Poly(α-L-glutamic acid)-Based Nanomaterials for Drug Delivery: History
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Contributor:
Il Kim
,
Zhang Yu
,
Wenliang Song
,
,
Deng-Guang Yu

Poly(α-L-glutamic acid) (PGA) is a class of synthetic polypeptides composed of the monomeric unit α-L-glutamic acid. Owing to their biocompatibility, biodegradability, and non-immunogenicity, PGA-based nanomaterials have been elaborately designed for drug delivery systems.

  • cancer therapy
  • drug delivery system
  • nanomaterials
  • prodrugs
  • poly(α-L-glutamic acid)

1. Introduction

Cancer is one of the leading causes of death in humans. Although chemotherapy has gained enormous achievements in cancer treatment, the non-specific drug distribution-induced systemic side effects of anticancer drugs are still a Gordian knot [1][2]. Unremitting efforts have been made in the development of novel therapeutic regimens for a satisfactory curative effect [3][4][5][6][7]. Nanomaterials based on the incorporation of small molecule cancer drugs into the biocompatible polymers have attracted considerable attention because they can precisely deliver drugs to sites of action [8][9][10][11].
Poly(α-L-glutamic acid) (PGA) is a kind of synthetic polypeptide containing the monomeric unit α-L-glutamic acid [12]. Owing to their inherent properties including biocompatibility, biodegradability, non-immunogenicity, and till date, PGA-based nanomaterials have been extensively applied in biomedical fields such as cancer therapy, wound healing, medical devices, bio-sensing, and tissue regeneration [13][14][15]. Traditionally, PGAs are chemically synthesized by the ring-opening polymerization (ROP) of the γ-protected L-glutamate N-carboxyanhydrides (LG NCAs) [16][17]. After post deprotection, the bare carboxyl groups in each repeat unit of PGAs provide the high functionality for the chemical conjugation of molecules [18]. On the other hand, the water-soluble PGA moieties can serve as the hydrophilic building blocks of amphiphilic polymeric nanocarriers to physically entrap the therapeutic agents [19]. The pKa of the pendent carboxyl side chains of PGAs is around 4.5. PGAs are negatively charged under physiological conditions; however, the pendent carboxyl side chains are positively charged when subject to acidic microenvironments, such as extracellular tumors (pH 6.8) and endosomes (pH 5.5) [12][20]. In addition, the ionic alternation transforms PGA moieties from hydrophilic and random-coiled conformation into hydrophobic and α-helical conformation, facilitating the stimuli-release of preloading.

2. PGA-Based Nanomaterials as DOX Delivery Systems

DOX, an anthracycline antibiotic, is the most prevalently used chemotherapeutic drug for the treatment of various cancers, such as cancers of the breast, stomach, lung, thyroid, ovary, and bladder [21][22][23]. DOX can penetrate the endonuclear DNA and suppress DNA replication, leading to cell apoptosis. Nevertheless, the short blood circulation period and inevitable adverse effects including cardiotoxicity, nephrotoxicity, and myelosuppression significantly reduce its therapeutic outcomes [24][25]. Chemical conjugation and physical encapsulation of DOX to biodegradable PGA present a viable method to enhance its bioavailability and reduce side effects [26][27][28][29][30][31]. Traditionally, hydrophobic drug loading procedures contain the dissolution of the amphiphilic polymers and small molecular drugs in organic solvents, and the subsequent removal of the organic solvents by solvent evaporation or dialysis [32]. Unlike conventional encapsulation procedures, PGA-based anionic polymers are specifically complex, with cationic DOX through electrostatic interactions, omitting the use of detrimental organic solvents and achieving approximately 100% loading efficacy [33]. Chen et al. designed a poly(ethylene glycol)-b-poly(α-L-glutamic acid) (mPEG-b-PGA) nanocarrier entrapped with DOX through electrostatic interaction and an intermolecular hydrophobic stack[34]. The PEG segments were mainly oriented at the outer periphery of nanocarriers preventing the adsorption of protein and identification by the phagocyte system, whereas the PGA segments were primarily situated in the aqueous interior of nanocarriers warranting high loading of DOX. Cellular uptake tests suggested that the resultant nanocarriers were up-taken into A549 cells via endocytosis. Subsequently, the endosomal acidic condition triggered the destabilization of nanocarriers, resulting in the release of DOX to cytoplasm. Because of the enhanced permeability and retention (EPR) effect, the resultant ionomer complex exhibited a prolonged blood circulation period, decreased systemic toxicity, and enhanced therapeutic efficacy in the treatment of nonsmall cell lung cancer. To enhance the stability of PGA-based nanocarriers, hydrophobic units such as leucine (Leu) and phenylalanine (Phe) are incorporated to construct three monomeric units of the copolypeptides [33][35].
Pioneered by Kataoka, who firstly conjugated DOX to the pendent carboxyl acids of poly(ethylene glycol)-b-poly(L-aspartate) (mPEG-b-PLA), chemical conjugation of DOX onto polypeptides also have attracted considerable attention in cancer therapy [36][37][38][39][40]. Xiao et al. developed a pH and redox dual-stimuli poly(ethylene glycol)-b-poly(γ-propargyl-L-glutamate) (mPEG-b-PPLG) prodrug nanogel by simultaneously coordinating DOX through an acid-labile hydrazone bond and cross-linking with a redox sensitive 2-azidoethyl disulfide bond via one-step “click chemistry” [41]. The resultant mPEG-b-PPLG prodrug nanogels exhibited elevated stability during blood circulation and stimuli release of DOX in tumor cells. Recently, Vicent also developed a family of PGA-based combination conjugates bearing chemotherapeutic drug (DOX) and aromatase inhibitors (aminoglutethimide, AGM) for the treatment of breast cancer[42][43]. DOX was directly bound to the carboxyl groups of PGA either by amide bond or acid-labile hydrazone bond, whereas AGM was incorporated into PGA via a library of glycine (Gly) linkages (such as Gly linker, Gly–Gly linker, and Gly-Phe-Leu-Gly linker), which are readily cleaved by protease Cathepsin B. The controllable release of DOX and AGM in intracellular microenvironments enabled the superior therapeutic effects on primary tumor growth, apoptosis of cancer cells, and lung metastasis. PGA-based biomaterials provide a superior nanoplatform for small molecular drugs and achieved an enhanced therapeutic effect in tumor therapy. These pioneering examples pave the way for chemical conjugation and physical encapsulation of chemotherapeutics by using PGA-based nanomaterials.

