Research ArticleExperimental Studies

Poly(Alkyloxyethylene-Lactate Phosphate) for Delivery of Doxorubicin: Synthesis and Characterization

KANJI YOSHIKAWA, TERUKI NII, KOLIO TROEV, KIMIKO MAKINO and ISSEI TAKEUCHI
Anticancer Research April 2022, 42 (4) 1801-1811; DOI: https://doi.org/10.21873/anticanres.15656

Abstract

Background/Aim: Serious side effects are associated with the use of doxorubicin. Nanoparticles as carriers for anticancer drugs are useful for reducing side effects and improving therapeutic effects. In this study, a polymer for preparing doxorubicin-containing nanoparticles was developed. Using a novel strategy, a biodegradable poly(oxyethylene glycol lactate H-phosphonate) based on dimethyl H-phosphonate and poly(ethylene glycol)-lactate (PEG-lactate) was synthesized. Materials and Methods: Poly(hexadecanyloxyethylene - lactate phosphate) was obtained via chlorination of poly(oxyethylene glycol - lactate H-phosphonate) with trichloroisocyanuric acid and the addition of 1-hexadecanol. The polymer was characterized by 1H NMR and 31P NMR. Results: The results of 1H NMR and 31P NMR showed that the polymer was successfully synthesized, and the yield was 46.9%. Conclusion: Poly(hexadecanyloxyethylene - lactate phosphate) has potential as a drug carrier.

Key Words:

The majority of anticancer drugs used today have serious side effects due to their nonselective distribution in the body. The results in a non-selective attack to normal cells (1), which causes various side effects such as canker sore, hair loss, vomit, anemia, and leucopenia. A promising approach to improve some characteristics of low molecular weight drugs, already approved and used in clinical practice, as well as to impart new valuable properties is the macromolecular approach, i.e., application of appropriate polymers for drug immobilization through chemical conjugation or physical binding to a polymer chain. Over the past decades, polymeric micelles have drawn considerable interest because of their great potential in anticancer drug delivery and diagnostic imaging applications (2–4). Various drugs have been encapsulated into the hydrophobic core of polymeric micelles to treat various diseases (5–7). Polyphosphoesters (PPEs) are essential building blocks of life in nature. They determine life in the form of deoxyribonucleic (DNA) and ribonucleic acid (RNA), and as pyrophosphates with high-energy phosphate bonds, they store chemical energy in organisms. The biodegradable and biocompatible polyphosphoesters, a family of polymers including poly(alkylene H-phosphonate)s and their derived polyphosphates and polyphosphoamidates, are promising polymers for drug delivery (8–11). Amphiphilic poly(alkylalkylene phosphate)s –co - and graft copolymers have been synthesized by ring-opening polymerization of 5 or 6-membered cyclic esters of phosphoric acid (12–36). Amphiphilic co- and graft polymers based on polyphosphoesters and: poly(ethylene glycol) (12–16); poly(L-lactic acid) (17, 18); poly(ε-caprolactone) (19–29); poly(hydroxybutyrate (30); folic acid-paclitaxel (31); poly(ethylene oxide) –paclitaxel (32, 33); poly(ethylene glycol)-doxorubicin (34); poly[2-(dimethylamino)ethyl methacrylate] (35) and thiols (36) have been described and used as carriers of hydrophobic drugs. There are no data in the literature on amphiphilic polyphosphoesters prepared via the polycondensation process. As a process for the preparation of amphiphilic polyphosphoesters, polycondensation has great advantages compared to the polymerization process, namely: (i) different starting hydroxyl-containing compounds can be used; (ii) synthesis proceeds without a catalyst; (iii) no need for purification of the reaction product; (iv) degraded products can be designed in advanced; (v) copolymers can be obtained; (vi) commercially available starting monomers.

The synthesis of polyphosphoesters with lactic acid units in the main polymer chain is interesting from both scientific and industrial points of view. Lactic acid is involved in energy production in the body and has high biocompatibility (37). Therefore, we aimed to synthesize a biocompatible and biodegradable polymer by incorporating a biodegradable lactate moiety into poly(oxyethylene H-phosphonate). The main aim of this study was the preparation of polyphosphoesters containing lactic acid units in the main polymer chain and their use as a carrier of hydrophobic drugs.

