Liposomal Bortezomib Nanoparticles via Boronic Ester Prodrug Formulation for Improved Therapeutic Efficacy in Vivo

Ashley, Jonathan D.; Stefanick, Jared F.; Schroeder, Valerie A.; Suckow, Mark A.; Kiziltepe, Tanyel; Bilgiçer, Başar

doi:10.1021/jm500352v

Cited by 71 publications

(63 citation statements)

References 41 publications

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“…S2) (50, 53). The results show that ChA has the highest affinity for BTZ, which is in agreement with literature reports that the catechols have greater reactivity than cis -diols in reacting with boronic acid (30, 53). Consequently, these biocompatible compounds were chosen as BCMs to functionalize telodendrimers to validate the methodology for nanocarrier design and optimize BTZ conjugation.…”

Section: Resultssupporting

confidence: 92%

Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment

et al. 2017

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We have developed multifunctional nanoparticles (NP) for co-delivery of bortezomib (BTZ) and doxorubicin (DOX) to synchronize their pharmacokinetic profiles and synergize their activities in solid tumor treatment, a need still unmet in the clinic. Micellar NP was formed by a spatially segregated, linear-dendritic telodendrimer containing three segments: a hydrophilic polyethylene glycol (PEG), a BTZ-conjugating intermediate, and a dendritic DOX-affinitive interior. BTZ-conjugated telodendrimers, together with DOX, self-assembled into monodispersed micelles (NP(BTZ-DOX)) with small particle sizes (20~30 nm) for dual drug delivery. NP(BTZ-DOX) displayed excellent drug loading capacity and stability, which minimized premature drug leakage and synchronized drug release profiles. BTZ release was accelerated significantly by acidic pH, facilitating drug availability in the acidic tumor microenvironment. Synergistic anticancer effects of combined BTZ and DOX were observed in vitro against both multiple myeloma and ovarian cancer cells. NP(BTZ-DOX) prolonged payload circulation and targeted tumors in vivo efficiently with superior signal ratios of tumor to normal organs. In vitro and in vivo proteasome inhibition analysis and biodistribution studies revealed decreased toxicity and efficient intratumoral BTZ and DOX delivery by nanoformulation. NP(BTZ-DOX) exhibited significantly improved ovarian cancer treatment in SKOV-3 xenograft mouse models in comparison with free drugs and their combinations, including BTZ and Doxil. In summary, tumor-targeted and synchronized delivery system elicits enhanced anticancer effects and merits further development in the clinical setting.

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Section: Resultssupporting

confidence: 92%

Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment

et al. 2017

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“… Liposomes have been used to encapsulate bortezomib, a proteasome inhibitor with high neurotoxicity. Due to the poor water solubility of bortezomib, instead of loading the drug in the aqueous core, direct conjugation of bortezomib to the surface of liposomes via a reversible boronic ester linkage was used . Liposomal bortezomib NPs showed size ranges of 100 nm with high reproducibility and encapsulation efficiency of 80%.…”

Section: Nanoparticle Delivery Systems For Myelomamentioning

confidence: 99%

“…Another study has developed liposomal carfilzomib NPs, such as the ones previously described for bortezomib, enriched with a VLA‐4 antagonist peptide. NPs were stable and reproducible with size 70 nm, and loading efficiency of 98%.…”

Section: Nanoparticle Delivery Systems For Myelomamentioning

confidence: 99%

Nanoparticle delivery systems, general approaches, and their implementation in multiple myeloma

Puente

Azab

2017

European J of Haematology

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Multiple myeloma (MM) is a hematological malignancy that remains incurable, with relapse rates greater than 90%. The main limiting factor for the effective use of chemotherapies in MM is the serious side effects caused by these drugs. The emphasis in cancer treatment has shifted from cytotoxic, non-specific chemotherapies to molecularly targeted and rationally designed therapies showing greater efficacy and fewer side effects. Traditional chemotherapy has shown several disadvantages such as lack of targeting capabilities, systemic toxicity and side effects; low therapeutic index, as well as, most anticancer drugs have poor water solubility. Nanoparticle delivery systems (NPs) are capable of targeting large doses of chemotherapies into the target area while sparing healthy tissues, overcoming the limitations of traditional chemotherapy. Here, we review the current state-of-the-art in nanoparticle-based strategies designed to treat multiple myeloma. Many nanoparticle delivery systems have been studied for myeloma using non-targeted NPs (liposomes, polymeric NPs, and inorganic NPs), triggered NPs, as well as targeted NPs (VLA-4, ABC drug transporters, bone microenvironment targeting). The results in preclinical and clinical studies are promising; however, there remains much to be learned in the emerging field of nanomedicine in myeloma.

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“…Apoptotic cells were detected with Annexin V (FITC) antibody (BD Pharmingen) using a Guava easyCyte 8HT Flow Cytometer (EMD Millipore) as described previously (27).…”

Section: Annexin V Analysismentioning

confidence: 99%

Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma

Ashley

Quinlan

Schroeder

et al. 2016

Molecular Cancer Therapeutics

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Here, we report the synthesis and evaluation of dual drugloaded nanoparticles as an effective means to deliver carfilzomib and doxorubicin to multiple myeloma tumor cells at their optimal synergistic ratio. First, various molar ratios of carfilzomib to doxorubicin were screened against multiple myeloma cell lines to determine the molar ratio that elicited the greatest synergy using the Chou-Talalay method. The therapeutic agents were then incorporated into liposomes at the optimal synergistic ratio of 1:1 to yield dual drug-loaded nanoparticles with a narrow size range of 115 nm and high reproducibility. Our results demonstrated that the dual drug-loaded liposomes exhibited synergy in vitro and were more efficacious in inhibiting tumor growth in vivo than a combination of free drugs, while at the same time reducing systemic toxicity. Taken together, this study presents the synthesis and preclinical evaluation of dual drug-loaded liposomes containing carfilzomib and doxorubicin for enhanced therapeutic efficacy to improve patient outcome in multiple myeloma.

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Liposomal Bortezomib Nanoparticles via Boronic Ester Prodrug Formulation for Improved Therapeutic Efficacy in Vivo

Cited by 71 publications

References 41 publications

Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment

Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment

Nanoparticle delivery systems, general approaches, and their implementation in multiple myeloma

Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma

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