Anticancer Drug Camptothecin Research Articles

Stimuli-responsive shell cross-linked micelles from amphiphilic four-arm star copolymers as potential nanocarriers for “pH/redox-triggered” anticancer drug release

A novel amphiphilic four-arm star copolymer [poly(ε-caprolactone)-b-poly(poly(ethylene glycol) methyl ether methacrylate-co-p-(2-methacryloxyethoxy) benzaldehyde)]4 [4-AS-PCL-P(PEGMA-co-MAEBA)] was designed and synthesized by a combination of ring-opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). Stimuli-responsive cross-linked micelles (SCMs) were prepared by crosslinking the shell structure of the self-assembled micelles from star copolymers. The SCMs could be de-cross-linked under low pH and redox conditions. After loading with the anticancer drug camptothecin (CPT), the SCMs displayed a good stability against extensive dilution and a slow sustained drug release at pH 7.4 with 15% in 24 h, while a fast release (54%) was observed at pH 5.0 and 10 mM DTT. Confocal microscopy studies and MTT assays revealed that the CPT-loaded SCMs showed a good uptake property and a high cytotoxicity against HepG2 tumor cells. The pH/redox dual stimuli-responsive cross-linked micelles are proposed to be a highly promising platform for the intracellular delivery of insoluble chemotherapeutics for cancer therapy.

The assembly of small molecule conjugate amphiphiles into a precise nanomedicine for colon cancer

A small molecule conjugate based on a traditional Chinese medicine cantharidin (CTR), which is an anhydride, and the anticancer drug camptothecin (CPT) was designed.

Isomahanine induces endoplasmic reticulum stress and simultaneously triggers p38MAPK-mediated apoptosis and autophagy in multidrug-resistant human oral squamous cell carcinoma cells.

Advanced oral squamous cell carcinoma (OSCC) is typically aggressive and closely correlated with disease recurrence and poor survival. Multidrug resistance (MDR) is the most critical problem leading to therapeutic failure. Investigation of novel anticancer candidates targeting multidrug-resistant OSCC cells may provide a basis for developing effective strategies for OSCC treatment. In the present study, we investigated the cytotoxic mechanism of a carbazole alkaloid, namely isomahanine, in a multidrug‑resistant OSCC cell line CLS-354/DX. We demonstrated that CLS-354/DX cells overexpressing multidrug resistance-associated protein1 (MRP1) were resistant to anticancer drugs cisplatin and camptothecin. Isomahanine effectively induced cytotoxicity against CLS-354/DX cells regardless of resistance. Apoptosis as determined by FITC‑AnnexinV/PI staining and western blot analysis of cleaved caspase-3 and cleaved poly(ADP‑ribose) polymerase (PARP) was significantly induced in a time-dependent manner upon isomahanine treatment. Isomahanine-induced caspase‑dependent apoptosis was determined using z-VAD‑fmk. The effects on autophagy in isomahanine-treated cells were investigated via conversion of LC3B and degradation of p62/SQSTM1(p62). Isomahanine obviously induced autophagic flux as shown by an increase in punctate GFP-LC3B and the LC3B-II/LC3B-I ratio with a concomitant decrease in p62 levels. Autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) protected isomahanine-induced cell death, indicating the activation of autophagic cell death. Endoplasmic reticulum (ER) stress and MAPK activation were examined to elucidate the mechanism underlying cell death. The expression levels of PERK, CHOP and phosphorylated MAPK (p38, ERK1/2 and JNK1/2) were upregulated following isomahanine treatment. We found that p38MAPK inhibitor (SB203580) significantly attenuated isomahanine-induced apoptosis and autophagic flux and this prevented cell death. Collectively, the present study demonstrated that isomahanine was able to induce ER stress and trigger p38MAPK-mediated apoptosis and autophagic cell death in multidrug-resistant OSCC cells. The potential cytotoxic action of isomahanine may provide the development of anticancer candidates for treating multidrug-resistant cancer.