Herein, we report the synthesis of (i) a new type of biodegradable multifunctional amphiphilic poly(oxyethylene glycol lactate H-phosphonate) based on dimethyl H-phosphonate and poly(ethylene glycol)-lactate (PEG-Lactate), which allows low molecular weight drugs to be chemically and physically immobilized, due to the presence of highly reactive P-H groups (11) and strong proton acceptor – P=O groups (Figure 1); (ii) the production of poly(hexadecanoyl oxyethylene glycol-lactate phosphate) via chlorination of poly(oxyethylene glycol lactate H-phosphonate) with trichloroisocyanuric acid in the presence of 1-hexadecanol. Poly(hexadecanoyl oxyethylene glycol-lactate phosphate) bears strong polar P=O groups in the repeating units. The phosphoryl group (P=O) is a suitable proton acceptor (about two orders of magnitude stronger as an acceptor than the C=O group) and forms strong hydrogen bonds with phenols and alcohols (38, 39).

Figure 1.
Figure 1.

Synthesis of poly(oxyethylene glycol lactate H-phosphonate).

Materials and Methods

Materials. Ethyl lactate (C5H10O3, purity >95.0%), Polyethylene glycol 600 (PEG600, HO(CH2CH2O)nH, nominal molecular weight: 600), Sodium methoxide (CH3ONa, purity ≥95.0%), acetonitrile, chloroform-d (CDCl3, purity ≥99.8%, containing 0.05 vol% TMS), 1-hexadecanol were purchased from FUJIFILM Wako Pure Chemical Corporation, Ltd. (Osaka, Japan). Dimethyl H-phosphonate (DMP, (CH3O)2P(O)H), trichloroisocyanuric acid (C3Cl3N3O3) were purchased from Sigma–Aldrich (St. Louis, MO, USA). Other chemicals were of the highest reagent grade commercially available. The precursor poly(oxyethylene polyethy-lene glycol-lactate (PEG-lactate) was obtained from ethyl lactate and polyethylene glycol, having a molecular weight of 600. Poly(oxyethylene glycol-lactate H-phosphonate) was obtained from dimethyl H-phosphonate and PEG-lactate. Poly(hexade-canyloxyethylene glycol-lactate phosphate) was then obtained from poly(oxyethylene glycol-lactate H-phosphonate), trichloroiso-cyanuric acid, and 1-hexadecanol.

Instrumentation. All 1H and 31P NMR spectra were recorded on an NMR system (JNM-AL400, JEOL Ltd., Akishima, Japan) operating at 400 MHz in CDCl3.

Synthesis of PEG-lactate. PEG-lactate was obtained from commercial Ethyl lactate and PEG600 (Figure 1). Before starting this reaction, PEG600 was azeotropically distilled with toluene, and ethyl lactate was vacuum distilled. PEG 600 (28.25 g, 4.71×10–2 mol) and ethyl lactate (8.34 g, 7.10×10–2 mol) were reacted with NaOMe (0.1 g, 0.0019 mol), as a catalyst, at 140°C in N2 at atmospheric pressure for 24 h. After the reaction, the pressure was reduced to remove ethanol that is a byproduct, and unreacted ethyl lactate. After reducing pressure for 3 h, the reaction was terminated by stopping the heating. The unpurified PEG-lactate was dissolved in 50 ml of chloroform, was added to 50 ml of purified water and shaken to extract hydrophilic NaOMe into the aqueous layer. The chloroform layer was collected, and magnesium sulfate was added to remove residual water. Chloroform was removed, and the residue was vacuumed overnight. Yield 68.6%. 13C{H}NMR (CDCl3), δ(ppm): 20.34, CH3CH; 61.64, HOCH2-; 64.40, CH3CH-; 66.72, -C(O)OCH2-; 68.83, -C(O)OCH2CH2O-; 70.28, HOCH2CH2O CH2-; 70.51, -(OCH2CH2O)-; 72.48, HOCH2CH2O-; 175.51, C=O.

