for this is carrier immunogenicity, which limits the total dose. It has
become recently appreciated that higher drug-loading (wt% drug in NP) leads to higher maximum tolerated doses,
and improved outcomes. Here, we have developed a polymeric nanocarrier library where the hydrophobic âcoreâ
contains varied proportions of H-bonding (monomer A) and Ï-interacting (monomer B) moieties so to optimize
drug-nanocarrier interactions.
Materials and Methods: Hydrophobic polymer âcoresâ were synthesized via anionic ring-opening
polymerization of monomer A and monomer B at 100, 90, 80, 60, 50 40 and 30 wt.% of B and end-capped with an
alkyne moiety. The core polymers were conjugated to hydrophilic stealth corona block, (poly(dimethylacrylamide)
(PDMA)-azide) via the copper-catalyzed Huisgen click-reaction and purified by dialysis. Difficult to load drugs, containing a mixture of H-bond acceptors/donors and Ï-interacting groups, were chosen. Polymer and drug were dissolved at a 1:1 ratio and solvent was removedby nitrogen-flow, followed by high vacuum. Films were rehyd rated at 10 mg/mL drug in DI water (stirred at 1200
rpm / 50°C) then centrifuged for 4 minutes at 7000 rpm; the supernatant was separated from pellet and
loaded drug was determined by HPLC analysis. The resulting concentration was used to calculate loading efficiency
(LE) and load capacity (LC); the latter was determined gravimetrically after supernatant lyophilization.
Results and Discussion: Drugs that have proportionally large potential for both H-bond and Ï-Ï interactions were
expected to load well into polymeric cores with complimentary interactions. Paclitaxel, which contains both H-bonding and Ï-interacting moieties displayed a loading maximum at 90%B (i.e., high Ï-interactions + low H-bond).
In contrast, etoposide displayed significantly higher (>2x) LE+LC in the absence of any H-bonding groups in the
core (100%B), whereas bortezomib and cyclosporin A (two drugs with a predominance of strong H-bond accepting
amide groups) had an increased loading with increasing H-bonding.
Conclusions: Highest drug loading occurs when the H-bond and Ï-Ï interactions between the core polymer and the
drug are maximized; for every drug this likely needs to be tailored. âUltraâ-high loading (>35% LC) of paclitaxel
and etoposide was achieved after core optimization, significantly higher than benchmark controls. Future works will evaluate additional
drugs as well as new core and corona chemistries to gain better understanding of the structure function relationships
of drug-loading.