Barriers and Strategies of Cationic Liposomes for Cancer Gene Therapy

Liu, Chunyan; Zhang, Ligang; Zhu, Wenhui; Guo, Raoqing; Sun, Huamin; Chen, Xi; Deng, Ning

doi:10.1016/j.omtm.2020.07.015

Cited by 132 publications

(88 citation statements)

References 190 publications

(313 reference statements)

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“…Recent developments in gene therapy over the last decade or so has drawn the renewed attention of many companies and researchers to the use of viral vectors (using various virus systems, e.g., adenovirus [44][45][46][47][48] and AAV [49][50][51]), along with completely synthetic particles, involving liposomes and nanoparticles [52][53][54][55][56][57], as drug (nucleic acid) delivery systems. Initially, interest in this area was predominately concerned with the delivery of DNA therapeutic material, however, interest has widened to include the use of RNA therapeutics [58] such as interference ribonucleic acids, RNAi [59,60], and messenger ribonucleic acids, mRNA [61,62] along with gene editing payload material [63][64][65][66].…”

Section: Discussionmentioning

confidence: 99%

Boundary convection during velocity sedimentation in the Optima analytical ultracentrifuge

Berkowitz¹,

Laue

2021

Preprint

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Analytical ultracentrifugation (AUC) provides the most widely applicable, precise and accurate means for characterizing solution hydrodynamic and thermodynamic properties. In recent times AUC has found broad application in the biopharmaceutical industry as a first-principle means for quantitatively characterizing biopharmaceuticals. Boundary sedimentation velocity AUC (SV-AUC) analysis is widely used to assess protein aggregation, fragmentation and conformational variants in the same solvents used during drug development and production. SV-AUC is especially useful for the analysis of drug substance, drug product and dosing solution, where other techniques may exhibit solvent matrix issues or concentration limitations. Recently, the only manufacturer of the analytical ultracentrifuge, released its newest (third generation) analytical ultracentrifuge, the Optima, in early 2017 to replace its aging 2nd generation XL series ultracentrifuges. However, SV-AUC data from four Optima units used in conducting characterization work on adeno-associated virus (AAV) has shown evidence of sample convection. Further investigation reveals that this problem arises from the temperature control system design, which is prone to producing destabilizing temperature induced density gradients that can lead to density inversions. The observed convection impacts both the qualitative and quantitative data generated by the Optima. The problem is intermittent and variable in severity within a given Optima unit and between Optima units. This convection appears to be mainly associated with low rotor speeds and dilute samples in dilute solvents, such as AAV samples in formulation buffers containing relatively low concentrations of salts, sugars, etc. Under these conditions it is found that a sufficiently robust stabilizing density gradient is not always present during sedimentation, making the sample susceptible to convection by localized density inversions. Because SV-AUC is used as an analytical tool in making critical decisions in the development and quality control of biotherapeutics, it is imperative to alert users about this potential problem. In general special attention to data quality needs to be made by those researchers working with very large biopharmaceutical particles (e.g. gene therapy products that involve viral vectors or nanoparticles), where the conditions leading to convection are most likely to occur. It is important to note that the XL series analytical ultracentrifuges do not suffer from this problem, indicating that this problem is unique to the Optima. Attributes that reveal the presence of this problem and strategies for its elimination or minimization are provided.

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Section: Discussionmentioning

confidence: 99%

Boundary convection during velocity sedimentation in the Optima analytical ultracentrifuge

Berkowitz¹,

Laue

2021

Preprint

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“…Thus, BP1001 is uniquely different from other liposomal oligo formulations, which typically utilize positively charged lipids to bind to the negatively charged oligonucleotides [ 135 , 136 ]. The neutral charge of DOPC lipids reduces liposomes’ interactions with charged plasma proteins, thereby increasing blood circulation time and cellular uptake [ 137 , 138 ]. Additionally, DOPC is non-immunogenic and has a very low fatty acid chain melting temperature (below freezing point), making it highly desirable for drug delivery.…”

Section: Bp1001: Liposomal P-ethoxy-grb2 Asomentioning

confidence: 99%

The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery

Gagliardi¹,

Ashizawa²

2021

Biomedicines

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Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential and numerous ASO drugs in preclinical research and clinical trials, there are many limitations to this technology. In this review we will focus on the challenges of ASO delivery and the strategies adopted to improve their stability in the bloodstream, delivery to target sites, and cellular uptake. Focusing on liposomal delivery, we will specifically describe liposome-incorporated growth factor receptor-bound protein-2 (Grb2) antisense oligodeoxynucleotide BP1001. BP1001 is unique because it is uncharged and is essentially non-toxic, as demonstrated in preclinical and clinical studies. Additionally, its enhanced biodistribution makes it an attractive therapeutic modality for hematologic malignancies as well as solid tumors. A detailed understanding of the obstacles that ASOs face prior to reaching their targets and continued advances in methods to overcome them will allow us to harness ASOs’ full potential in precision medicine.

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“…Research by Hattori et al [ 55 ] confirmed that the type of cationic lipids has a huge impact on the biological distribution and knockdown efficiency of siRNA in vivo. In other words, the therapeutic effect of CLs is determined by the rational design of lipid composition [ 56 ].…”

Section: Protective Carriers For Sirna Deliverymentioning

confidence: 99%

Nanoparticles as Drug Delivery Systems of RNAi in Cancer Therapy

Gao

Kuang

et al. 2021

Molecules

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RNA interference (RNAi) can mediate gene-silencing by knocking down the expression of a target gene via cellular machinery with much higher efficiency in contrast to other antisense-based approaches which represents an emerging therapeutic strategy for combating cancer. Distinct characters of nanoparticles, such as distinctive size, are fundamental for the efficient delivery of RNAi therapeutics, allowing for higher targeting and safety. In this review, we present the mechanism of RNAi and briefly describe the hurdles and concerns of RNAi as a cancer treatment approach in systemic delivery. Furthermore, the current nanovectors for effective tumor delivery of RNAi therapeutics are classified, and the characteristics of different nanocarriers are summarized.

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Barriers and Strategies of Cationic Liposomes for Cancer Gene Therapy

Cited by 132 publications

References 190 publications

Boundary convection during velocity sedimentation in the Optima analytical ultracentrifuge

Boundary convection during velocity sedimentation in the Optima analytical ultracentrifuge

The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery

Nanoparticles as Drug Delivery Systems of RNAi in Cancer Therapy

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