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30 ottobre 2019: TUMOR TARGETING and Production of polymeric NANOMEDICINES,

Dietro segnalazione del Prof. G.Tosi, nell'ambito el Corso CFT del Dipartimento di Scienze della Vita, si svolgerà un seminario

Mercoledì 30 OTTOBRE 2019, h. 16.00-18.00

Aula U0.1 [MO 51] - Via Campi 103, Modena

tenuto dal Dott. LEON WANG

TUMOR TARGETING and production of polymeric
NANOMEDICINES: evidence and examples

Chemical and Biological Engineering, Princeton University

 

1. Post-formulation 64-Cu labeled nanotracers to investigate size and surface property effects on
biodistribution and tumor localization in a mouse pancreatic cancer model.

Leon Z. Wangφ, , Chester E. Markwalterφ, , Prashanth K. Padakantiγ, Sean D. Carlinγ, Ola M. Sharafγ, Shadman-As-Sami Jahangirφ, Eric Blankemeyerγ, Abass Alaviγ, Robert H. Machγ, Robert K. Prud'hommeφ*

φ Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, United States.

γ Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States.

Positron emission tomography (PET) is an extremely sensitive diagnostic tool for use in the early detection
of cancers and other diseases. FDG-PET utilizing the PET active glucose analog, 18-fluorodeoxyglucose (18-
FDG), has shown promise in clinical cancer imaging but still has several shortcomings. For example, since
FDG utilizes glucose metabolism to detect tumors, it is less effective for slow-growing tumors and for
differentiating cancers from the surrounding inflammatory tissue. Here we present the formation of

nanoparticles using the continuous and scalable flash nanoprecipitation (FNP) process. Phthalocyanine-
based dyes are encapsulated inside NPs through a rapid mixing and precipitation process that is stabilized

by an amphiphilic block copolymer. After incubation of these NPs with copper ions in solution, the
encapsulated dyes exhibit absorbance shifts indicative of the chelation of copper ions into the macrocyclic
ring of the phthalocyanine. This absorbance shift was employed to quantify chelation and optimize reaction
conditions. Thus, using this same method but instead incubating the NPs with positron-emitting 64-Cu
yields PET active nanotracers. Under very mild conditions in a pH 5.5 aqueous buffer, the radiolabeling yield
was quantitative after 3hr of incubation at 37C. This technology, when combined with the flexibility of FNP,
allows for long timepoint biodistribution tracking of NPs with a variety of different properties such as size
and surface charge. In particular, when PS-b-PEG is used as the stabilizing polymer, NPs exhibit long
circulation times and enhanced tumor uptake due to the enhanced permeability and retention (EPR) effect.
This was demonstrated using our PET nanotracers in a xenograft pancreatic tumor model, which showed
high levels of PET activity in circulation at 3hrs and 6hrs post-injection and increasing tumor accumulation
over 24hrs (Fig. 1). The development, optimization, and validation of a scalable method to produce
nanotracers promises to expand the applications of NP-based PET imaging.

2. Sequential flash nanoprecipitation (sFNP) as a platform for the production of stable and high

core-loading nanoparticle systems.

Leon Z. Wang, Kurt D. Ristroph, Chester E. Markwalter, Parker K. Lewis, Robert K. Prud'homme*
Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, United States.

Nanoparticles have shown promise for use in both parenteral and oral delivery of therapeutics and
diagnostic contrast agents. Often, when designing these nanoscale constructs, the two most important
criteria are particle size and core loading. In oncology, for example, small particles below 100nm can have
improved specificity to tumors through the enhanced permeability and retention (EPR) effect. Likewise,
higher loading nanoparticles translate very well to more effective drug delivery – potentially enabling
improved efficacy and lower doses. Furthermore, from a medical imaging standpoint, higher concentration
of contrast agents in a small but densely loaded NP could allow for increased imaging sensitivity and earlier
detection of diseases. However, formulations of nanoparticles using stabilized emulsions or drug
absorption methods generally struggle to obtain core loadings of more than 10%. In previous work, Flash
NanoPrecipitation (FNP) has been demonstrated to produce size-tunable nanoparticles that can
encapsulate a variety of hydrophobic and hydrophilic compounds. Through rapid mixing of an organic
stream containing both hydrophobic core agent and amphiphilic stabilizer with an aqueous stream,
nanoparticles of sizes ranging from 80 nm to 150nm with up to 50% core loading can be generated.
However, with further increased core concentration in the organic stream, anchoring efficiency is
decreased as more stabilizer is kinetically trapped in the core by the aggregation process. This results in
larger and eventually, unstable particles. Here, we present the process of combining two rapid mixing
processes in series using connected confined impingement jet (CIJ) or multi-inlet vortex mixers (MIVM). By
separating the precipitation and stabilizing steps of traditional FNP, this time delay allows for particles to
precipitate before introduction of the amphiphilic stabilizer - improving surface anchoring efficiency of the
stabilizer. Using this sequential flash nanoprecipitation (sFNP) technology, stable particles could be
produced even at very high drug concentrations (100 mgml-1) in the organic stream. Optimizing this process, we were able to generate 80nm nanoparticles with up to 92% core loading for a variety of core material - including an imaging agent and a model hydrophobic drug. Additionally, the efficient anchoring of the block copolymer stabilizer allows these ultra-high loading NPs to remain stable for over six months in solution without significant aggregation or swelling. Thus, this scalable platform technology has shown potential to revolutionize nanotherapies in a wide variety of healthcare applications.

[Ultimo aggiornamento: 01/11/2019 09:58:44]