Tumoral acidic extracellular pH targeting of pH-responsive MPEG-poly(β-amino ester) block copolymer micelles for cancer therapy

Ko, Jin-Young; Park, Kyeongsoon; Kim, Yoo Shin; Kim, Min Sang; Han, Jong Kwon; Kim, Kwangmeyung; Park, Rang Woon; Kim, In San; Song, Hyun Kyu; Lee, Sang Soo; Kwon, Ick Chan

doi:10.1016/j.jconrel.2007.07.012

Cited by 283 publications

(194 citation statements)

References 28 publications

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“…The consequence of that phenomenon is that the pH of the extracellular space surrounding solid tumors is significantly lower than the pH of the surrounding normal tissues (1,(3)(4)(5)(6). Therefore, in recent years, several attempts have been made to use the solid tumor acidity to develop new pH-dependent approaches to cancer therapy (7)(8)(9)(10) or drug delivery (11)(12)(13)(14) because this venue seems most promising.…”

Section: Introductionmentioning

confidence: 99%

Suppression of Human Solid Tumor Growth in Mice by Intratumor and Systemic Inoculation of Histidine-Rich and pH-Dependent Host Defense–like Lytic Peptides

2009

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Previously, we reported that intratumor or systemic inoculation of a cationic 15-mer, innate immunity-like lytic peptide composed of D-and L-amino acids ([D]-K 6 L 9 ) caused growth arrest of 22RV1 prostate carcinoma xenografts in a mouse model. However, despite its therapeutic potential, this peptide has significant systemic toxicity at concentrations slightly higher than the therapeutic one. Here, we used the acidic environment created by solid tumors as a trigger to activate anticancer lytic peptides by making them cationic only at low pH levels. We achieved this selectivity by substituting lysines (pKa, f10.5) for histidines (pKa, f6.1) in the parental peptide [D]-K 6 L 9 . Histidine is protonated below pH 7. For that purpose, we replaced either three or all six lysines in the parental peptide with histidines to obtain the peptides [D]-K 3 H 3 L 9 and [D]-H 6 L 9 . Interestingly, in vitro experiments showed pH-dependent activity only with [D]-H 6 L 9 mainly toward cancer cell lines. However, both peptides showed reduced systemic toxicity compared with the parental peptide. Intratumor and systemic inoculation of these peptides resulted in a significant decrease in the 22RV1 prostate cancer tumor volume and systemic secretion of prostate-specific antigen in a xenograft mice model. Moreover, histologic modifications revealed a significant reduction in new blood vessels selectively in tumor tissues after treatment with the peptides compared with the untreated tumors. The lytic mode of action of these new peptides, which makes it difficult for the cancer cells to develop resistance, and their selective and pH-dependent activity make them potential candidates for treatment of solid cancer tumors.

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Section: Introductionmentioning

confidence: 99%

Suppression of Human Solid Tumor Growth in Mice by Intratumor and Systemic Inoculation of Histidine-Rich and pH-Dependent Host Defense–like Lytic Peptides

2009

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“…Then, properties of these biodegradable and pH-sensitive materials were also investigated. In 2006, Ko et al 29 and Hwang et al 30 designed and synthesized a novel pH-response micelle self-assembled from diblock polymer poly(ethylene glycol)-β-PAE, which was used as an anticancer drug carrier, exhibiting controlled release behavior with change of pH. In previous studies, our team also synthesized amphiphilic block copolymer with random hydrophobic/pH-sensitive structure of poly(ethylene glycol) methyl ether-β-(polylactic acid-co-poly[β-amino esters]) (MPEG-β-[PLA-co-PAE]) and doxorubicin (DOX) selected as the model drug, and some results have been achieved.…”