3. PGA-Based Nanomaterials as Pt Drugs Delivery Systems

Hydrophobic Pt drugs like cisplatin (CDDP), carboplatin, and oxaliplatin have become promising candidates for the treatment of malignant tumors [44][45][46]. Pt drugs can contact DNA to disrupt its replication and eventually result in the apoptosis of tumor cells [47], whereas extremely low solubility and severe side effects significantly reduce its tumor therapeutic efficacy [48][49]. To overcome this restriction, a variety of polymeric nanocarriers have been explored to entrap Pt drugs [50][51]. Kataoka et al. firstly attempted to conjugate CDDP to the pendent carboxyl groups of mPEG-b-PLA [52]. To note, a series of Pt drugs coordinated mPEG-b-PGA, such as NC-6004 and NC-4016, have been assessed in phase III clinical trials for patients with advanced or metastatic pancreatic cancer [53][54]. The hydrophilic shell endows both NC-6004 and NC-4016 with a long blood circulation period and increased drug accumulation in the targeted tumor tissues through EPR effect.
Even so, the resistance and internalization dilemmas like free cisplatin still exist. A major reason lies in the steric repulsion of the dense PEG shell, which inevitably results in the PEGylated Pt drugs-conjugated nanocarriers bypassing the tumor tissues or failing to be phagocytosed by the tumor tissues [55]. To overcome these obstacles, chemical and physical dePEGylation induced by particular tumor microenvironments, such as pH, redox, and enzyme, have been deeply explored [56][57]. More recently, Xu et al. fabricated two types of poly(L-glutamic acid)-cisplatin (PGA-Pt) nanocarriers with cleavable PEG, which are sensitive to extracellular pH (pHe) and matrix metalloproteinases-2/9 (MMP-2/9) [58]. The pHe-sensitive 2-propionic-3-methylmaleic anhydride (CDM)-derived amide linkage and MMP-2/9-responsive cleaved peptide PLGLAG were designed to bridge PGA and PEG, generating pHe-sensitive PEG-pHe-PGA and MMP-2/9-sensitive PEG-MMP-PGA. CDDP was coordinated with the corresponding graft copolymers, yielding the polymer–metal complexed nanoplatforms, PEG-pHe-PGA-Pt and PEG-MMP-PGA-Pt. Cellular uptake assays revealed that PEG-PGA-Pt exhibited the limited cell internalization in SKOV3 cells due to the steric repulsion between the dense PEG shell and cell membrane. Conversely, PEG-pHe-PGA-Pt exhibited a significantly higher cell internalization in SKOV3 cells due to the dePEGylation triggered by the cleavage of the CDM-derived amide bond. The endosomal pH condition induced the instability of the bare PGA-Pt core, leading to the increased release of CDDP into cytol. Compared to the traditional PEG-PGA-Pt, the detachable PEG-pHe-PGA-Pt and PEG-MMP-PGA-Pt not only retained the prolonged circulation time, the pH and MMP detachable PEGylated PGA-Pt nanoformulations enabled the enhanced cell internalization toward the high-grade serous ovarian cancer, eventually leading to the up-regulated antitumor efficacy.
Tang et al. integrated the merits of the “receptor-mediated cellular uptake” and “multi-drug delivery” into one nanoformulation [59]. Docetaxel (DTX) and CDDP were co-encapsulated into the amphiphilic poly(L-glutamic acid)-g-α-tocopherol/polyethylene glycol (PGA-g-Ve/PEG) nanocarriers through hydrophobic and chelation interaction, followed by the periphery decoration of an avb3 integrin targeting peptide c(RGDfK). Thanks to the targeting c(RGDfK), DTX/CDDP co-encapsulated nanoformulation exhibited a synergistically increased accumulation rate and retention time in mouse melanoma cells. Folic acid (FA), an active targeting ligand, has also been extensively utilized for targeted CDDP delivery. Qiao et al. recently designed the CDDP-loaded maleimide-poly(ethylene oxide)114-b-poly(L-glutamic acid)12 (Mal-PEG114-b-PLG12) vesicles for the targeted delivery of CDDP to tumor sites [60]. CDDP complexed to PGA moieties induced the self-assembly of the copolymer into vesicular morphologies via the formation of a hydrophobic domain, while PEG blocks served as the corona and interior layer of the vesicular morphologies. The reactive maleimide groups on the vesicle periphery could conjugate with FA thiol, yielding an active targeted DDS, which presented distinctly high cellular uptake and desired cytotoxicity toward HeLa cells. Targeting agents enable the targeted CDDP delivery to tumor sites, yet the dedicated and complicated modification procedures also increase the potential system toxicity.

