Cisplatin Loaded Poly(L-glutamic acid)-<I>g</I>-Methoxy Poly(ethylene glycol) Complex Nanoparticles for Potential Cancer Therapy: Preparation, <I>In</I> <I>Vitro</I> and <I>In Vivo</I> Evaluation

Abstract

A series of novel polypeptide-based graft copolymer poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol) (PLG-gmPEG) was synthesized through a Steglich esterification reaction of PLG with mPEG. The structure of the copolymers was confirmed by nuclear magnetic resonance spectra (NMR) and gel permeation chromatography (GPC). MTT assay demonstrated that the PLG-g-mPEGs had good cell compatibility. The unreacted carboxyl groups of the PLG-g-mPEGs were used to complex cisplatin to form polymer-metal complex nanoparticles (CDDP/PLG-g-mPEG) for cancer therapy. The average hydrodynamic radius of the CDDP/PLG-g-mPEG nanoparticles was in the range of 14-25 nm, which was beneficial for solid tumor targeting delivery. A sustained release without initial burst was achieved for the CDDP/PLG-gmPEG nanoparticles, indicating that the CDDP-loaded nanoparticles had great potential to suppress the drug release in blood circulation before the nanoparticles had arrived at targeting tumors. The CDDP/PLG-g-mPEG nanoparticles showed a much longer blood retention profile as compared with the free CDDP. This indicated that the CDDP-loaded nanoparticles had much more opportunity to accumulate in tumor tissue by exerting the EPR effect. In vitro tests demonstrated that the CDDP/PLG-g-mPEG nanoparticles could inhibit the proliferation of HeLa, MCF-7 and A549 cancer cells. At equal dose (4 mg kg −1 ), the CDDP/PLG-g-mPEG nanoparticles showed comparable in vivo antitumor efficacy and significantly lower systemic toxicity as compared with free cis-Diaminedichloroplatinum (cisplatin, CDDP) in MCF-7 tumor bearing mice. These suggested that the CDDP/PLG-g-mPEG nanoparticle drug delivery system had a great potential to be used for cancer therapy.

<p>Design of a Novel Theranostic Nanomedicine (III): Synthesis and Physicochemical Properties of Tumor-Targeting Cisplatin Conjugated to a Hydrophilic Polyphosphazene</p>

“…The overall releasing pattern and total accumulated amount of platinum released at pH 5 are very similar to the above results at pH 7. It is known that cisaconitic acid may be used as an acid-cleavable linker 12 but it seems not working in the present system for an unclear reason. 14,15 However, such a result is in consistent with the following xenograft results displaying that double dose of Polycisplatin exhibits almost the same efficacy at the double dose of cisplatin based on platinum metal.…”

“…For example, Kataoka group 5 incorporated cisplatin into polymeric micelles formed from a block copolymer composed of polyethylene glycol and poly(glutamic acid) (NC-6004), and Shen et al 6 prepared a cisplatin-loaded nanoparticles from PDEA (poly [2-(N,N-diethylamino) ethyl methacrylate]. There are many other attempts to deliver cisplatin by using polymeric micelles, 7,8 microspheres or nanoparticles [9][10][11][12][13] which are designed to take advantage of the enhanced permeability and retention (EPR) effect to target the tumor tissue for efficient delivery of the anticancer agent. Among the above several attempts, the long-circulating polymeric micelles NC-6004, liposomal cisplatin formulations SPI-077 and L-NDDP entered clinical trials.…”

C60 fullerene enhances cisplatin anticancer activity and overcomes tumor cell drug resistance

“…Drug resistance mechanisms analyzed in this work, namely Bax and p53 protein deletions as well as overexpression of drug resistance proteins Pgp and MRP-1, are among the most prominent and widespread factors in clinical therapy failure [51,52]. Therefore, the development of novel drug delivery systems, able to increase the efficacy of anticancer drugs and to circumvent resistance acquirement remains an extremely important task of modern pharmacology and medicine [7][8][9]. Reports of numerous groups working on the improvement of Cis therapy have already shown that several compounds possess these unique properties.…”

“…Moreover, conjugation of dichloro (1,2diaminocyclohexane) platinum(II) on nanoparticles coated with hyaluronic acid led not only to increase of its bioavailability, but also to effective circumvention of drug resistance of tumor cells to chemotherapy [7]. Therefore, novel nanocarriers should not only significantly lower the negative side effects of specific chemotherapeutic agents, but also enhance their anticancer activity [8,9].…”

Polymeric nanostructured materials for biomedical applications

“…The most commonly chosen hydrophobic blocks include poly(propylene oxide) (PPO), biodegradable aliphatic polyesters (PLA and PLGA), and poly(amino acid)s (e.g. PGA and PAA), which can segregate and form micellar cores in the aqueous environment, where the segregation process is driven by a combination of physical interactions, including hydrophobic and electrostatic interactions, metal complexation, and hydrogen bonding[66,326,328,346,[348][349][350][351][352][353][354][355].The hydrophobic core can serve as the sustained release reservoir of bioactive LMW drugs (e.g., antitumor drugs), whereas the hydrophilic shell can stabilize the hydrophobic core and make the micelle a stable vehicle for i.v. administration.…”