Functionalization of magnetic hollow spheres with 3-Aminopropyl)triethoxysilane (APTES) for controlled drug release

Direct functionalization strategy has been employed to modify the surface of the magnetic hollow spheres (MHS) with (3-aminopropyl)triethoxysilane (APTES) for controlled drug release. The MHS were prepared by the solvothermal method and characterized by X-ray diffraction, field emission scanning electron microscopy (FE-SEM), Fourier transform infrared spectroscopy, and vibrating sample magnetometer. The FE-SEM study shows that MHS have a size of ~200 nm and are made up of smaller nanoparticles (NPs) having average size of ~20–25 nm. MHS exhibits a superparamagnetic behavior with a saturation magnetization of 74 emu/g at room temperature. The direct functionalization of MHS with APTES provided an efficient loading of model anti-cancer drug Camptothecin (CPT). The drug release study performed at pH of 7.4 showed 30% of CPT release in a controlled way after 4 h.

Tumor-cell targeting polydiacetylene micelles encapsulated with an antitumor drug for the treatment of ovarian cancer.

Peptide functionalized polydiacetylene (PDA) micelles encapsulated with camptothecin (CPT) kill ovarian cancer cells by the lysosome release of anticancer drug CPT. Moreover, the sub-30 nm PDA micelles penetrate efficiently into a tumor for enhanced therapeutic efficacy.

Cytotoxic and Proinflammatory Effects of Metal-Based Nanoparticles on THP-1 Monocytes Characterized by Combined Proteomics Approaches.

Thorough characterization of toxic effects of nanoparticles (NP) is desirable due to the increasing risk of potential environmental contamination by NP. In the current study, we combined three recently developed proteomics approaches to assess the effects of Au, CuO, and CdTe NP on the innate immune system. The human monocyte cell line THP-1 was employed as a model. The anticancer drugs camptothecin and doxorubicin were used as positive controls for cell death, and lipopolysaccharide was chosen as a positive control for proinflammatory activation. Despite equivalent overall toxicity effect (50 ± 10% dead cells), the three NP induced distinctly different proteomics signatures, with the strongest effect being induced by CdTe NP, followed by CuO and gold NP. The CdTe toxicity mechanism involves down-regulation of topoisomerases. The effect of CuO NP is most reminiscent of oxidative stress and involves up-regulation of proteins involved in heat response. The gold NP induced up-regulation of the inflammatory mediator, NF-κB, and its inhibitor TIPE2 was identified as a direct target of gold NP. Furthermore, gold NP triggered activation of NF-κB as evidenced by phosphorylation of the p65 subunit. Overall, the combined proteomics approach described here can be used to characterize the effects of NP on immune cells.

A theranostic prodrug based on FRET for real-time drug release monitoring in response to biothiols

The clinical applications of tradition prodrug are restricted to a certain extent due to its some defects such as side effects, low selectivity and single function. Herein, we designed a theranostic strategy based on the fluorescence resonance energy transfer (FRET) mechanism. The theranostic prodrug was constructed with an anticancer drug camptothecin (CPT), a cleavable linker based on disulfide bonds (SS) and a fluorophore naphthalimide derivative (NAP). For this drug delivery and reporting system (NAP-SS-CPT), FRET occurs between CPT (energy donor) and NAP (energy receptor); and upon cellular uptake by GSH-overexpressing cancer cells, disulfide bonds could be successfully cleaved by the high concentration of GSH, and FRET process was interrupted to achieve dual fluorescence response and specifically release of CPT. The drug delivery system features some favorable properties, like excellent pH-stability, high selectivity and cytotoxicity towards GSH-overexpressing cells and relatively lower cytotoxicity towards normal cells. Fluorescence analysis reveals that NAP-SS-CPT shows a ratiometric fluorescence signal under excitation at 400nm for quantitative detection of GSH. Intracellular fluorescence imaging studies indicate that the prodrug can be efficiently internalized in HeLa cells and used for real-time monitoring of drug release. Moreover, MTT and flow cytometry assay indicate that NAP-SS-CPT exhibits high pro-apoptotic effect for cancer cells. This strategy may provide a new approach for cancer diagnosis and therapy.

Screening for inhibitors of topoisomerase I from Lycoris radiata by combining ultrafiltration with liquid chromatography/mass spectrometry.

