Using Peptide Aptamer Targeted Polymers as a Model Nanomedicine for Investigating Drug Distribution in Cancer Nanotheranostics.
Yongmei ZhaoZachary H HoustonJoshua D SimpsonLiyu ChenNicholas L FletcherAdrian V FuchsIdriss BlakeyKristofer J ThurechtPublished in: Molecular pharmaceutics (2017)
Theranostics is a strategy that combines multiple functions such as targeting, stimulus-responsive drug release, and diagnostic imaging into a single platform, often with the aim of developing personalized medicine.1,2 Based on this concept, several well-established hyperbranched polymeric theranostic nanoparticles were synthesized and characterized as model nanomedicines to investigate how their properties affect the distribution of loaded drugs at both the cell and whole animal levels. An 8-mer peptide aptamer was covalently bound to the periphery of the nanoparticles to achieve both targeting and potential chemosensitization functionality against heat shock protein 70 (Hsp70). Doxorubicin was also bound to the polymeric carrier as a model chemotherapeutic drug through a degradable hydrazone bond, enabling pH-controlled release under the mildly acid conditions that are found in the intracellular compartments of tumor cells. In order to track the nanoparticles, cyanine-5 (Cy5) was incorporated into the polymer as an optical imaging agent. In vitro cellular uptake was assessed for the hyperbranched polymer containing both doxorubicin (DOX) and Hsp70 targeted peptide aptamer in live MDA-MB-468 cells, and was found to be greater than that of either the untargeted, DOX-loaded polymer or polymer alone due to the specific affinity of the peptide aptamer for the breast cancer cells. This was also validated in vivo with the targeted polymers showing much higher accumulation within the tumor 48 h postinjection than the untargeted analogue. More detailed assessment of the nanomedicine distribution was achieved by directly following the polymeric carrier and the doxorubicin at both the in vitro cellular level via compartmental analysis of confocal images of live cells and in whole tumors ex vivo using confocal imaging to visualize the distribution of the drug in tumor tissue as a function of distance from blood vessels. Our results indicate that this polymeric carrier shows promise as a cancer theranostic, demonstrating active targeting to tumor cells with the capability for simultaneous drug release.
Keyphrases
- cancer therapy
- drug delivery
- drug release
- heat shock protein
- high resolution
- gold nanoparticles
- induced apoptosis
- breast cancer cells
- cell cycle arrest
- sensitive detection
- papillary thyroid
- heat shock
- magnetic nanoparticles
- fluorescence imaging
- mass spectrometry
- optical coherence tomography
- cell death
- photodynamic therapy
- squamous cell
- label free
- emergency department
- deep learning
- high throughput
- single cell
- adverse drug
- bone marrow
- cell therapy
- oxidative stress
- raman spectroscopy
- cell proliferation
- squamous cell carcinoma
- high resolution mass spectrometry
- childhood cancer
- big data
- endoplasmic reticulum stress
- liquid chromatography
- human health
- artificial intelligence
- climate change
- convolutional neural network