Applications of Polyethylene Glycols for Cancer Drug Delivery and Diagnostics
An Excerpt from: Hutanu D, Frishberg MD, Guo L, Darie CC (2014) Recent Applications of Polyethylene Glycols (PEGs) and PEG Derivatives. Mod Chem appl 2:132. doi: 10.4172/2329-6798.1000132
R&D efforts on novel applications for PEG derivatives, published in the first half of 2014, are focused in majority on drug delivery and targeted diagnostics, either via direct PEGylation of therapeutics [2,3,21,62–65]; or via PEG-containing vehicles, such as nanoparticles [64,65], liposomes [59], dendrimers [32,60], or micelles [57,58,61].Important parameters that influence the bioactivity of the PEGylated drugs include the length of the PEG chain, the PEGylation site, the linker chemistry, and the temperature selected for the PEGylation reaction. For example, heat treatment was shown to improve the bioactivity of C-terminally PEGylated staphylokinases, whereas an amyl linker for a 20 kDa PEG increased significantly the bioactivity of staphylokinases [62].The PEGylation of proteins is greatly influenced by the solvent used during the conjugation to the PEG. Peng et al. [22] discovered that organic solvents such as DMSO increase the degree of PEGylation, minimize the PEG hydrolysis, and decrease the PEGylation time for hydrophobic proteins such as G-CSF, compared to PEGylation in water phase. Selecting an organic solvent for hydrophobic proteins has the potential to reduce the cost of the reagents and the reaction times, parameters important for PEGylation processes on an industrial scale.Among the many improvements brought to therapeutics by PEGylation are the increased water solubility, improved stability, controlled release, extended drug half-life, and an enhanced PK/ PD (pharmacokinetic/pharmacodynamic) profile.PEGylation of therapeutic proteins occurs mainly on the N-terminal group, carbohydrates, sulfhydryl, and the aminoacids Thr, Cys, Asp, Glu Lys, His, Arg, Tyr, and Ser. In the course of the PEGylation of small molecule drugs, a multi-arm polyethylene glycol will bond multiple drug molecules, ensuring a high drug load and an enhanced drugrelease function [15]. As an example, increasing the molecular weight of the iRGD peptide by PEGylation prolonged the macromolecular extravasation and the overall drug penetration into tumors, and improved the pharmacokinetic profile of iRGD as compared to the unmodified peptide [21].PEG-containing vehicles for drug delivery such as liposomes [59], dendrimers [60], nanoparticles [64,65], or micelles [57,58,61] are valid alternatives to direct PEGylation of drugs.Mei et al. [59] developed a multistage liposome drug delivery system co-modified with RGD, TAT, a specific ligand and a penetrating peptide, containing a cleavable PEG that increased the stability and circulation time of the liposomes. Liposomes undergo passive extravasation to tumor tissues, where the dual ligands become exposed through controlled exogenous administration of reducing l-cysteine. Subsequently, RGD recognize integrins, commonly overexpressed on malignant tumors, and mediate the internalization in a synergistic effect with TAT, penetrating deep into avascular tumor spheroids.Another type of PEG containing vehicle, a multifunctional dendrimeric carrier was developed by Kong et al. [60] for targeted delivery of the hydrophobic anticancer drug 10-hydroxycamptothecin (10-HCPT). The dendrimers consisted of integrated hydrophobic C12 alkyl chains with polyethylene glycol chains, and c(RGDfK) ligands on the surface. The dendrimer-10- HCPT drug complex exhibited higher drug loading and stability, and increased water solubility when compared to free 10-HCPT drug. The dendrimer-drug complex showed a higher cytotoxicity towards 22RV1 cells that overexpress integrin αvβ3, and a lower cytotoxicity against MCF-7 cells with lower levels of integrin αvβ3, following selective internalization of the complex into carcinoma cells via integrin receptor mediated endocytosis.
