Image-guided and passively tumour-targeted polymeric nanomedicines for radiochemotherapy.
Drug targeting systems are nanometer-sized carrier materials designed for improving the biodistribution of systemically applied (chemo-) therapeutics. Reasoning that (I) the temporal and spatial interaction between systemically applied chemotherapy and clinically relevant fractionated radiotherapy is suboptimal, and that (II) drug targeting systems are able to improve the temporal and spatial parameters of this interaction, we have here set out to evaluate the potential of 'carrier-based radiochemotherapy'. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were used as a model drug targeting system, doxorubicin and gemcitabine as model drugs, and the syngeneic and radio- and chemoresistant Dunning AT1 rat prostate carcinoma as a model tumour model. Using magnetic resonance imaging and gamma-scintigraphy, the polymeric drug carriers were first shown to circulate for prolonged periods of time, to localise to tumours both effectively and selectively, and to improve the tumour-directed delivery of low molecular weight agents. Subsequently, they were then shown to interact synergistically with radiotherapy, with radiotherapy increasing the tumour accumulation of the copolymers, and with the copolymers increasing the therapeutic index of radiochemotherapy (both for doxorubicin and for gemcitabine). Based on these findings, and on the fact that its principles are likely broadly applicable, we propose carrier-based radiochemotherapy as a novel concept for treating advanced solid malignancies.
Lammers
T
T
Department of Innovative Cancer Diagnosis and Therapy, Clinical Cooperation Unit Radiotherapeutic Oncology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. t.lammers@dkfz.de
Subr
V
V
Peschke
P
P
Kühnlein
R
R
Hennink
W E
WE
Ulbrich
K
K
Kiessling
F
F
Heilmann
M
M
Debus
J
J
Huber
P E
PE
Storm
G
G
D000178:Acrylamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D003952:Diagnostic Imaging; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005682:Gadolinium; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D020714:Maximum Tolerated Dose; D050997:Nanomedicine; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000532:radiotherapy*; D011836:Radiation Tolerance; D051381:Rats; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D014018:Tissue Distribution; D000093542:Gemcitabine
D000178:Acrylamides; D000964:Antimetabolites, Antineoplastic; D007457:Iodine Radioisotopes; D003841:Deoxycytidine; C482378:N-(2-hydroxypropyl)methacrylamide co-polymer-doxorubicin conjugate; D004317:Doxorubicin; D005682:Gadolinium; D012264:Ribonucleotide Reductases; D000093542:Gemcitabine