Site-specific drug delivery by photochemical internalization enhances the antitumor effect of bleomycin.
OBJECTIVE
Photochemical internalization is under development for improving macromolecular therapy by inducing photochemical damage to endocytic vesicles. This damage leads to the release of therapeutic macromolecules entrapped in endocytic vesicles into the cytosol. The macromolecules may in this way be able to interact with therapeutic targets instead of being degraded by lysosomal hydrolases. Bleomycin is used in several standard cancer chemotherapy regimens. Its hydrophilic and relatively large chemical structure limits its ability to penetrate membrane structures, which causes the accumulation of bleomycin in endocytic vesicles. The purpose of this study was to evaluate the therapeutic potential of aluminum phthalocyanine disulfonate (AlPcS2a)-based photochemical delivery of bleomycin.


METHODS
Three tumors of different origin were grown s.c. in BALB/c (nu/nu) mice. The photosensitizer AlPcS2a and bleomycin were systemically administered and the tumor area was exposed to red light when the tumor volume had reached 100 mm3. The tumor volume was measured frequently after treatment and the time for the tumor volume to reach 800 to 1,000 mm3 was selected as the end point.


RESULTS
The photochemical delivery of bleomycin induced a delayed tumor regrowth, and in two out of three tumor models, lead to 60% complete response, whereas no complete responses were seen after treatment with bleomycin alone. A statistical model to assess synergism was established. Combination of the photochemical treatment and bleomycin was found to induce a synergistic delay in tumor growth.


CONCLUSIONS
AlPcS2a-based photochemical internalization of bleomycin induces a synergistic inhibition of tumor growth in three different tumor models. This treatment combination should be further considered for clinical utilization.
Berg
Kristian
K
Department of Radiation Biology and Oncologic Surgery, the Norwegian Radium Hospital, Montebello, Oslo, Norway. kristian.berg@labmed.uio.no
Dietze
Andreas
A
Kaalhus
Olav
O
Høgset
Anders
A
D000535:Aluminum; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D001761:Bleomycin / Q000627:therapeutic use*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy*; D006224:Cricetinae; D016503:Drug Delivery Systems; D011992:Endosomes; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000627:therapeutic use*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000188:drug therapy*; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D007211:Indoles; D009942:Organometallic Compounds; D017319:Photosensitizing Agents; D001761:Bleomycin; C064331:aluminum phthalocyanine disulfonate; D000535:Aluminum