title: Spatiotemporally photoradiation-controlled intratumoral depot for combination of brachytherapy and photodynamic therapy for solid tumor.
abstract: In an attempt to spatiotemporally control both tumor retention and the coverage of anticancer agents, we developed a photoradiation-controlled intratumoral depot (PRCITD) driven by convection enhanced delivery (CED). This intratumoral depot consists of recombinant elastin-like polypeptide (ELP) containing periodic cysteine residues and is conjugated with a photosensitizer, chlorin-e6 (Ce6) at the N-terminus of the ELP. We hypothesized that this cysteine-containing ELP (cELP) can be readily crosslinked through disulfide bonds upon exposure to oxidative agents, specifically the singlet oxygen produced during photodynamic stimulation. Upon intratumoral injection, CED drives the distribution of the soluble polypeptide freely throughout the tumor interstitium. Formation and retention of the depot was monitored using fluorescence molecular tomography imaging. When imaging shows that the polypeptide has distributed throughout the entire tumor, 660-nm light is applied externally at the tumor site. This photo-radiation wavelength excites Ce6 and generates reactive oxygen species (ROS) in the presence of oxygen. The ROS induce in situ disulfide crosslinking of the cysteine thiols, stabilizing the ELP biopolymer into a stable therapeutic depot. Our results demonstrate that this ELP design effectively forms a hydrogel both in vitro and in vivo. These depots exhibit high stability in subcutaneous tumor xenografts in nude mice and significantly improved intratumoral retention compared to controls without crosslinking, as seen by fluorescent imaging and iodine-125 radiotracer studies. The photodynamic therapy provided by the PRCITD was found to cause significant tumor inhibition in a Ce6 dose dependent manner. Additionally, the combination of PDT and intratumoral radionuclide therapy co-delivered by PRCITD provided a greater antitumor effect than either monotherapy alone. These results suggest that the PRCITD could provide a stable platform for delivering synergistic, anti-cancer drug depots.
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
authors.forename: Ratul
authors.initials: R
authors.lastname: Mukerji
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schaal
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
authors.forename: Xinghai
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Bhattacharyya
authors.affiliation: Department of Microbiology, St. Marianna University School of Medicine, Kawasaki, Kanagawa Prefecture, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Asai
authors.affiliation: Department of Radiology, Duke University, Durham, NC, 27708, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Chilkoti
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA. Electronic address: wengeliu@duke.edu.
authors.forename: Wenge
authors.initials: W
authors.lastname: Liu
mesh_terms: D000818:Animals; D001918:Brachytherapy / Q000379:methods*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods*; D002735:Chlorophyllides; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000528:radiation effects*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053769:Nanocapsules / Q000737:chemistry / Q000528:radiation effects*; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D010778:Photochemotherapy / Q000379:methods*; D011166:Porphyrins / Q000008:administration & dosage; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000627:therapeutic use; D062211:Spatio-Temporal Analysis; D016896:Treatment Outcome
chemical_list: D002735:Chlorophyllides; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; C062985:phytochlorin
keywords: Convection enhanced delivery; Crosslinking; Elastin-like polypeptide; Intratumoral drug delivery; Photodynamic therapy; Tumor retention