Bioactivation of Self-Immolative Dendritic Prodrugs by Catalytic Antibody 38C2

Shamis, Marina; Lode, Holger N.; Shabat, Doron

doi:10.1021/ja039052p

“…2). It has been suggested that when drug molecules are attached as end groups at the periphery, the dendrimer can be used as an efficient drug delivery platform [25]. For latest developments in this direction the reader is referred to Refs.…”

Section: Figurementioning

confidence: 99%

“…(22) and (24) it follows that the transition rates are given by (25) and is arbitrary. Note that has two components; the component of geometric origin, whereas e emerges from energetic consideration.…”

Section: Figrue 10mentioning

confidence: 99%

Some new aspects of dendrimer applications

Flomenbom

¹

,

Amir

²

,

Shabat

³

et al. 2005

Journal of Luminescence

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Dendrimers are characterized by special features that make them promising candidates for many applications. Here we focus on two such applications: dendrimers as light harvesting antennae, and dendrimers as molecular amplifiers, which may serve as novel platforms for drug delivery. Both applications stem from the unique structure of dendrimers. We present a theoretical framework based on the master equation within which we describe these applications. The quantities of interest are the first passage time (FPT) probability density function (PDF), and its moments. We examine how the FPT PDF and its characteristics depend on the geometric and energetic structures of the dendrimeric system. In particular, we investigate the dependence of the FPT properties on the number of generations (dendrimer size), and the system bias. We present analytical expressions for the FPT PDF for very efficient dendrimeric antennae and for dendrimeric amplifiers. For these cases the mean first passage time scales linearly with the system length, and fluctuations around the mean first passage time are negligible for large systems. Relationships of the FPT to light harvesting process for other types of system-bias are discussed.

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“…The unique architectural features of dendrimers offer additional elegant strategies to gain exquisite control over release of active drug. In particular, the production of dendrimers functionalized with catalytic antibodies [68] has spurred the development of dendrimers capable of ''selfimmolation'' [93][94][95].…”

Section: Release Of Covalently-delivered ''Pro-drugs''mentioning

confidence: 99%

“…To briefly explain, these unique assemblies have the ability to release all of their tail units (i.e., the active drug) through a self-immolative chain fragmentation, which is initiated by a single cleavage at the dendrimer's core [96]. The first generation of dendritic prodrugs was demonstrated by Shamis and coworkers who synthesized doxorubicin and camptothecin as tail units and designed a retro-aldol retro-Michael focal trigger provided by action of the catalytic antibody 38C2 [94]. This method showed a dramatic increase in toxicity to tumor cells upon bioactivation of the pro-drug compared with tests done in the absence of the activating antibody.…”

