Development and characterization of liposomal formulation of bortezomib

Deshantri, Anil K.; Metselaar, Josbert M.; Zagkou, Stavroula; Storm, Gert; Mandhane, Sanjay N.; Fens, Marcel H.A.M.; Schiffelers, Raymond M.

doi:10.1016/j.ijpx.2019.100011

Cited by 16 publications

(11 citation statements)

References 15 publications

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“…However, our data provide evidence that perturbation of the protein homeostasis is an option to target MYC-active PDACs. Considering the development of next-generation proteasome inhibitors [69], the development of new bortezomib formulations [72], or options to target the ubiquitin-proteasome system at different levels [45, 46, 73], will allow to advance the concept in the future.…”

Section: Discussionmentioning

confidence: 99%

Targeting the ubiquitin-proteasome system in a pancreatic cancer subtype with hyperactive MYC

Lankes

Hassan

Doffo

et al. 2020

Preprint

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AbstractPurposeThe myelocytomatosis oncogene (MYC) is an important driver in a subtype of pancreatic ductal adenocarcinoma (PDAC). However, MYC remains a challenging therapeutic target, therefore identifying druggable synthetic lethal interactions in MYC-active PDAC may lead to novel precise therapies.MethodsCluster analysis using direct MYC target genes was used to identify PDAC with active MYC. We profiled the transcriptome of established human cell lines, murine primary PDAC cell lines and also accessed public available repositories for transcriptomic profiling. Networks active in MYC hyperactive subtypes were analyzed by gene set enrichment analysis. An unbiased pharmacological drug screen with FDA-approved anti-cancer drugs was conducted to define MYC-associated vulnerabilities, which were validated by analysis of drug response repositories and genetic gain- and loss-of-function experiments.ResultsIn an unbiased pharmacological drug screen with FDA-approved anti-cancer drugs we detected that the proteasome inhibitor bortezomib triggers a MYC-associated vulnerability. By integrating publicly available data sets we found the unfolded protein response as a signature connected to MYC. Furthermore, the increased sensitivity of MYC hyperactive PDACs to bortezomib was validated in genetically modified PDAC cells.ConclusionsIn sum, we provide evidence that perturbing the ubiquitin proteasome system might be an option to target MYC hyperactive PDAC cells and our data provide the rationale to further develop precise targeting of the ubiquitin-proteasome system as a subtype-specific therapeutic approach.

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Section: Discussionmentioning

confidence: 99%

Targeting the ubiquitin-proteasome system in a pancreatic cancer subtype with hyperactive MYC

Lankes

Hassan

Doffo

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…However, our data provide evidence that perturbation of the protein homeostasis is an option to target MYC-active PDACs. Considering the development of next-generation proteasome inhibitors [89], the development of new bortezomib formulations [92], or options to target the ubiquitin-proteasome system at different levels [55,56,93], will allow to advance the concept in the future.…”

Section: Discussionmentioning

confidence: 99%

Targeting the ubiquitin‐proteasome system in a pancreatic cancer subtype with hyperactive MYC

et al. 2020

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The myelocytomatosis oncogene (MYC) is an important driver in a subtype of pancreatic ductal adenocarcinoma (PDAC). However, MYC remains a challenging therapeutic target, therefore identifying druggable synthetic lethal interactions in MYC-active PDAC may lead to novel precise therapies. First, to identify networks with hyperactive MYC, we profiled transcriptomes of established human cell lines, murine primary PDAC cell lines and accessed publicly available repositories to analyze transcriptomes of primary human PDAC. Networks active in MYC hyperactive subtypes were analyzed by gene set enrichment analysis. Next, we performed an unbiased pharmacological screen to define MYC-associated vulnerabilities. Hits were validated by analysis of drug-response repositories and genetic gain-and loss-of-function experiments. In these experiments, we discovered that the proteasome inhibitor Bortezomib triggers a MYC-associated vulnerability. In addition, by integrating publicly available data, we found the unfolded protein response as a signature connected to MYC. Furthermore, increased sensitivity of MYC-hyperactive PDACs to Bortezomib was validated in genetically modified PDAC cells. In sum, we provide evidence that perturbing the ubiquitin proteasome system might be an option to target MYC hyperactive PDAC cells. Our data provide the rationale to further develop precise targeting of the ubiquitin-proteasome system as a subtype-specific therapeutic approach.

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“…Nanomedicines provide a valuable means to tackle the solubility, stability, and systemic toxicity issues of chemical drugs. − Interestingly, Doxil, Caelyx (liposomal doxorubicin), and Oncocort (liposomal dexamethasone phosphate) have already been used clinically or in clinical trials to treat MM . There are also attempts to develop nanosystems to improve delivery of proteasome inhibitors. − For example, CFZ encapsulated in the poly(ethylene glycol)–poly(caprolactone) (PEG–PCL) diblock copolymer micelles revealed clearly better in vitro metabolic stability than CFZ-CD. , CFZ-loaded liposomes exhibited lower systemic toxicity and better tumor suppression than CFZ in MM xenograft mouse model . Very late antigen-4 (VLA-4) peptide-decorated liposomal CFZ demonstrated further enhancement in MM growth inhibition.…”

Section: Introductionmentioning

confidence: 99%

A6 Peptide-Tagged Core-Disulfide-Cross-Linked Micelles for Targeted Delivery of Proteasome Inhibitor Carfilzomib to Multiple Myeloma In Vivo

et al. 2020

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Carfilzomib (CFZ) is a second-generation proteasome inhibitor approved for treating relapsed/refractory multiple myeloma (MM). The clinical formulation utilizing sulfobutylether-β-cyclodextrin to solubilize CFZ (Captisol, CFZ-CD) shows, however, short circulation time, lack of cell selectivity, and unmet antitumor efficacy. Here, we designed and prepared A6 peptide (sequence: KPSSPPEE)-tagged coredisulfide-cross-linked biodegradable micelles (A6-PMs) for targeted CFZ therapy of CD44-overexpressing LP-1 human MM in vivo. A6-PMs had a small size of about 40 nm and stable CFZ encapsulation. CFZ-loaded micelles (CFZ-A6-PMs) showed a glutathione-triggered drug release profile with negligible drug leakage under physiological conditions. CFZ-A6-PMs displayed good proteasome activity inhibition and more potent apoptotic activity than CFZ-CD and nontargeted CFZ-PMs toward LP-1 MM cells in vitro. The in vivo fluorescence images revealed that Cy5labeled A6-PMs induced much higher tumor accumulation than the nontargeted Cy5-labeled PMs control. The systemic administration of CFZ-A6-PMs to subcutaneous LP-1 xenografts in mice brought about notably more potent tumor suppression, higher survival rate and lower systemic toxicities than clinically used CFZ-CD formulation. These A6-tagged core-disulfide-crosslinked micelles appear interesting for targeted delivery of proteasome inhibitors to CD44 + MM.

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Development and characterization of liposomal formulation of bortezomib

Abstract: Graphical abstract

Cited by 16 publications

References 15 publications

Targeting the ubiquitin-proteasome system in a pancreatic cancer subtype with hyperactive MYC

Targeting the ubiquitin-proteasome system in a pancreatic cancer subtype with hyperactive MYC

Targeting the ubiquitin‐proteasome system in a pancreatic cancer subtype with hyperactive MYC

A6 Peptide-Tagged Core-Disulfide-Cross-Linked Micelles for Targeted Delivery of Proteasome Inhibitor Carfilzomib to Multiple Myeloma In Vivo

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