A critical evaluation of drug delivery from ligand modified nanoparticles: Confounding small molecule distribution and efficacy in the central nervous system

Abstract

In this work, we sought to test how surface modification of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with peptide ligand alters the brain specific delivery of encapsulated molecules. For biodistribution studies, nanoparticles modified with rabies virus glycoprotein (RVG29) were loaded with small molecule drug surrogates and administered to healthy mice by lateral tail vein injection. Mice were perfused two hours after injection and major anatomical regions of the CNS were dissected (striatum, midbrain, cerebellum, hippocampus, cortex, olfactory bulb, brainstem, and cervical, thoracic, lumbar and sacral spinal cord). For functional studies, surface modified nanoparticles were loaded with the chemotherapeutic camptothecin (CPT) and administered to mice bearing intracranial GL261-Luc2 gliomas. Outcome measures included tumor growth, as measured by bioluminescent imaging, and median survival time. We observed that small molecule delivery from PLGA nanoparticles varied by as much as 150% for different tissue regions within the CNS. These differences were directly correlated to regional differences in cerebral blood volume. Although the presence of RVG29 enhanced apparent brain delivery for multiple small molecule payloads, we observed minimal evidence for targeting to muscle or spinal cord, which are the known sites for rabies virus entry into the CNS, and enhancements in brain delivery were not prolonged due to an apparent aqueous instability of the RVG29 ligand. Furthermore, we have identified concerning differences in apparent delivery kinetics as measured by different payloads: nanoparticle encapsulated DiR was observed to accumulate in the brain, whereas encapsulated Nile red was rapidly cleared. Although systemically administered CPT loaded nanoparticles slowed the growth of orthotopic brain tumors to prolong survival, the presence of RVG29 did not enhance therapeutic efficacy compared to control nanoparticles. These data are consistent with a model of delivery of hydrophobic small molecules to the brain that does not rely on internalization of polymer nanoparticles in target tissue. We discuss an important risk for discordance between biodistribution, as typically measured by drug surrogate, and therapeutic outcome, as determined by clinically relevant measurement of drug function in a disease model. These results pose critical considerations for the methods used to design and evaluate targeted drug delivery systems in vivo.

PLGA protein nanocarriers with tailor-made fluorescence/MRI/PET imaging modalities

“…Furthermore, conventional approaches to physically blend imaging probes within the carrier can lead to incomplete conclusions or misinterpretations on the carrier's biodistribution. 18,19 For example, loading two different molecules as probes into the same carrier led to opposite conclusions regarding the kinetics of brain-specific delivery. 19 A growing body of evidence suggests that new methods will be required to monitor nanocarriers' biodistribution avoiding interference of the imaging moieties with the encapsulated drug or leaching of the imaging probes.…”

“…18,19 For example, loading two different molecules as probes into the same carrier led to opposite conclusions regarding the kinetics of brain-specific delivery. 19 A growing body of evidence suggests that new methods will be required to monitor nanocarriers' biodistribution avoiding interference of the imaging moieties with the encapsulated drug or leaching of the imaging probes. 19,20 Here, we report on PLGA nanocapsules (NCs) as a multimodal theranostic platform for in vivo drug delivery.…”

“…19 A growing body of evidence suggests that new methods will be required to monitor nanocarriers' biodistribution avoiding interference of the imaging moieties with the encapsulated drug or leaching of the imaging probes. 19,20 Here, we report on PLGA nanocapsules (NCs) as a multimodal theranostic platform for in vivo drug delivery. We describe the chemical synthetic routes to covalently label the PLGA with biocompatible small molecule fluorophores or radioligands.…”

CNS Anticancer Drug Discovery and Development: 2016 conference insights

“…This research requires an future science group www.futuremedicine.com advanced understanding of nanoparticle delivery mechanisms and assessing how drug encapsulation affects movement across the BBB [3]. Highlighted in this discussion were options to alter the size and loading of nanoparticles, such as varying the compositions of poly(lactic-coglycolic) acid-based nanoparticles as a means to control drug concentrations in the CNS.…”

“…In 1999, temozolomide (TMZ) was the last drug approved by the US FDA as an anticancer agent for high-grade gliomas, although bevacizumab received FDA regulatory approval for the treatment of recurrent/progressive glioblastoma (GBM) in 2009. Following the 2014 CADDDC, a comprehensive white paper was published to provide guidance to the field and, hopefully, to stimulate greater interaction Levin, Abrey, Heffron et al future science group between academia and the pharmaceutical/ biotechnology industries [1][2][3].…”