Vitamin B₁₂: A Tunable, Long Wavelength, Light-Responsive Platform for Launching Therapeutic Agents

Abstract

CONSPECTUS Light-responsive agents offer the promise of targeted therapy, whose benefits include (i) prolonged action at the target site, (ii) overall reduced systemic dosage, (iii) reduced adverse effects, and (iv) localized delivery of multiple agents. Although photoactivated prodrugs have been reported, these species generally require short wavelengths (<450 nm) for activation. However, maximal tissue penetrance by light occurs within the “optical window of tissue” (600–900 nm), well beyond the wavelength range of most existing photocleavable functional groups. Furthermore, since multidrug therapy holds promise for the treatment of complex diseases, from cancer to neurological disorders, controlling the action of multiple drugs via wavelength modulation would take advantage of a property that is unique to light. However, discrimination between existing photoresponsive moieties has thus far proven to be limited. We have developed a vitamin B12/light-facilitated strategy for controlling drug action using red, far-red, and NIR light. The technology is based on a light-triggered reaction displayed by a subset of B12 derivatives: alkyl-cob(III)alamins suffer photohomolysis of the C–Co(III) bond. The C–Co(III) bond is weak (<30 kcal/mol), and therefore all wavelengths absorbed by the corrin ring (330–580 nm) induce photocleavage. In addition, by appending fluorophores to the corrin ring, long wavelength light (>600 nm) is readily captured and used to separate the Co-appended ligand (e.g., a drug) from B12. Consequently, it is now feasible to preassign the wavelength of homolysis by simply installing a fluorescent antenna with the desired photophysical properties. The wavelength malleability inherent within this strategy has been used to construct photoresponsive compounds that launch different drugs by simply modulating the wavelength of illumination. In addition, these phototherapeutics have been installed on the surface and interior of cells, such as erythrocytes or neural stem cells, and released upon expoure to the appropriate wavelength. We have shown that cytotoxic agents, such as doxorubicin, anti-inflammatories, such as dexamethasone, and anti- and pro-vascular agents are readily released from cellular vehicles as biologically active agents. We have also demonstrated that the concept of “optical window of tissue” phototherapeutics is not just limited to prodrugs. For example, stem cells have received considerable attention in the area of regenerative medicine. Hydrogels serve as scaffolds for stem cell growth and differentiation. We have shown that the formation of hydrogels can be triggered, in the presence of cells, using appropriately designed alkyl-cob(III)alamins and long wavelength light. The potential applications of phototherapeutics are broad and include drug delivery for a variety of indications, tissue engineering, and surgery.

Optochemical Control of Biological Processes in Cells and Animals

“…[218] The weak cobalt–carbon bond is photocleaved at 330–580 nm, releasing the R group (e.g., a drug or a fluorophore). [219] Additional chromophores were conjugated to vitamin B 12 , such as Cy5, Cy7, or Alexa700, to act as antennas to allow further red-shifted photocleavage with 640–780 nm light.…”

Recent Advances of Light-Mediated Theranostics

“…Until now, a variety of visible light responsive organic moieties, such as vitamin B 12 derivatives 62-64, trithiocarbonates 65, 66 etc., have been utilized for visible light-mediated drug delivery. For instance, Lawrence's group have reported a series of vitamin B 12 derivatives for tuneable visible light-controlled drug activation and bioimaging in living cells (Figure 4A) 63. Since the cobalt(III)-alkyl (Co(III)-C) bond in vitamin B 12 was quite weak (cleavage energy < 30 kcal mol -1 ), light in the range from 330 nm to 560 nm could be absorbed by the corrin ring to induce photocleavage of axial ligand (e.g., anticancer drugs, cyclic adenosine monophosphates (cAMP), fluorophores, etc).…”

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

“…Antibodies (their size is about 12 nm) endowed with fluorescent dyes (e.g., Alexa Fluor 488 λEm=525 nm and Texas Red λEm=609 nm) [15][16][17] were used in the development of a wide range of effective targeted therapies [18][19][20][21][22] but they create clustering artifacts due to limited antibody penetration, which have an impact on insufficient labeling density. Thus, ligands that have been exploited for chemotherapeutic agent targeting systems can include monoclonal antibodies [23][24][25][26][27][28] but also low molecular weight receptor-binding conjugates such as dyelabeled peptides (arginine-glycine-aspartic acid-Cyt5,5) [29], peptide hormones [30,31], receptor antagonist and agonists [32], aptamers [33][34][35], transferrin [36][37], oligosaccharides [38], glycoconiugates [39], polyunsaturated fatty acids [40], oligopeptides [41,42], vitamin B12 [43], folic acid [44][45][46][47][48][49][50][51][52][53][54] and hyaluronic acid [55,56]. These ligands can be regarded as a tumor-specific receptor to construct a "guided molecular ...…”

“…Irradiation of photosensitizers can generate highly reactive singlet oxygen species or superoxide radical anion (1O 2 and/or O 2 -) that causes destruction in malignant tissue [76][77][78]. Light-responsive compounds offer the promise of targeted therapy, which has several benefits including: prolonged action at the target site, overall reduced systemic dosage, reduced adverse effects, and localized delivery of multiple agents [43]. An efficient PDT photosensitizer requires the following features: a high quantum yield for singlet oxygen generation (фʌ), efficient uptake into the diseased tissue (be preferentially retained by the target tissue), and localization in regions of the cell which are vulnerable to singlet oxygen damage [79][80][81].…”