Section: Release Of Covalently-delivered ''Pro-drugs''mentioning

confidence: 99%

Dendrimers in Cancer Treatment and Diagnosis

Sampathkumar

¹

,

Yarema

²

2003

Nanotechnologies for the Life Sciences

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The sections in this article are Overview Introduction Basic Properties and Applications of Dendrimers Structural Features and Chemical and Biological Properties Basic Features of Dendritic Macromolecules are Inspired by Nature Comparison of the Properties of Dendrimers and Conventional Synthetic Polymers Comparison of the Properties of Dendrimers and Proteins (a Biological Polymer) Dendritic Macromolecules Possess a Wealth of Possible Applications Methods for Dendrimer Synthesis History and Basic Strategies Cascade Reactions are the Foundation of Dendrimer Synthesis Dendrimer Synthesis has Expanded Dramatically in the Past Two Decades Strategies, Cores, and Building Blocks for Dendritic Macromolecules Dendrimers are Constructed from Simple “Building Blocks” The Synthesis of Dendrimers Follows Either a Divergent or Convergent Approach Heterogeneously‐functionalized Dendrimers Basic Description and Synthetic Considerations Glycosylation is an Example of Surface Modification with Multiple Bioactivities Dendrimers in Drug Delivery Dendrimers are Versatile Nano‐devices for the Delivery of Diverse Classes of Drugs Dendritic Drug Delivery: Encapsulation of Guest Molecules Dendrimers have Internal Cavities that can Host Encapsulated Guest Molecules Using Dendrimers for Gene Delivery Release of Encapsulated “Pro‐drugs” Covalent Conjugation Strategies Dendrimers Overcome many Limitations Inherent in Polymeric Conjugation Strategies Dendrimer Conjugates can be Used as Vaccines Release of Covalently‐delivered “Pro‐drugs” Fine‐tuning Dendrimer Properties to Facilitate Delivery and Ensure Bioactivity Delivery Requires Avoiding Non‐specific Uptake “Local” Considerations: Contact with, and Uptake by, the Target Cell Drug Delivery: Ensuring the Biocompatibility of Dendritic Delivery Vehicles Biocompatibility Entails Avoiding “Side Effects” such as Toxicity and Immunogenicity Water Solubility and Immunogenicity Inherent and Induced Toxicity Dendrimers in Cancer Diagnosis and Treatment Dendrimers have Attractive Properties for Cancer Treatment Dendrimer‐sized Particles Passively Accumulate at the Sites of Tumors Multifunctional Dendrimers can Selectively Target Biomarkers found on Cancer Cells Methods for Targeting Specific Biomarkers of Cancer Targeting by Folate, a Small Molecule Ligand Targeting by Monoclonal Antibodies Dendrimers in Cancer Diagnosis and Imaging Labeled Dendrimers are Important Research Tools for Biodistribution Studies Towards Clinical Use: MRI Imaging Agents Steps Towards the Clinical Realization of Dendrimer‐based Cancer Therapies The Stage is now set for Dendrimer‐based Cancer Therapy Boron Neutron Capture Therapy Innovations Promise to Speed Progress “Mix‐and‐Match” Strategy of Bifunctional Dendritic Clusters Towards Therapeutic Exploitation of Glycosylation Abnormalities found in Cancer Towards Targeting Metabolically‐engineered Carbohydrate Epitopes Concluding Remarks Acknowledgments

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“…The excellent retro-aldolase activity (2, 3) of Abs 38C2 (4) and 93F3 (5) has allowed us to design, synthesize, and evaluate prodrugs of various chemotherapeutic agents that can be activated by retro-aldol reactions (6)(7)(8)(9)(10). In a syngeneic mouse model of neuroblastoma, systemic administration of an etoposide prodrug and intratumor injection of Ab 38C2 inhibited tumor growth (11).…”

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confidence: 99%

Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation

Abraham

¹

,

Guo

²

,

Li

³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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An obstacle in the utilization of catalytic Abs for selective prodrug activation in cancer therapy has been systemic tumor targeting. Here we report the generation of catalytic Abs that effectively target tumor cells with undiminished prodrug activation capability. Ab conjugates were prepared by covalent conjugation of an integrin ␣v␤3-targeting antagonist to catalytic Ab 38C2 through either sulfide groups of cysteine residues generated by reduction of the disulfide bridges in the hinge region or surface lysine residues not involved in the catalytic activity. Using flow cytometry, the Ab conjugates were shown to bind efficiently to integrin ␣v␤3-expressing human breast cancer cells. The Ab conjugates also retained the retro-aldol activity of their parental catalytic Ab 38C2, as measured by methodol and doxorubicin (dox) prodrug activation. Complementing these Ab conjugates, an evolved set of dox prodrugs was designed and synthesized. Dox prodrugs that showed higher stability and lower toxicity were evaluated both in the presence and absence of the integrin ␣v␤3-targeting 38C2 conjugates for cell-killing efficacy by using human breast cancer cells. Our study reveals that cell targeting and prodrug activation capabilities can be efficiently combined for selective chemotherapy with novel dox prodrugs.aldolase Ab ͉ Ab conjugate ͉ doxorubicin ͉ integrin ␣v␤3

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Bioactivation of Self-Immolative Dendritic Prodrugs by Catalytic Antibody 38C2

Cited by 208 publications

References 21 publications

Some new aspects of dendrimer applications

Some new aspects of dendrimer applications

Dendrimers in Cancer Treatment and Diagnosis

Synthesis of the next-generation therapeutic antibodies that combine cell targeting and antibody-catalyzed prodrug activation

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