4. PGA-Based Nanomaterials as CPT Delivery Systems

As a topoisomerase I inhibitor, CPT which is derived from the Chinese tree Camptotheca acuminata, can induce a variety of tumor cell apoptosis [61][62][63][64]. Unfortunately, the relatively low aqueous solubility and pH-dependent lactone ring stability of CPT severely constrain its clinical application [65]. Towards this end, both Singer and Klein’s groups demonstrated that the water solubility and lactone ring stability could greatly be enhanced by the conjugation of CPT to the residing carboxylic acid of PGA [66][67]. Researchers have also combined CPT with other chemotherapeutic drugs for synergistic cancer treatment [68][69]. Xiao et al. developed a redox responsive nanoformulation via the self-assembly of poly(L-glutamic acid)-g-poly(ethylene oxide) (PGA-g-mPEG) based CPT conjugate and simultaneous entrapment of DOX by hydrophobic interaction[68]. CPT was linked to PGA-g-mPEG via a disulfide bridge which was readily detachable in a glutathione (GSH) environment. It was observed that the intracellular GSH concentration plays a decisive role in the release of DOX and CPT from nanoformulation. As proved by the flow cytometry and the cellular uptake tests, the acidic endo-lysosomal microenvironment induced the release of DOX, GSH in the cytoplasm, and cleaved the disulfides, releasing CPT from the resultant nanoformulation. The low combination index value (approximately ~0.3) substantiated the valid cancer cell apoptosis based on the nanoformulation co-loaded with CPT and DOX. A semisynthetic analog of CPT, 7-Ethyl-10-hydroxy camptothecin (SN38), has been approved by FDA for colorectal carcinoma therapy [70]. Recently, Tamaddon et al. prepared a double hydrophilic poly(2-ethyl 2-oxazoline) block poly (L-glutamic acid) (PEtOx-b-PGA) prodrug by coupling SN38 to the pendent carboxyl group of PGA [71]. Compared to free drugs, cell culture assays displayed a higher intracellular accumulation and at least four times more specific cytotoxicity than the coupled SN38 in the CT26 cell line. Moreover, the as-prepared SN38 conjugate exhibited outstanding anti-tumor activity and was significantly superior to commercial irinotecan, especially on advanced tumors with a reduced mortality rate of 2.5 times. All these studies suggest that CPT-derived topoisomerase I inhibitors can exert their tumor cell apoptosis effect in tumor therapy. Further efforts are needed to investigate the more detailed action mechanism of these nanoformulations.