Although crude Amaryllidaceae alkaloids (AAs) extracted from Lycoris radiata are reported to exhibit significant anti-cancer activity, both the specific responsible alkaloid(s) and their targets remain elusive. Screening anti-cancer AAs targeted on topoisomerase I from crude AAs could be very helpful in tackling these two challenging questions. An ultrafiltration method combined with liquid chromatography/electrospray ionization mass spectrometry (UF-LC/MS) was developed to screen for the inhibitors of topoisomerase I, which has been reported to mediate DNA unwinding during carcinoma proliferation. Enrichment factors (EFs) of different AAs were used to evaluate the binding affinity between AAs and topoisomerase I, and the AAs with higher EFs were further tested to validate the method. Eleven AAs from Lycoris radiata (ten of which were identified) were screened using UF-LC/MS, and a glaring discrepancy in EFs was revealed for the first time. One of the AAs, hippeastrine, with the highest EF at 49.3%, was further tested against topoisomerase I, and the IC50 value of hippeastrine was determined to be 23.0μmol/L, which is comparable with the well-known anti-cancer drug camptothecin at 19.3μmol/L. A simple, rapid and effective screening method using UF-LC/MS was developed and successfully applied to screen candidate inhibitors of topoisomerase I from crude AAs in Lycoris radiata, which may pave the way to further understand the potential anti-cancer constituents and mechanisms of Lycoris radiata. Copyright © 2016 John Wiley & Sons, Ltd.

Cytoskeletal interference – A new mode of action for the anticancer drugs camptothecin and topotecan

The anticancer drugs camptothecin (CPT) and topotecan (TPT) are known DNA topoisomerase I inhibitors which cause DNA damage and lead to cell death. In this study we provide evidence that CPT and TPT also interfere with the elements of cytoskeleton ― microtubules and actin filaments which could be partly responsible for their cytotoxic properties. CPT and TPT apparently affected microtubule structures in living cells (Hela and U2OS) and inhibited tubulin polymerization in vitro with IC50 values of 74.57±9.96µM and 121.55±58.68µM, respectively. TPT significantly affected the nucleation and growth phase during the microtubule assembly in vitro, whereas the mode of action of CPT was different in that it specifically affected the ‘tread milling’ of polymerized microtubules. Cell cycle effects of CPT and TPT varied with their concentrations. CPT and TPT induced G2/M arrest and promoted the population to 76.94±11.20% and 83.91±2.43% at a concentration of 9.4nM and 46.9nM, respectively. As the concentration increased, cells were blocked in S phase with a dose-dependent reduction in G2/M population. In addition, CPT and TPT exhibited a certain effect on actin filaments by reducing the mass of actin filaments. The interactions of CPT and TPT with microtubules and actin filaments present new insights into their modes of action.

Increased level of Oct-1 protein in tumor cells modulates cellular response to anticancer drugs.

The effect of overexpression of Oct-1 protein isoforms on the cell response to two anticancer drugs camptothecin and dexamethasone was studied. The effect of Oct-1 isoforms on regulated gene transcription was estimated by the difference in the level of mRNA in Burkitt's lymphoma cells (Namalwa line) untransfected and stably transfected with Oct-1 isoforms. The response to anticancer drugs of the Oct-1 target genes involved in the development of apoptosis depended, firstly, on the type of drug, secondly, on the concentration of Oct-1 in cells. and, thirdly, on the Oct-1 isoform with which these cells were transfected.

A flexible polymersome system with tunable morphology and release profiles for efficient intracellular delivery

Polymersomes are widely used as drug delivery system however they have shortcomings in drug-eluting properties that are attributable to the high molecular weight of the copolymers forming their membrane. Here we demonstrate for the first time how novel class of polymersomes from very short, liquid to soft star-shaped copolymers can be empowered to form an efficient drug delivery system. The copolymers undergo self-assembly in water into a stable, nano-sized rod or a spherical shape polymersomes. Increasing the Mw of the hydrophobic moieties the CMC value is decreased accompanied with the tendency to form a more spherical structure. The poorly water-soluble anticancer drug camptothecin was loaded into the fabricated polymersomes, resulting in a high drug loading content, and released over a period of over three days. Furthermore, this biocompatible system could deliver a variety of drugs intracellularly in a rapid yet controlled manner. Therefore, this nano system’s tailorable properties, biocompatibility and ability to incorporate hydrophobic drugs and release them intracellularly are desirable traits for anti-cancer delivery system and other biomedical applications.