Section: Zhang Et Almentioning

confidence: 99%

Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery

Zhang¹,

Xiong²,

Sun³

et al. 2014

IJN

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A novel amphiphilic triblock pH-sensitive poly( β -amino ester)- g -poly(ethylene glycol) methyl ether-cholesterol (PAE- g -MPEG-Chol) was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthesized copolymer was determined with proton nuclear magnetic resonance and gel permeation chromatography. The grafting percentages of MPEG and cholesterol were determined as 10.93% and 62.02%, calculated from the area of the characteristic peaks, respectively. The amphiphilic copolymer was confirmed to self-assemble into core/shell micelles in aqueous solution at low concentrations. The critical micelle concentrations were 6.92 and 15.14 mg/L at pH of 7.4 and 6.0, respectively, obviously influenced by the changes of pH values. The solubility of pH-responsive PAE segment could be transformed depending on the different values of pH because of protonation–deprotonation of the amino groups, resulting in pH sensitivity of the copolymer. The average particle size of micelles increased from 125 nm to 165 nm with the pH decreasing, and the zeta potential was also significantly changed. Doxorubicin (DOX) was entrapped into the polymeric micelles with a high drug loading level. The in vitro DOX release from the micelles was distinctly enhanced with the pH decreasing from 7.4 to 6.0. Toxicity testing proved that the DOX-loaded micelles exhibited high cytotoxicity in HepG2 cells, whereas the copolymer showed low toxicity. The results demonstrated how pH-sensitive PAE- g -MPEG-Chol micelles were proved to be a potential vector in hydrophobic drug delivery for tumor therapy.

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“…The hydrophobic drugs can be encapsulated in micelles to function in the acidic state of TME. The typical doxorubicin-encapsulated pH responsive polymeric micelles have been observed to release the maximum of 70% of the target molecule or drug at the pH level of 6.4, while it stops at the pH of 7.4 [41].The ability of this polymeric micelles to detect the antitumor region had been experimented in vivo.…”

Section: Ph Levelmentioning

confidence: 99%

Theranostic Probes for Targeting Tumor Microenvironment: An Overview

Sikkandhar

Nedumaran

Ravichandar

et al. 2017

Preprint

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Long gone was the time when tumors were thought to be insular masses of cells, residing independently at specific sites in an organ. Now, researchers gradually realize that tumors interact with the extracellular matrix (ECM), blood vessels, connective tissues and immune cells in their environment, which is now known as the tumor microenvironment (TME). It is found that the interactions between tumors and their surrounding promote tumor growth, invasion and metastasis. The dynamics and diversity of TME cause the tumors to be heterogeneous and thus pose a challenge for cancer diagnosis, drug design and therapy. As TME is significant in enhancing tumor progression, it is vital to identify the different components in the TME. This review explores how different factors in the TME supply tumors with the required growth factors and signaling molecules to proliferate, invade and metastasis. We also examine the development of TME-targeted nanotheranostics over the recent years for cancer therapy, diagnosis and anticancer drug delivery system. This review further discusses the limitations and future perspective of nanoparticle based theranostics when used in combination with current imaging modalities like Optical Imaging, Magnetic Resonance Imaging (MRI) and Nuclear Imaging (PET and SPECT).

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Tumoral acidic extracellular pH targeting of pH-responsive MPEG-poly(β-amino ester) block copolymer micelles for cancer therapy

Cited by 283 publications

References 28 publications

Suppression of Human Solid Tumor Growth in Mice by Intratumor and Systemic Inoculation of Histidine-Rich and pH-Dependent Host Defense–like Lytic Peptides

Suppression of Human Solid Tumor Growth in Mice by Intratumor and Systemic Inoculation of Histidine-Rich and pH-Dependent Host Defense–like Lytic Peptides

Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery

Theranostic Probes for Targeting Tumor Microenvironment: An Overview

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Tumoral acidic extracellular pH targeting of pH-responsive MPEG-poly(β-amino ester) block copolymer micelles for cancer therapy

Cited by 283 publications

References 28 publications

Suppression of Human Solid Tumor Growth in Mice by Intratumor and Systemic Inoculation of Histidine-Rich and pH-Dependent Host Defense–like Lytic Peptides

Suppression of Human Solid Tumor Growth in Mice by Intratumor and Systemic Inoculation of Histidine-Rich and pH-Dependent Host Defense–like Lytic Peptides

Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for&nbsp;anticancer drug delivery

Theranostic Probes for Targeting Tumor Microenvironment: An Overview

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Product

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Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery