Search

The physicochemical properties of camptothecin (CPT) limit its clinical application. To maximize drug efficacy, a novel intelligent prodrug delivery nanoplatform with a tumor microenvironment-cleavable core crosslinking strategy was proposed based on a phenylboronic acid (PBA) modified polyethylene glycol (PEG)-polyglutamic acid (PGlu) polymer with disulfide-bonded CPT, called PBA-PEG-P(Glu-co-GlussCPT). The fabricated nanoplatform was a spherical micelle that could withstand dilution and carry a large number of therapeutic molecules to the tumor tissues, thereby minimizing premature drug release. Moreover, the nanoplatform release 6.2 ± 0.62, 12.4 ± 1.8, 46.7 ± 0.33, and 79.2 ± 1.58% of CPT after incubation in 0.02, 1, 5, and 10 mM dithiothreitol for 24 h, respectively, exhibiting good reduction-sensitivity. Moreover, the nanoplatform exhibited significant antiproliferative activity against tumor cells. In addition, with PBA modification, the nanoplatform demonstrated enhanced endocytosis efficiency. This prodrug nanoplatform also exhibited significant in vivo antitumor efficacy on both murine and human hepatoma xenograft models, without showing significant systemic toxicity but demonstrating good biocompatibility. In other words, this novel intelligent prodrug delivery nanoplatform with tumor microenvironment-cleavable core crosslinking strategy and active targeting strategy based on prodrug polymer PBA-PEG-P(Glu-co-GlussCPT) demonstrated multiple functions and significant potential for antitumor drug delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A carrier-free and reduction-degradable Janus prodrug, termed as CPT-SS-GEM, was fabricated by redox-sensitive disulfide bond linked gemcitabine and camptothecin. This amphiphilic prodrug showed high drug loading capacity, 42.6% of CPT and 32.2% of GEM, respectively. Benefiting from its amphiphilic property, CPT-SS-GEM prodrug could self-assemble into Janus nano-prodrug in water without aid of any excipient. The morphology of the nano-prodrug was spherical particle confirmed by TEM. The rapid drug release from the nano-prodrug proceeded in a reduction-dependent manner, more than 90% of the native CPT and GEM were released in the mimic microenvironment of tumor cells (pH 6.5 PBS containing 2 mM DTT) within a period of 3 h. The concurrent and ratio-metric release of CPT and GEM endowed the Janus nano-prodrug CPT-SS-GEM with pronounced in vitro synergistic antiproliferative effect in multiple cancer cell lines when the inhibition rate of cancer cell proliferation exceeded 50%, including A549, NCI-H460, HCT116, HT-29, and MCF-7/ADR. The combination index values showed as followings, 1.04-0.4 (A549), 0.24-0.60 (NCI-H460), 0.42-0.16 (HCT116), 1.98-0.15 (HT-29), 0.36-0.19 (MCF-7/ADR). Taken together, the carrier-free, redox-sensitive Janus nano-prodrug CPT-SS-GEM is a promising candidate as synergistic combination of chemotherapeutics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Surface modification of nanoparticles with poly (ethylene glycol) (PEG) shows poor cellular uptake, although it affords long circulation time and passive targeting potential to the tumor tissue. In this research, poly(ethylene glycol) shell-sheddable nanomicelle prodrug of camptothecin (CPT) was developed, in order to enhance the cellular uptake ability, achieve the passive targeting potential to tumor tissue and long circulation time, and to improve the stability of CPT in aqueous media. Firstly, the five-member rings in poly (L-succinimide) (PSI) were successively opened by the amino terminated disulfide-linked poly (ethylene glycol) monomethyl ether (mPEG-SS-NH2) and 6-aminocaproic acid to produce the graft copolymer of mPEG-SS-NH-g-PHAsp. And then, the resultant prodrug of mPEG-SS-NH-g-PHAsp-CPT was obtained by the esterification between carboxylic groups of mPEG-SS-NH-g-PHAsp and 20-OH of CPT. The prodrug was able to form spherical micelles in aqueous media because of its amphiphilic nature with average particle size of about 100nm measured by dynamic light scattering (DLS), suggesting its passive targeting potential to tumor tissue. Due to the detachment of PEG shell in the presence of dithiothreitol (DTT), the nanomicelle showed a tendency to aggregation, intense release of CPT, and enhanced cellular uptake ability. Also, the mPEG-SS-NH-g-PHAsp-CPT nanomicelle effectively protected the active lactone ring of CPT from hydrolysis under physiological condition. Compared with free CPT, mPEG-SS-NH-g-PHAsp-CPT nanomicelle showed essentially decreased cytotoxicity against L929 cell line in 24h, especially at high dosage, indicating its great potential as tumor tissue targeted prodrug., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Abstract: This research is aimed to develop a nanomicelle delivery system in order to enhance the solubility and stability of camptothecin (CPT) in aqueous media. In this case, α,β-poly[(N-carboxybutyl)-l-aspartamide] (PBAsp)–CPT was conjugated by the esterification between PBAsp and 20-OH of CPT, and hence used to fabricate nanomicelles with a particle size between the pore size of blood capillary in normal tissue and that in tumor tissue. It was worthy of note that the drug-loaded system of PBAsp–CPT nanomicelle improved the solubility and stability of CPT in aqueous media. However, with an increase of the CPT loading in PBAsp–CPT, the solubility sharply decreased. Meanwhile, the sizes of PBAsp–CPT nanomicelles showed a tendency of increase. Moreover, the drug release of PBAsp–CPT nanomicelles displayed a linear sustaining profile, and hence resulted in the essential decrease of cytotoxicity to L929 cell line. The assembled nanomicelles based on the PBAsp–CPT conjugates showed a great potential as polymer prodrug of tumor therapy, and the controlled nano-scale might achieve the passive tumor targeting. [Copyright &y& Elsevier]