Drug delivery via PEG-modified nanoparticles is described in several 2014 publications. Super paramagnetic iron oxide nanoparticles containing a self-assembled copolymer of reducible polyamidoamine (rPAA) with polyethylene glycol/dodecyl amine on the surface, were employed for Doxorubicin delivery for cancer therapy [30]. For drug delivery, the intercalating area between the alkyl grafts of reducible copolymers and the oleic acid layer on the surface of the nanoparticles stored the hydrophobic drug, while the PEG chains improved the dispersion of the nanoparticles in aqueous environment. Doxorubicin delivered via these nanoparticles inhibited successfully the growth of xenograft MDA-MB-231 breast tumors in mice.Drug encapsulation in maleimide-polyethyleneglycol- poly(d,l-lactic-coglycolide) particles (PEG-PLGA) was investigated for targeted drug delivery of Cisplatin [2]. The Cisplatin encapsulating particles were produced using a single step electrospray technique, and were further modified with a CD44 monoclonal antibody targeting the counterpart receptor. Cisplatin-encapsulating CD44-PEG-PLGA particles targeted efficiently CD44-overexpressed ovarian cancer cells, and exhibited an increased anti-proliferative ability at normal chemotherapy concentrations, as compared to the free form of Cisplatin.Polyethyleneglycol-poly (l-lactic-co-glycolic acid) nanoparticles were also employed for targeted drug delivery of Paclitaxel [64]. PEG-PLGA nanoparticles functionalized with an iNGR moiety presented the highest accumulation and deepest penetration at glioma sites. Paclitaxel-loaded iNGR-NP showed promising anti-angiogenesis activity and improved survival time for mice with intracranial glioma.Micellar drug delivery systems were explored by Xu et al. [63] for delivery of atorvastatin calcium (Ator). Delivery micelles consisted of amphiphilic copolymers of methoxy polyethylene glycol-s-s-vitamin E succinate (PSV). Ator-loaded PSV micelles showed good colloidal stability, high drug loading, and great encapsulation efficiency. The release of the Ator drug into the cytosol was facilitated by detachment of the PEG shell in the presence of high concentration of intracellular glutathione. The Ator-loaded micelles were shown to inhibit significantly the migration and invasion of 4T1 metastatic breast cancer cells.Dual drug delivery coupled with a targeted approach in a polypeptide-based micelle system was accomplished by Song et al. [58]. The micelle was composed of an amphiphilic copolymer prepared by grafting α-tocopherol and polyethylene glycol onto poly(lglutamic acid), while the surface of the micelles was modified with an αvβ3 integrin targeting peptide, c(RGDfK). The incorporation into micelles of two drugs, Docetaxel and Cisplatin, was accomplished via hydrophobic and chelation effects. The drugs co-delivered in micelles showed synergistic cytotoxicity, long circulation time, and enhanced internalization into mouse melanoma (B16F1) cells.Polymeric micelles have also been employed for diagnostic purposes as delivery vehicles for diagnostic reagents.As a first example, Kim et al. [57] developed pH-responsive polymeric micelles loaded with MRI contrast agents for use in cancer diagnostics. Self-assembled micelles made of amphiphilic block copolymers: methoxy polyethylene glycol-b-poly(lhistidine) and methoxy polyethylene glycol-b-poly(l-lactic acid)- diethylenetriaminopentaacetic acid dianhydride-gadolinium chelate, proved stable at physiological pH, but collapsible in acidic conditions due to protonation of imidazole groups. The destabilization of the micelles in the acidic tumoral environment allowed the preferential accumulation of the MRI contrast agent in the tumoral regions, enabling the detection of small tumors within minutes. As a second example, Guo et al. [61] reported the development of PEG-polyaspartamide micelles loaded with a photosensitizer (Ce6) and cyanine dye (Cypate), with a dual role, cancer diagnostics and cancer photo-therapy. Photosensitizerloaded micelles that also integrated a cyanine dye enabled localizing of the tumors via dual photoacoustic/near-infrared fluorescent imaging, and simultaneously induced photothermal damage to cancer cells by sequential synergistic photothermal /photodynamic therapy.
TABLE 1:
Polyethylene Glycol (PEG) Compound PEG Applications Reference
Biotin PEG SGA Ester, MW 3500 Cell PEGylation [26]
Methoxy PEG Amine, HCl Salt, MW 2000 Diagnostics [57]
4arm PEG Succinimidyl Carboxymethyl Ester, MW 40000 Drug delivery [24]
Maleimide PEG Amine, MW 3500 Drug delivery [2]
Maleimide PEG Hydroxyl, MW 3500 Drug delivery [58]
Maleimide PEG NHS Ester MW 1000 Drug delivery [59]
Maleimide PEG NHS Ester, MW 2000 Drug delivery [21]
Maleimide PEG NHS Ester, MW 3500 Drug delivery [59]
Maleimide PEG NHS Ester, MW 5000 Drug delivery [60]
Methoxy PEG Amine, MW 12kDa Drug delivery [61]
Methoxy PEG Amine, MW 20kDa Drug delivery [62]
Methoxy PEG Carboxyl, MW 3500 Drug delivery [32]
Methoxy PEG Carboxyl, MW 1000 Drug delivery [63]
Methoxy PEG NHS Ester, MW 5000 Drug delivery [60]
Methoxy PEG Propionaldehyde, MW 5000, MW 20kDa Drug delivery [62]
PEG Maleimide, MW 10000 Drug delivery [22]
PEG NHS Ester MW 5000 Drug delivery [59]
PEG Succinimidyl Carbonate, MW 10000 Drug delivery [22]
PEG Thiol, MW 5000 Drug delivery [59]
Amine PEG Carboxyl, HCl Salt, MW 5000 Drug delivery, Diagnostics [3]
t-Boc Amine PEG Amine, HCl Salt, MW 5000 Drug delivery, Diagnostics [3]
Amine PEG Carboxyl, MW 3500 Drug delivery, Nanoparticle PEGylation [64]
Methoxy PEG Amine, MW 3500 Drug delivery, Nanoparticle PEGylation [64]
List of References
For the full version of the review article published by JenKem Technology USA and Clarkson University please click visit the open source journal Modern Chemistry & Applications.
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