Synthesis of poly(oxyethylene-lactate H-phosphonate). Poly (oxyethylene-lactate H-phosphonate) was obtained from commercial DMP and PEG-lactate (Figure 1). The total synthesis was carried out under an N2 atmosphere in a vacuum distillation setup. DMP (1.11 g, 1.01×10–2 mol) and PEG-lactate 4.00 g (5.95×10–3 mol) were reacted at 145°C in N2 at atmospheric pressure for 6 h. The reaction was kept at these conditions for 6 h and terminated after the temperature of the methanol vapors dropped down, and its distillation visibly stopped. The polymerization reaction was performed at the vacuum of 1 mmHg at elevated temperatures at 185°C for 6 h. The product obtained from the polycondensation of DMP with PEG-Lactate was a sticky solid and slightly yellow. 31P{H} and 31P NMR spectroscopy were used to determine the structure. Yield 85.1%. 31P{H}NMR spectrum (CDCl3) shows signals at δ, ppm, Integral intensity (II), content %: 10.60, II=1, 3%; 9.91, II=15.16, 46%; 9.24, II=5.10, 15.5%; 7.84, II=5.67, 17.2%; 7.28, II=4.54, 13.8%; 6.45, II=1.5, 4.5%. In 31P NMR spectrum signal at δ, ppm: 9.92, d quintet, 1J(P,H)=723.89 Hz, 3J(P,H)=8.58 Hz, - CH2OP(H)(O)OCH2; 9.24, dq, 1J(P,H)=725.83 Hz, 3J(P,H)=8.74Hz, - CH2OPH(O)OCH(CH3)-); 7.88, (Intensity 5.67) dt, 1J(P,H)=734.73 Hz, 3J(P,H)=8.58 Hz, -CH(CH3)OP(H)(O) OCH(CH3)-. The signal at 7.28 (Intensity 4.54) represents a multiplet.

Synthesis of poly(hexadecanyloxyethylene glycol-lactate phosphate). Poly(oxyethylene glycol-lactate chlorophosphate) was obtained from poly(oxyethylene glycol-lactate H-phosphonate) and trichloroisocyanuric acid (Figure 2). The entire synthesis was carried out under a N2 atmosphere. The solution of poly(oxyethylene glycol-lactate H-phosphonate) (3.75 g, 5.07×10−3 mol) in acetonitrile (20 ml) was added in one portion of tricholoisocyanuric acid solution (0.396 g, 1.69×10−3 mol) in acetonitrile (5 ml). The reaction mixture was kept at 40°C for 3 h. The byproduct isocyanuric acid was removed from the solution by filtration, and then the solution was added to 2.00 g of 1-hexadecanol and stirred at 70°C for 48 h. The residue of 1-hexadecanol was removed from the solution by filtration, and the solvent was removed by drying under reduced pressure overnight. The residue was dissolved in 5 ml of methanol. This solution was placed in a cellulose dialysis membrane [Molecular weight cut off (MWCO): 500 to 1,000], and the external solution was dialyzed against methanol for 24 h. After dialysis, the solvent was removed and dried under reduced pressure overnight to give the final product. Yield 46.9%. 31P {H} NMR spectrum [CDCl3, shows signals at δ, ppm, integral intensity (II), content %: 0.78, II=0.64, 6.2 %; 0.43, II=1.87, 18.12%; –0.21, II=4.51, 43,7%; –1.31, II=2.30, 22.3 %; –12.16, II=1.0, 9.7%].

Figure 2.
Figure 2.

Synthesis of poly(hexadecanyloxyethylene glycol-lactate phosphate).