5. PGA-Based Nanomaterials as VDA Delivery Systems

VDA can selectively modulate tumor vasculature and rapidly induce the shutdown of tumor blood vessels, leading to widespread tumor cell ischemic necrosis [72][73]. Combretastatin A4 (CA4) is a crucial agent for clinical cancer therapy. As a kind of microtubule depolymerizing agent, CA4 can attach to the colchicine adhering site of β-tubulin, resulting in cytoskeletal destabilization and morphological variation of the endothelial cell [74][75][76]. The poor aqueous solubility of CA4 is the greatest hindrance for the extensively clinical application. Tong et al. designed a polymeric CA4 conjugate via coordination of CA4 to poly(L-glutamic acid)-CA4 (PGA-CA4)[77]. Intra-tumor distribution experiments indicated that PGA-CA4 nanoconjugates were predominantly localized around tumor blood vessels due to the active targeting property of CA4. This enabled the long-term release of CA4 inside solid tumor cells. The gradually increased CA4 concentration around tumor blood vessels caused the steady tumor blood deprivation and effective tumor regression. Owing to the vascular-dependent distribution character, the obtained PGA-CA4 exhibited a long retention time in plasma and the murine colon C26 tumor cell compared to commercial combretastatin-A4 phosphate (CA4P). After a single administration, PGA-CA4 induced enduring angiorrhexis and tumor destruction in 72 h, leading to a tumor suppression rate of 74%.
However, several side effects, such as polarization induced by PGA-CA4, significantly restricted the antitumor activity. To this end, the same group also combined this nanomedicine with other antineoplastic agents for enhanced cancer therapy [78][79]. For instance, they utilized the phosphoinositide 3-kinase gamma isoform (PI3Kγ) selective inhibitors synergizing with PGA-CA4 to reduce the immunosuppressive effects[80]. The number of M2-like tumor-related macrophage obviously decreased while the cytotoxic T lymphocytes markedly improved due to PI3Kγinhibitor. Remarkably, the combination of PI3Kγ inhibitor and PGA-CA4 prevented the tumor growth and extended the mean survival time, significantly enhancing the tumor therapeutic efficacy. Even though CA4-conjugated nanocarriers effectively inhibited tumor growth and tumor proliferation, CA4 could not be tested by multispectral optoacoustic tomography and immunofluorescence assay, hindering the observation of the intra-tumor distribution of CA4.

6. PGA-Based Nanomaterials as Gas Molecule Delivery Systems

Mammalian tissues generate many kinds of gas molecules, such as nitric oxide (NO), carbon monoxide (CO), and sulfur dioxide (SO2), which play a transmitter role in a series of biological activities and regulate the biochemical or physiological processes in the human body [81]. Recently, gas therapy has become an emerging tumor therapeutic technique because there is no drug resistance, it has minimal side effects and there is no byproduct [82]. Numerous gas nanogenerators are designed to delivery and produce safe gas molecules for the treatment of tumors [83][84]. NO, is an endogenously generated radical gas molecule, involved in various physiological functions, such as cardiovascular homeostasis, neurotransmission, and immune response to infection and angiogenesis [85]. NO can modulate P-glycoprotein expression without multi-drug resistance at low dosages, while high concentrations of NO can damage DNA and mitochondria in solid tumors, leading to cell mortality [86]. Hong et al. fabricated (poly-L-lysine/poly-L-glutamic acid)n (PLL/PGA)n multilayer films with different thicknesses for controlled NO releasing [87]. By applying the layer-by-layer self-assembly approach, PLL and PGA were employed to construct the multilayer films via electrostatic interaction, where PLL served as the positively charged blocks and PGA acted as the negatively charged blocks. A proton-responsive NO donor, N-diazeniumdiolate, was loaded into (PLL/PGA)n multilayer films via a high pressure reaction under NO atmosphere. The as-obtained (PLL/PGA)n multilayer films displayed a continued NO releasing behavior, suggesting the controllable NO delivery for tumor treatment. SO2 has been recognized as a promising gasotransmitter for regulation of the cardiovascular system. Xiao et al. developed a polymeric GSH-responsive nanomedicine of SO2 to combat MCF-7 ADR human breast cancer cells in synergy with DOX [88][89]. N-(3-azidopropyl)-2,4-dinitrobenzenesulfonamide (AP-DNs), a small molecular generator of SO2, was coupled onto the pendent groups of methoxy poly(ethylene glycol)-block-poly (g-propargyl-L-glutamate) (mPEG-b-PPLG) copolymer via “click chemistry”, yielding the polymeric nanomedicine of SO2, mPEG-b-PLG (DNs). DOX was finally encapsulated into mPEG-b-PLG (DNs) nanomedicine via self-assembly. Upon GSH triggering, the obtained mPEG-b-PLG (DNs) nanomedicine simultaneously released SO2 and DOX, causing an enhancement of reactive oxygen species (ROS) in tumor tissue and synergistic anti-proliferation effects against MCF-7/ADR cells.

This entry is adapted from the peer-reviewed paper 10.3390/biom12050636

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