Drug Release from Nanoparticles: Modulating Hydrophobic Prodrug Degradation Rates with Lipid Excipients

Drug Release from Nanoparticles: Modulating Hydrophobic Prodrug Degradation Rates with Lipid Excipients

Brian K. Wilson¹ and Robert K. Prud’homme¹

¹Princeton University, Princeton NJ, USA

Abstract

Nanoparticles have received substantial attention as delivery vehicles for therapeutics, yet many drugs have undesirable solubility profiles resulting in low drug loading, poor encapsulation efficiency and burst release profiles when used in nanoparticle formulations [1]. Flash NanoPrecipitation (FNP) provides a platform for preparing block copolymer stabilized nanoparticles of hydrophobic materials. Converting small molecule therapeutics into hydrophobic prodrugs allows the use of FNP to prepare nanoparticles with high drug loading and nearly complete encapsulation by altering the solubility profile of the therapeutic [1]. Camptothecin (CPT) is a natural alkaloid anticancer agent that exhibits an undesirable solubility profile for parenteral delivery as a solution or nanoparticle formulation. Covalent modification of camptothecin with an ester linkage allows the design of degradable prodrugs that improves encapsulation (> 99%) of the active CPT moiety while also providing controlled release, on the order of several days to weeks, from a nanoparticle formulation containing zwitterionic amphiphile excipients.

Free camptothecin (CPT) cannot be readily encapsulated due to a lactone ring that equilibrates to open carboxylate form at neutral pH, increasing the aqueous solubility of CPT and causing burst release from nanoparticle formulations containing free CPT. Conjugation of a hydrophobic molecule to CPT through the C20 hydroxyl via an ester moiety renders the CPT prodrug more hydrophobic. The hydrophobic “anchor” in the CPT prodrug determines the increase in overall hydrophobicity and therefore encapsulation efficiency of the CPT prodrug during FNP. Prodrugs must be significantly hydrophobic (LogP > 9) in order to achieve complete encapsulation efficiency (> 99% by HPLC) without the use of additional hydrophobic excipients such as tocopherols.

Free CPT is expected to be released from the prodrug form and nanoparticle core by hydrolysis of the lipid anchor ester linker. Preparation of nanoparticles with a core composed only of hydrophobic CPT prodrug show negligible degradation of the CPT prodrug and therefore nearly unmeasurable free CPT release. Inclusion of a zwitterionic, amphiphilic excipient increases the rate of CPT prodrug degradation and free CPT release. These amphiphiles adsorb at the hydrophobic prodrug core surface, alongside the stabilizing poly(lactic acid)-block-poly(ethylene glycol) block copolymer, disrupting the purely hydrophobic surface thereby providing an ingress route for water that may then hydrolyze the prodrug and release the active drug.

Nanoparticle formulations making use of prodrug compounds to increase loading and encapsulation efficiency are sensitive not only to the chemistry used to prepare the prodrug compound but also the effect excipients have on the overall hydrophobicity or amphiphilicity of the nanoparticle formulation. This excipient or particle matrix effect on release rate enables tunable release from a single prodrug chemistry, decoupling formulation-variable controlled release from repeated covalent modifications of a therapeutic compound to adjust its release rate.

References

1.         S.M. Ansell, et. al., Journal of Medicinal Chemistry 2008, 51(11), 3288-3296