Application of chloroquine as an endosomal escape enhancing agent: new frontiers for an old drug

Hajimolaali, Mohammad; Mohammadian, Hosein; Shirini, Amin; Shal, Mostafa Khalife; Nezhad, Hami Barazandeh; Iranpour, Sheida; Eftekhari, Reza Baradaran; Dorkoosh, Farid Abedin

doi:10.1080/17425247.2021.1873272

Cited by 27 publications

(19 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 C). Co-treatment of endosome disrupting HIV TAT peptides 29 and the small molecule chloroquine 30 did not lead to increased cell killing of either cell line although it must be noted that robust toxicity was seen when both lines were treated with the latter alone making any effects of GZMB-MU2 difficult to assess (data not shown). It is possible that while these agents may have released a fraction the protein conjugate into the cytosol of PIP-PC3 cells, the levels of which were simply not high enough to activate apoptotic pathways.…”

Section: Resultsmentioning

confidence: 95%

Targeted delivery of cytotoxic proteins to prostate cancer via conjugation to small molecule urea-based PSMA inhibitors

Rogers

Rosen

Antony

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Prostate cancer cells are characterized by a remarkably low proliferative rate and the production of high levels of prostate-specific proteases. Protein-based toxins are attractive candidates for prostate cancer therapy because they kill cells via proliferation-independent mechanisms. However, the non-specific cytotoxicity of these potent cytotoxins must be redirected to avoid toxicity to normal tissues. Prostate-Specific Membrane Antigen (PSMA) is membrane-bound carboxypeptidase that is highly expressed by prostate cancer cells. Potent dipeptide PSMA inhibitors have been developed that can selectively deliver and concentrate imaging agents within prostate cancer cells based on continuous PSMA internalization and endosomal cycling. On this basis, we conjugated a PSMA inhibitor to the apoptosis-inducing human protease Granzyme B and the potent Pseudomonas exotoxin protein toxin fragment, PE35. We assessed selective PSMA binding and entrance into tumor cell to induce cell death. We demonstrated these agents selectively bound to PSMA and became internalized. PSMA-targeted PE35 toxin was selectively toxic to PSMA producing cells in vitro. Intratumoral and intravenous administration of this toxin produced marked tumor killing of PSMA-producing xenografts with minimal host toxicity. These studies demonstrate that urea-based PSMA inhibitors represent a simpler, less expensive alternative to antibodies as a means to deliver cytotoxic proteins to prostate cancer cells.

show abstract

Section: Resultsmentioning

confidence: 95%

Targeted delivery of cytotoxic proteins to prostate cancer via conjugation to small molecule urea-based PSMA inhibitors

Rogers

Rosen

Antony

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…These features varied substantially from the uniform amphisomes present in untreated control oocytes. In addition to lysosomal accumulation, chloroquine can also accrue within acidic endosomal organelles, leading to perturbation of their acidity, increased osmotic pressure, and eventual membrane rupture; responses that have been exploited in the context of drug delivery and release within target cells ( Yu et al, 2016 ; Hajimolaali et al, 2021 ). Given this insight, it is possible that chloroquine action within the oocyte may be attributed to a compromise of endosome integrity, accounting for the irregular amphisome morphology witnessed after chloroquine challenge.…”

Section: Discussionmentioning

confidence: 99%

The Impact of Aging on Macroautophagy in the Pre-ovulatory Mouse Oocyte

Peters

Caban

McLaughlin

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Accompanying the precipitous age-related decline in human female fertility is an increase in the proportion of poor-quality oocytes within the ovary. The macroautophagy pathway, an essential protein degradation mechanism responsible for maintaining cell health, has not yet been thoroughly investigated in this phenomenon. The aim of this study was to characterize the macroautophagy pathway in an established mouse model of oocyte aging using in-depth image analysis-based methods and to determine mechanisms that account for the observed changes. Three autophagy pathway markers were selected for assessment of gene and protein expression in this model: Beclin 1; an initiator of autophagosome formation, Microtubule-associated protein 1 light chain 3B; a constituent of the autophagosome membrane, and lysosomal-associated membrane protein 1; a constituent of the lysosome membrane. Through quantitative image analysis of immunolabeled oocytes, this study revealed impairment of the macroautophagy pathway in the aged oocyte with an attenuation of both autophagosome and lysosome number. Additionally, an accumulation of amphisomes greater than 10 μm2 in area were observed in aging oocytes, and this accumulation was mimicked in oocytes treated with lysosomal inhibitor chloroquine. Overall, these findings implicate lysosomal dysfunction as a prominent mechanism by which these age-related changes may occur and highlight the importance of macroautophagy in maintaining mouse pre-ovulatory oocyte quality. This provides a basis for further investigation of dysfunctional autophagy in poor oocyte quality and for the development of therapeutic or preventative strategies to aid in the maintenance of pre-ovulatory oocyte health.

show abstract

“…However, the last hypothesis does not explain the absence of rising efficacy of PEI-polyplexes containing chloroquine in THE earliest studies [72,75]. Even though the additional mechanisms of chloroquine's effects on endosomal escape remain unknown, the fact that swelling and gene delivery are enhanced is undeniable [71].…”

Section: Ph-buffering Effects (Swelling)mentioning

confidence: 99%

“…While virus vectors use endosome membrane penetration to escape, several non-viral delivery mechanisms have been demonstrated [70]. Hajimolaali and colleagues give the following classification of the main known methods of endosomal escape by non-viral vectors: membrane pore formation, membrane fusion accompanied by cargo release, photochemical disruption, and pH-buffering effects [71,72].…”

Section: Endosomal Escapementioning

confidence: 99%

Non-Viral Carriers for Nucleic Acids Delivery: Fundamentals and Current Applications

Shtykalova

Deviatkin

Freund

et al. 2023

Life

View full text Add to dashboard Cite

Over the past decades, non-viral DNA and RNA delivery systems have been intensively studied as an alternative to viral vectors. Despite the most significant advantage over viruses, such as the lack of immunogenicity and cytotoxicity, the widespread use of non-viral carriers in clinical practice is still limited due to the insufficient efficacy associated with the difficulties of overcoming extracellular and intracellular barriers. Overcoming barriers by non-viral carriers is facilitated by their chemical structure, surface charge, as well as developed modifications. Currently, there are many different forms of non-viral carriers for various applications. This review aimed to summarize recent developments based on the essential requirements for non-viral carriers for gene therapy.

show abstract

Application of chloroquine as an endosomal escape enhancing agent: new frontiers for an old drug

Cited by 27 publications

References 99 publications

Targeted delivery of cytotoxic proteins to prostate cancer via conjugation to small molecule urea-based PSMA inhibitors

Targeted delivery of cytotoxic proteins to prostate cancer via conjugation to small molecule urea-based PSMA inhibitors

The Impact of Aging on Macroautophagy in the Pre-ovulatory Mouse Oocyte

Non-Viral Carriers for Nucleic Acids Delivery: Fundamentals and Current Applications

Contact Info

Product

Resources

About