Gadolinium texaphyrin–methotrexate conjugates. Towards improved cancer chemotherapeutic agents

Abstract

Conjugates between methotrexate (MTX, Matrex, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-l-glutamic acid), an antifolate cancer chemotherapeutic to which resistance is often observed, and motexafin gadolinium (MGd), an experimental agent demonstrating selective tumor localization, are described. These systems were prepared in order to test whether linking these two species would produce agents with enhanced activity relative to MTX alone. Both ester- and amide-linked conjugates were synthesized starting from MGd and MTX. The ester conjugate showed greater in vitro anti-proliferative activity against the A549 lung carcinoma cell line at short incubation times than did MTX alone. Neither the amide conjugate, nor MGd, showed any observable activity under these in vitro conditions. These results are rationalized in terms of enhanced cellular uptake of both the ester and amide conjugates that is coupled with an effective rate of release (e.g., inherent or enzyme-mediated hydrolysis) in the case of the ester-linked conjugate, but not the corresponding amide system.

Hypoxia-targeted drug delivery

“…394 A particular gadolinium(III) complex, i.e., Gd 3+texaphyrin (motexafin gadolinium, MGd), proved water soluble and capable of targeting preferentially cancerous lesions. 395,396 To improve the cancer targeting of Pt(IV) complexes, Sessler et al developed the MGd-Pt(IV) conjugates by tethering gadolinium-texaphyrin complex with inert Pt(IV) centers prodrug through an axial succinate linker (128, Fig. 26).…”

Photoinduced Reduction of PtIVwithin an Anti-Proliferative PtIV-Texaphyrin Conjugate

“…The synthesis of conjugates 4 and 5 is shown in Scheme . Briefly, the mono‐ and bis‐amine derivatives of MGd 1 10 were subjected to carbodiimide coupling conditions in the presence of the Pt IV ‐containing precursor 3 ; after purification, this gave conjugates 4 and 5 in yields of 40 and 20 %, respectively.…”

Porphyrinoid Drug Conjugates

“…These results support the desire for a tumor-specific controlled release (Figure 6A). 52 This was evidenced by cell proliferation studies in which A549 human lung cancer cells were non-responsive to exposure by 5 but responsive to treatments with labile 6 (Figure 6B). Based on this early work, it was also inferred that effective intracellular release of an appended therapeutic would prove essential were the putative conjugate to achieve the design objective of targeted drug delivery.…”

“…MRI Capabilities of Gadolidium-Bound Texaphyrins (A) MGd. (B) T1-weighted brain MRI scans of a patient with non-small-cell lung cancer: Left, noncontrast scan at baseline; right, noncontrast scan after 10 daily administration of MGd at of 5 mg/kg/day.Copyright 2016 Wiley 52.…”