Understanding nanomedicine treatment in an aggressive spontaneous brain cancer model at the stage of early blood brain barrier disruption

Janowicz, Phillip W.; Houston, Zachary H.; Bunt, Jens; Fletcher, Nicholas L.; Bell, Craig A.; Cowin, Gary; Howard, Christopher B.; Taslima, Dewan; Holthe, Nicholas Westra van; Prior, Amber R.; Soh, Vanessa; Ghosh, Saikat; Humphries, James; Huda, Pie; Mahler, Stephen M.; Richards, Linda J.; Thurecht, Kristofer J.

doi:10.1016/j.biomaterials.2022.121416

Cited by 17 publications

(30 citation statements)

References 38 publications

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“…αPEG-αEphA2 bispecific antibody (αEphA2 BsAb, 4B3) was produced in our lab using protocols previously described. 29,41 αEphA2 monoclonal antibody (αEphA2 mAb, 4B3) was kindly provided by Professor Bryan Day (QIMR Berghofer Medical Research Institute, Australia). EphA2 (D4A2) XP Rabbit mAb (#6997) for western blot was purchased from Cell Signaling Technology, Danvers, United States.…”

Section: Methodsmentioning

confidence: 99%

Development and Validation of a Targeted Treatment for Brain Tumors Using a Multi-Drug Loaded, Relapse-Resistant Polymeric Theranostic

et al. 2023

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This study aimed to develop a multifunctional polymer platform that could address the issue of treatment resistance when using conventional chemotherapeutics to treat glioblastoma (GBM). An antibody-conjugated, multi-drug loaded hyperbranched polymer was developed that provided a platform to evaluate the role of targeted nanomedicine treatments in overcoming resistant GBM by addressing the various complications with current clinically administered formulations. The polymer was synthesized via reversible addition fragmentation chain transfer polymerization and included the clinical first-line alkylating agent temozolomide (TMZ) which was incorporated as a polymerizable monomer, poly (ethylene glycol) (PEG) units to impart biocompatibility and enable conjugation with αPEG-αEphA2 bispecific antibody (αEphA2 BsAb) for tumor targeting, and hydrazide moieties for attachment of a secondary drug which allows exploration of synergistic therapies. To overcome the resistance to TMZ, the O 6 alkylguanine DNA alkyltransferase (AGT, DNA repair protein) inhibitor, dialdehyde O 6 benzylguanine (DABG) was subsequently conjugated to the polymer via an acid labile hydrazone linker to facilitate controlled release under conditions encountered within the tumor microenvironment. The prolonged degradation half-life (4−5 h) of the polymer conjugated TMZ in vitro offered a potential avenue to overcome the inability to deliver these drugs in combination at therapeutic doses. Although only 20% of DABG could be released within the studied timeframe (192 h) under conditions mimicking the acidic nature of the tumor environment, cytotoxicity evaluation using cell assays confirmed the improved therapeutic efficacy toward resistant GBM cells after attaching DABG to the polymer delivery vehicle. Of note, when the polymeric delivery vehicle was specifically targeted to receptors (Ephrin A2) on the surface of the GBM cells using our in-house developed EphA2 specific BsAb, the dual-drug-loaded polymer exhibited an improved therapeutic effect on TMZresistant cells compared to the free drug combination. Both in vitro and in vivo targeting studies showed high uptake of the construct to GBM tumors with an upregulated EphA2 receptor (T98G and U251) compared to a tumor that had low expression (U87MG), where a dual tumor xenograft model was used to demonstrate the enhanced accumulation in tumor tissue in vivo. Despite the synthetic challenges of developing systems to effectively deliver controlled doses of TMZ and DABG, these studies highlight the potential benefit of this formulation for delivering multi-drug combinations to resistant GBM tumor cells and offer a platform for future optimization in therapeutic studies.

