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 convention 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.

Combined cancer therapy with hyaluronan-decorated fullerene-silica multifunctional nanoparticles to target cancer stem-like cells

“…The unique physicochemical properties of nanoparticles offer the opportunity to integrate different theranostic modalities within a single nanoplatform for combination therapy together with imaging. The enhanced antitumor capacity of combination therapy has been demonstrated with non-stem cancer cells [19,23–27]. However, no study was reported to investigate the combination of chemotherapy, PDT, and PTT for killing the CSCs.…”

Synthesis and Application of Injectable Bioorthogonal Dendrimer Hydrogels for Local Drug Delivery

“…Another strategy of depot-forming hydrogels is based on in-situ phase separation, which can be induced by changing the solubility of the polymer with respect to induction of pH, 48 temperature, 49–50 ultrasound, 51 or radiation. 52 Due to the acidic tumor microenvironment of head and neck cancers, it is desirable to incorporate pH-sensitive linkages, e.g., ester linkage, or thermo-sensitive linkages into DH formulations. It will not only release chemotherapeutic agents but disintegrate the drug-loaded dendrimer cargos in a synergistic manner.…”

Engineering the Architecture of Elastin‐Like Polypeptides: From Unimers to Hierarchical Self‐Assembly

“…The T t can be tuned to between room and physiological temperature by control of two sequence‐specific variables: 1) hydrophobicity of the guest (X residue). ELPs that contain guest amino acids with moderately hydrophobic side chains (e.g., valine, isoleucine, and alanine) phase separate below 37 °C across a range of ELP MWs . 2) MW: for a given ELP sequence the T t can be further tuned by its MW as the T t decreases with increasing MW.…”

“…ELPs that contain guest amino acids with moderately hydrophobic side chains (e.g., valine, isoleucine, and alanine) phase separate below 37°C across a range of ELP MWs. [204][205][206][207][208][209][210][211][212] 2) MW: for a given ELP sequence the T t can be further tuned by its MW as the T t decreases with increasing MW. Simultaneous optimization of both variables is usually sufficient to design an ELP that will phase separate at a defined concentration in a narrow temperature range of interest.…”