Light-controlled release of caged doxorubicin from folate receptor-targeting PAMAM dendrimer nanoconjugate

Abstract

We report the synthesis and in vitro evaluation of folate receptor-targeted nanoconjugate that releases its therapeutic payload via a photochemical mechanism.The targeted delivery of therapeutic and imaging agents using nanoconjugates is a burgeoning field. [1][2][3][4] Strategies to develop cancer-cell specific nanoconjugates vary, but all attempts to selectively deliver therapeutics to cells use nanoscale carriers such as dendritic macromolecules, 2 liposomes, 5 polymers, 6 metal nanoparticles 3 or viruses 7 that include targeting and therapeutic agents. The desired result is less side toxicity in normal cells and more effective tumoricidal activity. Nanoconjugates also can be designed such that the therapeutic agents are released, and therefore active, only under particular conditions. The release mechanisms currently being explored are based primarily on reactions catalyzed by endogenous physiological factors such as reduction, 1 low pH, 3 and hydrolytic enzymes. 4 This communication describes a photochemical-based approach to release targeted drugs after delivery. In this scenario, the targeted drug conjugate is first placed on a surface, such as skin, or lung/gastrointestinal tract epithelium. After the exposure, the nanoconjugate drug is specifically taken up by the tumor cells and is washed away from the normal tissue; light is then applied from a laser device attached to an endoscope to specifically target the cancer cells. The strategy presented may be broadly applied to other cell targeting systems, particularly those that require time-and tissue-dependent control of drug activation.Photocaging refers to the temporary inactivation of a biologically active molecule using a protective photocleavable group. Upon UV irradiation of the photocleavable group, the active form of the caged molecule is irreversibly released. 8 Photocaging has been frequently applied in vitro towards the spatiotemporal control of biological processes 9-11 and the light-triggered payload release from nanoscale materials. 12,13 However, it has only been rarely applied in in vivo experiments 14,15 because of the low level tissue penetration and phototoxicity associated with short wavelength UV light.Recent advances in two-photon excitation 14,15 and optical fiber technology, however, have made it possible to cleave photocaged compounds by irradiation in the near-IR (720-800 nm 14 ). Because of this potential for higher level tissue penetration, we have applied the † Electronic supplementary information (ESI) available: Experimental details for synthesis and characterization of 1-9; details for photocleavage experiments of 3 and 7. See DOI: 10.1039/b927215cFax: (734) 615-0621; Tel: (734) 615-0618. NIH Public Access Author ManuscriptChem Commun (Camb). Author manuscript; available in PMC 2010 July 12. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript photocaging approach towards the targeted delivery of doxorubicin, 16 an anticancer drug that inhibits DNA replication through intercalation (Fig. 1).In ...

Light-Sensitive Polymeric Nanoparticles Based on Photo-Cleavable Chromophores

“…308 The covalent attachment of a drug to a hydrophilic polymeric carrier system via a cleavable molecule and the triggered degradation of the linker is another promising method. [301][302] Investigations on light-sensitive materials based on both of the described concepts are part of this thesis and were described in previous chapters (see chapter 5.3 and 5.4). …”

“…[298][299][300][301] An interesting example to realize this concept was recently described by Choi et al The investigated approach is based on a doxorubicin-PAMAM dendrimer conjugate where the hydrophilic drug is connected to the preformed dendrimer via a photo-cleavable linker. 302 As this was shown to be highly efficient for the release of doxorubicin upon irradiation, it is of great interest to extend this conception to a broad variety of polymeric carrier systems such as e.g. microgels.…”

“…Therefore, in a first synthetic approach the route described by Choi et al 302 was modified accordingly. Figure 80 depicts the examined pathway.…”

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 ...…”

4-Hydroxytamoxifen probes for light-dependent spatiotemporal control of Cre-ER mediated reporter gene expression

“…6,7 Reporter expression can be localized to a specific region upon direct exposure to a specific wavelength of light, which releases and activates the photocaged molecule. Photocaging has been used in a variety of applications from studies of transcription, 8 protein-protein interactions, 9,10 cell migration and proliferation, 11 protein phosphorylation, 12 and targeted drug delivery, [13][14][15][16] as well as gene expression using…”