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Section: Methodsmentioning

confidence: 99%

Development and Validation of a Targeted Treatment for Brain Tumors Using a Multi-Drug Loaded, Relapse-Resistant Polymeric Theranostic

et al. 2023

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“…Similar observations of increased in vivo anticancer activity of polypropyleneimine dendrimer loading with another chemotherapeutic agent have also been reported [ 160 , 161 ]. Of note, hyperbranched polyermic NPs, which are slightly different from dendrimers in topological structures, have also been recently proposed as delivery agents for chemotherapeutic agents at brain cancer sites [ 162 ].…”

Section: Overview Of the State-of-the-art Nps For Neuro-oncology Appl...mentioning

confidence: 99%

Smart Nanoformulations for Brain Cancer Theranostics: Challenges and Promises

Ahmad

Varghese

Panda

et al. 2022

Cancers

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Despite their low prevalence, brain tumors are among the most lethal cancers. They are extremely difficult to diagnose, monitor and treat. Conventional anti-cancer strategies such as radio- and chemotherapy have largely failed, and to date, the development of even a single effective therapeutic strategy against central nervous system (CNS) tumors has remained elusive. There are several factors responsible for this. Brain cancers are a heterogeneous group of diseases with variable origins, biochemical properties and degrees of invasiveness. High-grade gliomas are amongst the most metastatic and invasive cancers, which is another reason for therapeutic failure in their case. Moreover, crossing the blood brain and the blood brain tumor barriers has been a significant hindrance in the development of efficient CNS therapeutics. Cancer nanomedicine, which encompasses the application of nanotechnology for diagnosis, monitoring and therapy of cancers, is a rapidly evolving field of translational medicine. Nanoformulations, because of their extreme versatility and manipulative potential, are emerging candidates for tumor targeting, penetration and treatment in the brain. Moreover, suitable nanocarriers can be commissioned for theranostics, a combinatorial personalized approach for simultaneous imaging and therapy. This review first details the recent advances in novel bioengineering techniques that provide promising avenues for circumventing the hurdles of delivering the diagnostic/therapeutic agent to the CNS. The authors then describe in detail the tremendous potential of utilizing nanotechnology, particularly nano-theranostics for brain cancer imaging and therapy, and outline the different categories of recently developed next-generation smart nanoformulations that have exceptional potential for making a breakthrough in clinical neuro-oncology therapeutics.

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“…121 One complication that could potentially arise from this approach is the nonselectivity of molecules that can enter the brain, potentially allowing overload of undesirable molecules in the parenchyma. While it is well-understood that the BBB does begin to lose integrity within the vicinity of certain pathologies (e.g., GB), 122 the use of FUS/OD significantly enhances this effect and likely improves the homogeneity of drug accumulation in diseased tissue. In the case of FUS, this can be achieved to relatively high spatial resolution as it is typically guided by MRI.…”

Section: Antibody Drug Conjugates (Adcs)mentioning

confidence: 99%

Antibody-Based Formats to Target Glioblastoma: Overcoming Barriers to Protein Drug Delivery

et al. 2022

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Glioblastoma (GB) is recognized as the most aggressive form of primary brain cancer. Despite advances in treatment strategies that include surgery, radiation, and chemotherapy, the median survival time (∼15 months) of patients with GB has not significantly improved. The poor prognosis of GB is also associated with a very high chance of tumor recurrence (∼90%), and current treatment measures have failed to address the complications associated with this disease. However, targeted therapies enabled through antibody engineering have shown promise in countering GB when used in combination with conventional approaches. Here, we discuss the challenges in conventional as well as future GB therapeutics and highlight some of the known advantages of using targeted biologics to overcome these impediments. We also review a broad range of potential alternative routes that could be used clinically to administer anti-GB biologics to the brain through evasion of its natural barriers.

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Understanding nanomedicine treatment in an aggressive spontaneous brain cancer model at the stage of early blood brain barrier disruption

Cited by 17 publications

References 38 publications

Development and Validation of a Targeted Treatment for Brain Tumors Using a Multi-Drug Loaded, Relapse-Resistant Polymeric Theranostic

Development and Validation of a Targeted Treatment for Brain Tumors Using a Multi-Drug Loaded, Relapse-Resistant Polymeric Theranostic

Smart Nanoformulations for Brain Cancer Theranostics: Challenges and Promises

Antibody-Based Formats to Target Glioblastoma: Overcoming Barriers to Protein Drug Delivery

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