HCPT-loaded Nanoparticles Research Articles

Hydroxycamptothecin nanoparticles based on poly/oligo (ethylene glycol): Architecture effects of nanocarriers on antitumor efficacy

Nanoparticles decorated with hydrophilic PEG chains had been emerged as effective drug delivery system due to their biocompatibility and biodegradability, while, the influence of their architecture on antitumor efficacy remained challenging. In this study, the linear poly(ethylene glycol) (PEG45), brush oligo(triethylene glycol) (TEG10), and oligo(ethylene glycol) dendron (G2), which showed the similar molar mass but different architecture, were utilized as nanocarriers to prepare 10-hydroxycamptothecin (HCPT) nanoparticles. It was found that all of three HCPT NPs (PEG45 NPs, TEG10 NPs, and G2 NPs) presented similar DLCs (∼60%), zeta potentials (−13 to −16 mv), and stabilities, meanwhile, the particle sizes, morphologies, release profiles, and anticancer efficacies were affected by the architecture of nanocarriers. Changing the architecture from linear, brush to dendron, the mean particles diameter was decreased from 240 to 170 nm, the sustained releases were elongated from 5 to 9 days. More importantly, the cytotoxicity of G2 NPs based on OEG dendron was enhanced significant comparing with linear PEG45 NPs, the IC50 was decreased almost 10.1-fold (p < 0.01). Besides, the tumor inhibition rate of G2 NPs was 1.7-fold higher than PEG45 NPs, showing significantly optimized antitumor efficacy in vivo. These results suggested the architecture of nanocarriers could affect the antitumor activity, due to the steric hindrance of nanocarriers influence the morphologies of HCPT-loaded nanoparticles.

Effect of alkyl chain on cellular uptake and antitumor activity of hydroxycamptothecin nanoparticles based on amphiphilic linear molecules

Drug-loaded nanoparticles utilizing amphiphilic molecules as nanocarriers were developed broadly for nanoscale drug delivery system. Linear amphiphilic molecule (PEG45C18) based on PEG and alkyl chain was designed and synthesized. To study the influence of alkyl chain on antitumor activity, 10-hydroxycamptothecin (HCPT) was selected as the hydrophobic drug, amphiphilic molecule (PEG45C18) and hydrophilic PEG (PEG45) were applied as nanocarriers to form HCPT-loaded nanoparticles (HCPT/PEG45C18 NPs and HCPT/PEG45 NPs). These two nanoparticles presented high drug-loading content, stability, but different release manner and antitumor efficacy. The HCPT/PEG45C18 NPs existed slower release manner but higher antitumor activity than HCPT/PEG45 NPs, IC50 value was decreased approximately 8.5-fold against 4T1 cells in vitro. Moreover, the antitumor efficacy of HCPT/PEG45C18 NPs on 4T1-bearing mice was promoted significantly, the inhibition rate based on average tumor weight was 1.5-fold higher than HCPT/PEG45 NPs, besides, HCPT/PEG45C18 NPs exhibited better tumor accumulation than HCPT/PEG45 NPs. These results suggested alkyl chain affect the antitumor activity significantly due to nanoparticles decorated with alkyl chains existing higher endocytosis efficacy to cells. According to the enhanced antitumor efficacy, it was suggested that HCPT/PEG45C18 NPs showed the potential application for cancer therapy in clinic, and alkyl chains should be considered for designing biomaterials.

Enhanced drug loading capacity of 10-hydroxycamptothecin-loaded nanoparticles prepared by two-step nanoprecipitation method

The application of poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) micelles was dampened by their inherent low drug-loading capability. In this study, a series of new poly(ethylene glycol)/poly(l-lactic acid) (PEG/PLLA) multiblock copolymers were facilely synthesized to obtain excellent nanoparticle drug carrier. The structure and composition of the copolymers were investigated by nuclear magnetic resonance (NMR), fourier transform infrared spectroscopy (FT-IR), and gel permeation chromatography (GPC). PEG/PLLA multiblock copolymers with critical micellar concentration (CMC) of 0.91–5.16 mg/L could self-assemble into stable micelles with average diameters of 83.5–142.5 nm. With the resulting multiblock copolymers, stable micelle structure 10-hydroxycamptothecin (HCPT)-loaded nanoparticles were successfully prepared by a two-step nanoprecipitation method, achieving superior drug loading content (11.7%) as well as satisfactory encapsulation efficiency (77.2%) due to interior-chemistry interaction. HCPT-loaded nanoparticles were characterized in terms of size, size distribution and morphology. The results obtained from X-ray powder diffraction (XRD) measurement suggested that HCPT was molecularly dispersed in nanoparticles. In vitro drug release of HCPT-loaded nanoparticles showed sustained-release profiles and was affected by copolymer composition. Stability studies showed that HCPT-loaded nanoparticles presented excellent stability in simulated physiological environments. These results suggest that PEG/PLLA nanoparticles prepared by two-step nanoprecipitation method are stable and promising candidate for delivery of HCPT.