Results

Synthesis of PEG-lactate. PEG-lactate was synthesized via a transesterification of PEG600 with ethyl lactate. The structure and composition of the reaction product were confirmed by 1H and 13C{H}NMR spectroscopy. In the 1H NMR spectrum (Figure 3), there is no signal for CH3CH2O protons at 1.32 ppm. This revealed that the reaction product did contain free ethyl lactate. The two doublets at 1.43 and 1.428 ppm in the 1H NMR spectrum can be assigned to CH3CH- protons. Obviously, poly(ethylene glycol-lactate) represents a racemic mixture of levo and dextro forms. The multiplet in the area 4.28 to 4.34 ppm can be assigned to CH3CH- and CH2CH2OC(O) protons. This signal for CH3CH-proton has to be a quartet, the one for CH2CH2OC(O) protons is a triplet but, as a result of overlapping, the signal appears as a multiplet. The yield of the poly(ethylene glycol.-lactate) was calculated using the integral intensities of CH3 and OCH2CH2 protons. The ratio of the number of protons of the methyl group of the lactating segment to the protons of PEG is 3:52. Therefore, the yield of poly(ethylene glycol - lactate) is quantitative. In the 13C{H}NMR spectrum (Figure 4), the signal at 14.21 ppm for CH3CH2O carbon atom disappears. Data from 13C{H} NMR spectroscopy confirm the structure of the reaction product.

Figure 3.
Figure 3.

1H NMR spectrum of the reaction product obtained from poly(ethylene glycol) 600 and ethyl lactate.

Figure 4.
Figure 4.

13C{H} NMR spectrum of the reaction product obtained from poly(ethylene glycol) 600 and ethyl lactate.

Synthesis of poly(oxyethylene-lactate H-phosphonate). Poly(oxyethylene glycol-lactate H-phosphonate) was synthesized via a conventional two-stage polycondensation technique reacting poly(ethylene glycol-lactate) with dimethyl H-phosphonate (Figure 1). The signals at 9.92, 9.24, 7.86 ppm in 31P{H}NMR spectrum (Figure 5) appear in (Figure 6) as a doublet of quintets, doublet of quartets, and doublet of triplets and must be assigned to the phosphorous atom with the following substituents: -CH2OP(O)(H)OCH2-; -OCH2P(O)(H) OCH(CH3); -(CH3)CHOP(O)(H)OCH(CH3)-, respectively. The presence of a doublet of quintets indicates that the molar ratio between starting monomers is unexpected. It can be explained by the big difference in the reactivity of primary and secondary hydroxyl groups. At the specific degree of completion of transesterification reaction the monotransesterified product I reacts with poly(ethylene glycol-lactate) (Figure 7).

Figure 5.
Figure 5.

31P{H} NMR spectrum of poly(oxyethylene glycol- lactate H-phosphonate).

Figure 6.
Figure 6.

31P NMR spectrum of poly(ethylene glycol- lactate H-phosphonate) in Figure 2.

Figure 7.
Figure 7.

Reaction of the monotransesterified product I with poly(ethylene glycol-lactate).

Synthesis of poly(hexadecanyloxyethylene glycol-lactate phosphate). Poly(hexadecanyloxyethylene glycol-lactate phosphate) was obtained in two stage (Figure 2). In the first stage, synthesis of poly(oxyethylene glycol-lactate chlorophosphate) proceeds via chlorination of poly(oxyethylene glycol-lactate H-phosphonate) with trichloroisocyanuric acid. In the second stage poly(oxyethylene glycol-lactate chlorophosphate) reacts with hexadecanol to produce poly(hexadecanyloxyethylene glycol-lactate phosphate). 31P {H} NMR spectrum (Figure 8) shows signals at 0.78, II=0.64, 6.2 %; 0.43, II=1.87, 18.12 %; –0.21, II=4.51, 43,7 %; –1.31, II=2.30, 22.3 %; –12.16, II=1.0, 9.7%. Based on the data from the integral intensities of the signals for phosphorus atoms of poly(oxyethylene glycol-lactate H-phosphonate) and poly(hexadecanylo-xyethylene glycol lactate phosphate), the signal at –0.21 ppm can be assigned to the following type of phosphorus atom -CH2O-P(O)[OCH2(CH2)14CH3]OCH2-; the one at -1.3 ppm to the -(CH3)CHOP(O) [OCH2(CH2)14CH3] OCH(CH3) and at 0.43 ppm to - OCH2P(O)[OCH2(CH2)14 CH3] OCH(CH3). The signal at -12 ppm can be assigned to pyrophosphate structure, the formation of which is possible due to the reaction of intermediate phosphorchloride (-CH2OP(O) (Cl)OCH2-) with the newly formed hydroxyphosphate groups (-CH2OP(O)(OH)OCH2-).

