pH-Sensitive Nanomicelles for Controlled and Efficient Drug Delivery to Human Colorectal Carcinoma LoVo Cells

PLOS ONE, Dec 2019

Background The triblock copolymers PEG-P(Asp-DIP)-P(Lys-Ca) (PEALCa) of polyethylene glycol (PEG), poly(N-(Nā€™,Nā€™-diisopropylaminoethyl) aspartamide) (P(Asp-DIP)), and poly (lysine-cholic acid) (P(Lys-Ca)) were synthesized as a pH-sensitive drug delivery system. In neutral aqueous environment such as physiological environment, PEALCa can self-assemble into stable vesicles with a size around 50-60 nm, avoid uptake by the reticuloendothelial system (RES), and encase the drug in the core. However, the PEALCa micelles disassemble and release drug rapidly in acidic environment that resembles lysosomal compartments. Methodology/Principal Findings The anticancer drug Paclitaxel (PTX) and hydrophilic superparamagnetic iron oxide (SPIO) were encapsulated inside the core of the PEALCa micelles and used for potential cancer therapy. Drug release study revealed that PTX in the micelles was released faster at pH 5.0 than at pH 7.4. Cell culture studies showed that the PTX-SPIO-PEALCa micelle was effectively internalized by human colon carcinoma cell line (LoVo cells), and PTX could be embedded inside lysosomal compartments. Moreover, the human colorectal carcinoma (CRC) LoVo cells delivery effect was verified in vivo by magnetic resonance imaging (MRI) and histology analysis. Consequently effective suppression of CRC LoVo cell growth was evaluated. Conclusions/Significance These results indicated that the PTX-SPION-loaded pH-sensitive micelles were a promising MRI-visible drug release system for colorectal cancer therapy.

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pH-Sensitive Nanomicelles for Controlled and Efficient Drug Delivery to Human Colorectal Carcinoma LoVo Cells

et al. (2014) pH-Sensitive Nanomicelles for Controlled and Efficient Drug Delivery to Human Colorectal Carcinoma LoVo Cells. PLOS ONE 9(6): e100732. doi:10.1371/journal.pone.0100732 pH-Sensitive Nanomicelles for Controlled and Efficient Drug Delivery to Human Colorectal Carcinoma LoVo Cells Shi-Ting Feng" 0 Jingguo Li" 0 Yanji Luo" 0 Tinghui Yin 0 Huasong Cai 0 Yong Wang 0 Zhi Dong 0 Xintao Shuai 0 Zi-Ping Li 0 Stephanie Filleur, Texas Tech University Health Sciences Center, United States of America 0 1 Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University , Guangzhou , China , 2 PCFM Lab of Ministry of Education, School of Chemistry and Chemical Engineering, Sun Yat-Sen University , Guangzhou , China , 3 Department of Medical Ultrasonic, The Third Affiliated Hospital of Sun Yat-Sen University , Guangzhou , China Background: The triblock copolymers PEG-P(Asp-DIP)-P(Lys-Ca) (PEALCa) of polyethylene glycol (PEG), poly(N-(N',N'diisopropylaminoethyl) aspartamide) (P(Asp-DIP)), and poly (lysine-cholic acid) (P(Lys-Ca)) were synthesized as a pH-sensitive drug delivery system. In neutral aqueous environment such as physiological environment, PEALCa can self-assemble into stable vesicles with a size around 50-60 nm, avoid uptake by the reticuloendothelial system (RES), and encase the drug in the core. However, the PEALCa micelles disassemble and release drug rapidly in acidic environment that resembles lysosomal compartments. Methodology/Principal Findings: The anticancer drug Paclitaxel (PTX) and hydrophilic superparamagnetic iron oxide (SPIO) were encapsulated inside the core of the PEALCa micelles and used for potential cancer therapy. Drug release study revealed that PTX in the micelles was released faster at pH 5.0 than at pH 7.4. Cell culture studies showed that the PTX-SPIOPEALCa micelle was effectively internalized by human colon carcinoma cell line (LoVo cells), and PTX could be embedded inside lysosomal compartments. Moreover, the human colorectal carcinoma (CRC) LoVo cells delivery effect was verified in vivo by magnetic resonance imaging (MRI) and histology analysis. Consequently effective suppression of CRC LoVo cell growth was evaluated. Conclusions/Significance: These results indicated that the PTX-SPION-loaded pH-sensitive micelles were a promising MRIvisible drug release system for colorectal cancer therapy. - Funding: This work was supported by: 1. National Natural Science Foundation of China (81000626); 2. Zhujiang Scientific and Technological New Star Foundation (2012J2200084); 3. Fundamental Research Funds for the Central Universities (10ykpy11); 4. Natural Science Foundation of Guangdong Province (S2013010016004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. " These authors contributed equally and are co-first authors on this work. Colorectal carcinoma (CRC) is a malignant disease on the rise. It is the second most common cancer in general and the most common of the gastrointestinal tract cancers [1]. It is currently the second leading cause of death in both female and male patients. Surgical resection is preferred as a curative treatment in early stages of CRC while drug therapy becomes the main preference in advanced or recurrent stages. [2]. In the past decades, a large number of anticancer drugs were identified, although most of them are hydrophobic and poorly soluble in aqeous. Paclitaxel (PTX) is one of the most potent anticancer drugs that can be used in the therapy of several solid tumors. Taxol is one of the formulations of PTX with stratified aqueous solubility and lower toxicity [3,4]. Nevertheless, the clinical use of PTX is limited by high toxicity and low bioavailability [5]. PTX has been found to have side effects including neurotoxicity, hypersensitivity reactions, cardiotoxicity, and nephrotoxicity [6]. Moreover, for PTX, it has been found that the concentration of drug in tumor is rather low. Its use has remained limited due to this unsatisfactory therapeutic efficacy [7]. In comparison, nanoparticles, such as cationic polymers and cationic peptides loaded with anti-tumor drugs, have potential to overcome these shortcomings. These various carriers had been widely studied for targeted tumor therapies. In fact, the release of a drug in plain carriers usually lasts for days or even weeks. Even if effective delivery to tumor tissue and cells is achieved, it is still difficult to achieve an ideal therapeutic effect and reduce the probability of drug resistance [8]. As a result, the amount of released drug is a key for chemotherapeutic agents to efficiently kill the cancer cells and studies involving rapid and adequateh intracellular drug release from nanocarriers are of particular importance at present. In recent years, nanocarriers with a triggered release mechanism have been developed (...truncated)


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Shi-Ting Feng, Jingguo Li, Yanji Luo, Tinghui Yin, Huasong Cai, Yong Wang, Zhi Dong, Xintao Shuai, Zi-Ping Li. pH-Sensitive Nanomicelles for Controlled and Efficient Drug Delivery to Human Colorectal Carcinoma LoVo Cells, PLOS ONE, 2014, 6, DOI: 10.1371/journal.pone.0100732