Long circulating 10-hydroxycamptothecin-loaded nanoparticles fabricated from poly(ethylene glycol)/poly(L-lactic acid) multiblock copolymers

ABSTRACTA series of poly(ethylene glycol) (PEG)/poly(L-lactic acid) (PLLA) multiblock copolymers were facilely synthesized using triphosgene as coupling agent. With the resulting multiblock copolymers, 10-hydroxycamptothecin (HCPT)-loaded nanoparticles were successfully prepared by dialysis method. The results obtained from dynamic light scattering (DLS) measurements confirmed that HCPT-loaded nanoparticles had the size of less than 200 nm and the average diameter decreased with increasing PLLA content. TEM images demonstrated that most of the drug-loaded nanoparticles had a distinct spherical shape and smooth surface without any aggregation. Atomic force microscopy (AFM) images further indicated that the nanoparticles were in spherical shape with smooth surface, no drug crystal was visualized on their surface. To investigate the drug state in HCPT-loaded nanoparticles, differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) measurements were carried out. The results from these tests suggested that HCPT was molecularly dispersed in the amorphous polymer matrix. Drug loading content and in vitro drug release behavior of HCPT-loaded nanoparticles showed dependence on polymer composition. Cytotoxicity test indicated that HCPT-loaded nanoparticles exhibited greatly superior cytotoxicity compared to free HCPT due to its molecular dispersion in the polymer matrix. Furthermore, the nanoparticles significantly increased the duration of the drug in circulation. All these results demonstrated that PEG/PLLA nanoparticles have great potential as promising delivery system for poorly soluble antitumor drugs.

Long circulating 10-hydroxycamptothecin-loaded nanoparticles fabricated from poly(ethylene glycol)/poly(L-lactic acid) multi-block copolymers

ABSTRACTA series of poly(ethylene glycol) (PEG)/poly(L-lactic acid) (PLLA) multi-block copolymers were facilely synthesized using triphosgene as coupling agent. With the resulting multi-block copolymers, 10-hydroxycamptothecin (HCPT)-loaded nanoparticles were successfully prepared by dialysis method. The results obtained from dynamic light scattering (DLS) measurements confirmed that HCPT-loaded nanoparticles had the size of less than 200 nm and the average diameter decreased with increasing PLLA content. TEM images demonstrated that most of the drug-loaded nanoparticles had a distinct spherical shape and smooth surface without any aggregation. Atomic force microscopy (AFM) images further indicated that the nanoparticles were in spherical shape with smooth surface, no drug crystal was visualized on their surface. To investigate the drug state in HCPT-loaded nanoparticles, differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) measurements were carried out. The results from these tests suggested that HCPT was molecularly dispersed in the amorphous polymer matrix. Drug loading content and in vitro drug release behavior of HCPT-loaded nanoparticles showed dependence on polymer composition. Cytotoxicity test indicated that HCPT-loaded nanoparticles exhibited greatly superior cytotoxicity compared to free HCPT due to its molecular dispersion in the polymer matrix. Furthermore, the nanoparticles significantly increased the duration of the drug in circulation. All these results demonstrated that PEG/PLLA nanoparticles have great potential as promising delivery system for poorly soluble antitumor drugs.