Figure 8.
Figure 8.

31P {H} NMR spectrum of poly(hexadecanyloxyethylene glycol lactate phosphate).

Discussion

A novel amphiphilic poly(oxyethylene glycol-lactate H-phosphonate) containing a lactate moiety was synthesized. The main polymer chain was built up of PEG 600 and lactate segments linked by phosphate moieties. PEG-lactate was prepared via transesterification of ethyl lactate with PEG 600. The reaction started with a nucleophilic attack of the hydroxyl group of PEG to the carbon atom of the carbonyl group, which is an electrophilic center. Then, based on PEG-lactate, poly(oxyethylene glycol lactate H-phosphonate) was synthesized via the conventional two-stage polycondensation technique. The first stage of the reaction was carried out at 145°C under a N2 atmosphere. A 1.7 molar excess of DMP was used. It is known that the secondary hydroxyl group is a weaker nucleophile compared to the primary. As a result, an unexpected block polymer was obtained. Chlorination of poly(oxyethylene glycol-lactate H-phosphonate) with trichloroisocyanuric acid (40, 41) resulted in the formation of poly(oxyethylene glycol-lactate chlorophosphate). By changing the molar ratio between starting monomers, the degree of chlorination can be controlled. The physical properties, namely hydrophilic/hydrophobic balance of the polymer, can be controlled by introducing different substituents in the side chain. The addition of hexadecanol to poly(oxyethylene glycol-lactate chlorophosphate) amphiphilic poly(hexadecanyloxyethylene glycol-lactate phosphate) was synthesized. The polymer can incorporate bioactive substances through hydrophobic interactions. In addition, the presence of a highly polar P=O group polymer can encapsulate drugs via hydrogen bonding. Drugs containing amino groups such as doxorubicin, or hydroxyl groups would be adsorbed on the polymer via a hydrogen bond, therefore the drug loading rate and efficiency can be expected to increase.

This polymer would contain an anti-cancer drug and release the drugs by responding to acidic conditions with unique cancer characteristics (42). This is mainly due to the existence of phosphoester units in this polymer (43). The characteristics of drug release are effective in cancer therapy. The tumor microenvironment is composed of cancer cells, stromal cells, and extracellular matrix, which is high density and solid condition (44, 45). The condition leads to a poor anti-cancer effect (46, 47). Therefore, it is important to interact with the cells or permeate into stiffness conditions to achieve an efficient anti-cancer effect by using nanoparticles or micelles (48, 49). When the micelles composed of this polymer are prepared, the micelles’ surface is PEG. The micelles could be able to invade the solid tumor condition because the structure of PEG is soft (50, 51).

Conclusion

In this study, we successfully synthesized a novel amphiphilic polymer based on biocompatible and biodegradable poly(oxyethylene H-phosphonate). This polymer can be used as a carrier for proper drug release and degradation of its substrate by introducing a lactate moiety to enhance the degradability of poly(alkylalkylene phosphate). Moreover, it is suggested that doxorubicin could be efficiently encapsulated through P=O groups and alkyl chain in the polymer structure. The application of this polymer as a drug nanocarrier for cancer treatment needs to be further investigated.

Acknowledgements

The Authors are grateful to Mr. T. Sakuma and Ms. K. Mochizuki from Tokyo University of Science for technical assistance at the early stages of this study.

Footnotes

  • Authors’ Contributions

    K. Yoshikawa, K. Troev and I. Takeuchi designed the study and wrote the initial draft of the manuscript. T. Nii and K. Makino contributed to the analysis and interpretation of data and assisted in the preparation of the manuscript. All Authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Conflicts of Interest

    The Authors declare that they have no potential conflicts of interest regarding this study.

  • Received November 24, 2021.
  • Revision received February 8, 2022.
  • Accepted February 18, 2022.

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Poly(Alkyloxyethylene-Lactate Phosphate) for Delivery of Doxorubicin: Synthesis and Characterization
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