Synthesis and Antitumor Properties of BQC-Glucuronide, a Camptothecin Prodrug for Selective Tumor Activation.

Major limitations of camptothecin anticancer drugs (toxicity, nonselectivity, water insolubility, inactivation by human serum albumin) may be improved by creating glucuronide prodrugs that rely on beta-glucuronidase for their activation. We found that the camptothecin derivative 5,6-dihydro-4H-benzo[de]quinoline-camptothecin (BQC) displays greater cytotoxicity against cancer cells than the clinically used camptothecin derivatives SN-38 and topotecan even in the presence of human serum albumin. We synthesized the prodrug BQC-glucuronide (BQC-G), which was 4000 times more water soluble and 20-40 times less cytotoxic than BQC. Importantly, even in the presence of human serum albumin, BQC-G was efficiently hydrolyzed by beta-glucuronidase and produced greater cytotoxicity (IC50 = 13 nM) than camptothecin, 9-aminocamptothecin, SN-38, or topotecan (IC50 > 3000, 1370, 48, and 28 nM, respectively). BQC-G treatment of mice bearing human colon cancer xenografts with naturally or artificially elevated beta-glucuronidase activity produced significant antitumor activity, showing that BQC-G is a potent prodrug suitable for selective intratumoral drug activation.

Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer.

Werner syndrome protein (WRN) is a RecQ helicase that participates in DNA repair, genome stability and cellular senescence. The five human RecQ helicases, RECQL1, Bloom, WRN, RECQL4 and RECQL5 play critical roles in DNA repair and cell survival after treatment with the anticancer drug camptothecin (CPT). CPT derivatives are widely used in cancer chemotherapy to inhibit topoisomerase I and generate DNA double-strand breaks during replication. Here we studied the effects of CPT on the stability and expression dynamics of human RecQ helicases. In the cells treated with CPT, we observed distinct effects on WRN compared to other human RecQ helicases. CPT altered the cellular localization of WRN and induced its degradation by a ubiquitin-mediated proteasome pathway. WRN knockdown cells as well as CPT treated cells became senescent and stained positive for senescence-associated β-galactosidase at a higher frequency compared to control cells. However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in CPT treated cells. Approximately 5-23% of breast cancer tumors are known to respond to CPT-based chemotherapy. Interestingly, we found that the extent of CPT-induced WRN degradation correlates with increasing sensitivity of breast cancer cells to CPT. The abundance of WRN decreased in CPT-treated sensitive cells; however, WRN remained relatively stable in CPT-resistant breast cancer cells. In a large clinical cohort of breast cancer patients, we find that WRN and topoisomerase I expression correlate with an aggressive tumor phenotype and poor prognosis. Our novel observations suggest that WRN abundance along with CPT-induced degradation could be a promising strategy for personalizing CPT-based cancer chemotherapeutic regimens.

GSH-responsive biotinylated poly(vinyl alcohol)-grafted GO as a nanocarrier for targeted delivery of camptothecin

A water-soluble and biocompatible polymer, i.e. biotinylated poly(vinyl alcohol)-grafted graphene oxide (GO), was used as a nanocarrier for targeted delivery of anticancer drug camptothecin (CPT).

Dual-channel NIR activatable theranostic prodrug for in vivo spatiotemporal tracking thiol-triggered chemotherapy.