Promoting Antitumor Activities of Hydroxycamptothecin by Encapsulation into Acid-Labile Nanoparticles Using Electrospraying

Acid-labile nanoparticles are proposed to enhance the tumor targeting and anti-tumor therapy of hydroxycamptothecin (HCPT) in response to the acidic microenvironment within cells and tumor tissues. HCPT was entrapped into matrix polymers containing acid-labile segments and galactose moieties (PGBELA) through an electrospraying technique. The antitumor activities of HCPT-loaded nanoparticles were evaluated both on HepG2 cells and after intravenous injection into H22 tumor-bearing mice. The electrosprayed nanoparticles were obtained with enhanced loading efficiency and extended release of HCPT compared with other nanoparticle preparation methods. The acid-lability and targeting capability of PGBELA nanoparticles resulted in a 5 times higher inhibitory activity after incubation in pH6.8 media compared to that of pH7.4. Animal studies indicated that both the blood circulation time and tumor distribution of PGBELA nanoparticles were significantly increased. HCPT/PGBELA nanoparticles indicated a superior in vivo antitumor activity and fewer side effects than other treatments on the basis of tumor growth, animal survival rate, tissue necrosis and cell apoptosis evaluation. Biodegradable PGBELA nanoparticles are capable of achieving site-specific drug delivery by active targeting and triggered release by acidic pH both in tumor tissues and after internalization within tumor cells, thereby providing a novel strategy for cancer treatment.

Co‐delivery of 10‐Hydroxycamptothecin with Doxorubicin Conjugated Prodrugs for Enhanced Anticancer Efficacy

Well-defined amphiphilic linear-dendritic prodrugs (MPEG-b-PAMAM-DOX) are synthesized by conjugating doxorubicin (DOX), to MPEG-b-PAMAM through the acid-labile hydrazone bond. The amphiphilic prodrugs form self-assembled nanoparticles in deionized water and encapsulate the hydrophobic anticancer drug 10-hydroxycamptothecin (HCPT) with a high drug loading efficiency. Studies on drug release and cellular uptake of the co-delivery system reveal that both drugs are released in a pH-dependent manner and effectively taken up by MCF-7 cells. In vitro methyl thiazolyl tetrazolium (MTT) assays and drug-induced apoptosis tests demonstrate the HCPT-loaded nanoparticles suppress cancer cell growth more efficiently than the MPEG-b-PAMAM-DOX prodrugs, free HCPT, and physical mixtures of MPEG-b-PAMAM-DOX and HCPT at equivalent DOX or HCPT doses.

Hydroxycamptothecin‐loaded Fe3O4 nanoparticles induce human lung cancer cell apoptosis through caspase‐8 pathway activation and disrupt tight junctions

10-Hydroxycamptothecin (HCPT) elicits strong anti-cancer effects and is less toxic than camptothecin (CPT), making it widely used in recent clinical trials. However, its low solubility limits its application as an effective anti-cancer therapy. In the present study we investigate the hypothesis that the unique water dispersible oleic acid-Triton X-100-coated Fe3O4 nanoparticles loaded with HCPT disrupt epithelial cell-cell junctions and induce human lung cancer cell apoptosis through the caspase-8 pathway. We characterized the HCPT-loaded nanoparticles and determined their effects on lung cancer cell viability and apoptosis by using immunofluorescence light microscopy and SDS-PAGE/immunoblots. We found that HCPT-loaded nanoparticles elicited an anti-proliferative effect in a dose-dependent manner. HCPT-loaded nanoparticles reduced the expression of cell-cell junction protein claudins, E-cadherin and ZO-1, and transmission electron microcopy demonstrated a disrupted tight junction ultrastructure. Transepithelial electric resistance was also reduced, indicating the reduction of tight junction functions. The HCPT-loaded nanoparticles increased phosphorylation of p38 and SAPK/JNK while it showed no effects on p42/44 MAP kinase. Compared with void Fe3O4 nanoparticles or HCPT drug alone, HCPT drug-loaded nanoparticles evoked synergistic effects by increasing cell apoptosis with enhanced activation of the caspase-8 pathway. Therefore, our current study highlights the potential of HCPT drug-loaded nanoparticles as a chemotherapeutic agent for increasing anti-cancer drug efficacy.

Preparation and properties of hydroxycamptothecin-loaded nanoparticles made of amphiphilic copolymer and normal polymer

