Radiation-guided drug delivery to mouse models of lung cancer.
OBJECTIVE
The purpose of this study was to achieve improved cancer-specific delivery and bioavailability of radiation-sensitizing chemotherapy using radiation-guided drug delivery.


METHODS
Phage display technology was used to isolate a recombinant peptide (HVGGSSV) that binds to a radiation-inducible receptor in irradiated tumors. This peptide was used to target nab-paclitaxel to irradiated tumors, achieving tumor-specificity and enhanced bioavailability of paclitaxel.


RESULTS
Optical imaging studies showed that HVGGSSV-guided nab-paclitaxel selectively targeted irradiated tumors and showed 1.48 ± 1.66 photons/s/cm(2)/sr greater radiance compared with SGVSGHV-nab-paclitaxel, and 1.49 ± 1.36 photons/s/cm(2)/sr greater than nab-paclitaxel alone (P < 0.05). Biodistribution studies showed >5-fold increase in paclitaxel levels within irradiated tumors in HVGGSSV-nab-paclitaxel-treated groups as compared with either nab-paclitaxel or SGVSGHV-nab-paclitaxel at 72 hours. Both Lewis lung carcinoma and H460 lung carcinoma murine models showed significant tumor growth delay for HVGGSSV-nab-paclitaxel as compared with nab-paclitaxel, SGVSGHV-nab-paclitaxel,and saline controls. HVGGSSV-nab-paclitaxel treatment induced a significantly greater loss in vasculature in irradiated tumors compared with unirradiated tumors, nab-paclitaxel, SGVSGHV-nab-paclitaxel, and untreated controls.


CONCLUSIONS
HVGGSSV-nab-paclitaxel was found to bind specifically to the tax-interacting protein-1 (TIP-1) receptor expressed in irradiated tumors, enhance bioavailability of paclitaxel, and significantly increase tumor growth delay as compared with controls in mouse models of lung cancer. Here we show that targeting nab-paclitaxel to radiation-inducible TIP-1 results in increased tumor-specific drug delivery and enhanced biological efficacy in the treatment of cancer.
Hariri
Ghazal
G
Department of Radiation Oncology, Vanderbilt University, Nashville, Tennessee, USA.
Yan
Heping
H
Wang
Hailun
H
Han
Zhaozhong
Z
Hallahan
Dennis E
DE
D000418:Albumins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000595:Amino Acid Sequence; D000818:Animals; D001682:Biological Availability; D018287:Carcinoma, Large Cell / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D006168:Guinea Pigs; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008969:Molecular Sequence Data; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011817:Rabbits; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D010455:Peptides; D017239:Paclitaxel
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