Real-time tracking for where (W), when (W), and how (H) prodrugs are delivered and activated in vivo is a great challenge for prodrug development. Disulfide linkage-based prodrugs as well as their delivery systems have been studied extensively, but the WWH question in spatial and temporal (spatiotemporal) precision remains unanswered. Herein, we present a novel prodrug of camptothecin (CPT) linked to a near-infrared (NIR) cyanine dye via a disulfide linkage (Cy-S-CPT). The cleavage of the disulfide bond in Cy-S-CPT by endogenous glutathione (GSH) can activate the anti-cancer drug CPT and induce a remarkable fluorescence shift from 825 to 650 nm, thereby providing dual fluorescent channels to real-time track the prodrug biodistribution and activation in vivo. Impressively, the dual-channel NIR fluorescence bioimaging exhibits the pervasive drug distribution, i.e., the biodistribution of the intact prodrug was traced at the 825 nm-NIR fluorescence channel, whereas the activated drug was tracked at the 650 nm red fluorescence channel. In this way, we can overcome the blind spot in the metabolism kinetics of prodrugs in a certain organ or tissue. As demonstrated, the prodrug prompts activation in all the organs, particularly in the liver after an intravenous injection, and achieves predominant accumulation and activation in tumors at 24 h post injection. Cy-S-CPT loaded in PEG-PLA nanoparticles display significantly improved therapeutic efficacy and low side effects with respect to the clinical used drug CPT-11. As a consequence, the NIR spatiotemporal bioimaging in vivo with dual fluorescence channels allows the prodrug release profile to be extracted precisely, particularly in visualizing drug-released information from complex biological systems such as mice, thereby providing a unique opportunity to take insight into the relationship between theranosis and pharmacokinetics.

Fabrication and Characterization of a Porous Silicon Drug Delivery System with an Initiated Chemical Vapor Deposition Temperature-Responsive Coating.

This paper reports on the fabrication of a pSi-based drug delivery system, functionalized with an initiated chemical vapor deposition (iCVD) polymer film, for the sustainable and temperature-dependent delivery of drugs. The devices were prepared by loading biodegradable porous silicon (pSi) with a fluorescent anticancer drug camptothecin (CPT) and coating the surface with temperature-responsive poly(N-isopropylacrylamide-co-diethylene glycol divinyl ether) (pNIPAM-co-DEGDVE) or non-stimulus-responsive poly(aminostyrene) (pAS) via iCVD. CPT released from the uncoated oxidized pSi control with a burst release fashion (∼21 nmol/(cm(2) h)), and this was almost identical at temperatures both above (37 °C) and below (25 °C) the lower critical solution temperature (LCST) of the switchable polymer used, pNIPAM-co-DEGDVE (28.5 °C). In comparison, the burst release rate from the pSi-pNIPAM-co-DEGDVE sample was substantially slower at 6.12 and 9.19 nmol/(cm(2) h) at 25 and 37 °C, respectively. The final amount of CPT released over 16 h was 10% higher at 37 °C compared to 25 °C for pSi coated with pNIPAM-co-DEGDVE (46.29% vs 35.67%), indicating that this material can be used to deliver drugs on-demand at elevated temperatures. pSi coated with pAS also displayed sustainable drug delivery profiles, but these were independent of the release temperature. These data show that sustainable and temperature-responsive delivery systems can be produced by functionalization of pSi with iCVD polymer films. Benefits of the iCVD approach include the application of the iCVD coating after drug loading without causing degradation of the drug commonly caused by exposure to factors such as solvents or high temperatures. Importantly, the iCVD process is applicable to a wide array of surfaces as the process is independent of the surface chemistry and pore size of the nanoporous matrix being coated.

A linear polyethylenimine (LPEI) drug conjugate with reversible charge to overcome multidrug resistance in cancer cells

Multidrug resistance (MDR) is an important hindrance to efficient cancer chemotherapy. Cancer cell lysosomes play an important role in intrinsic MDR by accumulating chemotherapy drugs and deactivating their therapeutic action. The cationic polymer polyethyleneimine (PEI) can disrupt the endosomal/lysosomal membrane via the proton-sponge effect (PSE). However, its positive charge makes it toxic and so it cannot be used in vivo. Here, linear PEI (LPEI) is used to demonstrate that a pH-triggered charge-reversal carrier can solve this problem. The imines are amidized by masking a lysosomal pH-active agent. LPEI regenerates its positive charge in the acidic endosomal/lysosomal cell compartments and disrupts the endosomal/lysosomal membrane, resulting in delivery of the drugs into the cytoplasm and nuclei where they exert their pharmacologic activity. Folic acid targeting groups are introduced into the polymer to increase its cancer-cell targeting capability. An anticancer drug camptothecin (CPT) conjugated to the carrier by intracellular cleavable disulfide bonds shows improved cytotoxicity over free CPT.