Stabilized micelle structure nanoparticles were prepared using Pluronic F127 and poly(butylcyanoacrylate) (PBCA). To increase the drug loading of nanoparticles, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was additionally included into the nanoparticle composition. The poorly soluble anticancer drug 10-hydroxycamptothecin (HCPT) was used as a model drug and incorporated into nanoparticles. The results obtained from FT-IR and DSC confirmed that HCPT was molecularly dispersed in nanoparticles and no chemical reaction occurred. The size of the nanoparticles measured by DLS demonstrated that the size distribution was narrow and the average diameter was less than 200 nm. The morphology of the nanoparticles observed by TEM indicated that the nanoparticles exhibited a smooth surface and distinct spherical shape. In vitro release experiments indicated that the HCPT-loaded nanoparticles showed sustained release profiles. The results of a drug loading test revealed that adding TPGS could increase the drug loading. The drug loading of stabilized micelle structure nanoparticles with 70% of TPGS was about 0.0425 ± 0.0011% w/w compared to 0.0254 ± 0.0008% w/w found for the nanoparticles without TPGS. The results of CMC value tests showed that the CMC values of the stabilized nanoparticles were approximately 10-fold lower than those of the nonstabilized micelles (from 2.0 × 10 −5 to 2.5 × 10 −4 M). Cytotoxicity tests showed that the cytotoxicity of HCPT-loaded nanoparticles against cancer cells in vitro was remarkably higher than that of free drugs. 10-Hydroxycamptothecin-loaded nanoparticles may serve as a stable delivery system for poorly soluble HCPT.

Hydroxycamptothecin-loaded nanoparticles enhance target drug delivery and anticancer effect

BackgroundHydroxycamptothecin (HCPT) has been shown to have activity against a broad spectrum of cancers. In order to enhance its tissue-specific delivery and anticancer activity, we prepared HCPT-loaded nanoparticles made from poly(ethylene glycol)-poly(γ-benzyl-L-glutamate) (PEG-PBLG), and then studied their release characteristics, pharmacokinetic characteristics, and anticancer effects. PEG-PBLG nanoparticles incorporating HCPT were prepared by a dialysis method. Scanning electron microscopy (SEM) was used to observe the shape and diameter of the nanoparticles. The HCPT release characteristics in vitro were evaluated by ultraviolet spectrophotometry. A high-performance liquid chromatography (HPLC) detection method for determining HCPT in rabbit plasma was established. The pharmacokinetic parameters of HCPT/PEG-PBLG nanoparticles were compared with those of HCPT.ResultsThe HCPT-loaded nanoparticles had a core-shell spherical structure, with a core diameter of 200 nm and a shell thickness of 30 nm. Drug-loading capacity and drug encapsulation were 7.5 and 56.8%, respectively. The HCPT release profile was biphasic, with an initial abrupt release, followed by sustained release. The terminal elimination half-lives (t 1/2 β) of HCPT and HCPT-loaded nanoparticles were 4.5 and 10.1 h, respectively. Peak concentrations (Cmax) of HCPT and HCPT-loaded nanoparticles were 2627.8 and 1513.5 μg/L, respectively. The apparent volumes of distribution of the HCPT and HCPT-loaded nanoparticles were 7.3 and 20.0 L, respectively. Compared with a blank control group, Lovo cell xenografts or Tca8113 cell xenografts in HCPT or HCPT-loaded nanoparticle treated groups grew more slowly and the tumor doubling times were increased. The tumor inhibition effect in the HCPT-loaded nanosphere-treated group was significantly higher than that of the HCPT-treated group (p < 0.01). Tumor inhibition in the control group by PEG-PBLG nanoparticles was not observed (p > 0.05).ConclusionCompared to the HCPT- and control-treated groups, the HCPT-loaded nanoparticle-treated group showed a more sustained release, a longer circulation time, increased delivery to tissue, and an enhanced anticancer effect. HCPT-loaded nanoparticles appear to change the pharmacokinetic behavior of HCPT in vivo.

10-Hydroxycamptothecin loaded nanoparticles: Preparation and antitumor activity in mice

10-Hydroxycamptothecin (HCPT) loaded nanoparticles made from poly(caprolactone-co-lactide)-b–PEG–b-poly(caprolactone-co-lactide) (PCLLA–PEG–PCLLA) block copolymer, were prepared by a novel two-step nanoprecipitation method using an interior-chemistry strategy. The satisfactory drug loading content (> 13%) as well as high encapsulation efficiency (> 85%) was achieved. Cytotoxicity test indicated that the HCPT-loaded nanoparticles had enhanced in vitro cytotoxicity compared to free drug. Progressively, in vivo antitumor activity and HCPT biodistribution in sarcoma-180 (S-180) bearing mice after intravenous injection of the HCPT-loaded nanoparticles show that HCPT-loaded nanoparticles exhibited superior in vivo antitumor effect and remarkably different biodistribution than the commercially available HCPT injection.