(56c) Drug Release from Nanoparticles: Modulating Hydrophobic Prodrug Degradation Rates with Lipid Excipients

Wilson, B. K., Princeton University
Prud'homme, R. K., Princeton University

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


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.

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

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.


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