Abstract 4405: Tumor-targeted nanotherapeutics

Abstract Directing anticancer agents specifically to tumors and/or cancer cells by targeting specific extracellular receptors fulfills the following three most important tasks: (1) preventing or at least substantially limiting adverse side effects on healthy tissues, (2) enhancing drug internalization by cancer cells, and (3) overcoming (at least in part) resistance mechanisms that are based on the active efflux of exogenous drugs from cancer cells. We developed several tumor-targeted nanoscale-based formulations: various nanocarriers (liposomes, lipid nanoparticles, dendrimers, polymers, quantum dots, mesoporous silica and supermagnetic iron oxide nanoparticles); different anticancer drugs (doxorubicin, paclitaxel, camptothecin, and cisplatin); suppressors of cellular drug resistance and tumor grows (antisense oligonucleotides or siRNA targeted to BCL2, MDR1, MRP1, HIF1A, CD44 mRNA); and tumor-targeting agent - luteinizing hormone-releasing hormone (LHRH). The proposed nanotherapeutics were tested in vitro and in vivo using established lung and ovarian cancer cell lines and highly metastatic cancer cells isolated from malignant intraperitoneal ascites from patients with advanced ovarian carcinoma. These cells were used to initiate orthotopic models of lung and ovarian cancers in nude mice that were often accompanied by the development of metastases. Tumor-targeted nanoscale-based drug formulations were delivered intravenously and intraperitoneally (for ovarian cancer) or intravenously and by inhalation (for lung cancer). Treatment with the developed therapeutics led to the suppression of targeted proteins, efficient induction of cell death, effective tumor shrinkage, prevention the development of metastases and limitation of adverse side effects. Acknowledgements: The work was supported by R01CA100098, R01CA111766, and R01CA138533 grants from NIH. Note: This abstract was not presented at the meeting. Citation Format: Olga B. Garbuzenko, Andriy Kuzmov, Justin E. Sapiezynski, Oleh Taratula, Vatsal Shah, Min Zhang, Ronak Savla, Shali John, Lorna Rodriguez-Rodriguez, Tamara Minko. Tumor-targeted nanotherapeutics. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4405. doi:10.1158/1538-7445.AM2015-4405

Light- and pH-activated intracellular drug release from polymeric mesoporous silica nanoparticles

Surface modified mesoporous silica nanoparticles (MSNs) with reduced toxicity were prepared for light and pH dual triggerable drug delivery system. Both 413nm light and acidic environment can activate the drug release process, improving the pharmacological action. By applying rhodamine B (RhB) as a model drug, the accumulative RhB release is as high as 95% in pH 5.0 and in irradiation of 413nm light, compared to only 55% in pH 7.4 and in dark. The anti-cancer drug camptothecin (CPT) loaded nanoparticles can kill cancer cells with IC50 value of 0.02μgmL−1 in exposure of 413nm light, which is much lower than free CPT (about 0.1μgmL−1). Multimodal nonlinear optical imaging microscopy (NLOM) was employed to acquire in vitro coherent anti-Stokes Raman (CARS) and two-photon excited fluorescence (TPEF) images of live MCF-7 cells and showed that the nanoparticles can be taken up by breast tumor cell MCF-7 with high efficiency, indicating its great potential for anti-cancer drug delivery system.

Mucoadhesive drug carrier based on functional-modified cellulose as poorly water-soluble drug delivery system

The purpose of this study was to design and characterise an oral mucoadhesive micellar drug carrier. In this regard, a mucoadhesive hydrophobic cationic aminocellulose was easily synthesised under mild homogeneous conditions with high yield. The cellulose derivative resulted in strongly improved mucoadhesive properties but was pH dependent. Furthermore, the hydrophobic anticancer drug camptothecin was successfully encapsulated into the mucoadhesive cellulose derivative micelles with spherical shape stability of 233 nm in diameter and low particle size distribution. The CPT-loaded nanocarriers provided high encapsulation efficiency about 86.4%. In vitro release, CPT-loaded cellulose derivative micelles showed a reduction in release rate compared with physically pure CPT solution. The release results also indicated that a sustained release of CPT to >80% over 4 d for pH 6.8 and 7.4. Therefore, mucoadhesive hydrophobic cationic aminocellulose micelles seem to be a promising carrier for various pharmaceutical applications especially for poorly water-soluble drug delivery system.