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. 2024 Oct 12;7(11):7535–7543. doi: 10.1021/acsabm.4c01123

Stable Porous Organic Cage Nanocapsules for pH-Responsive Anticancer Drug Delivery for Precise Tumor Therapy

Yanping Deng †,*, Zhenhong Du †, Shunfu Du ‡,∥, Nan Li †, Wenjing Wang ‡,∥, Kongzhao Su ‡,∥,*, Daqiang Yuan ‡,∥,*
PMCID: PMC11577425  PMID: 39395005

Abstract

graphic file with name mt4c01123_0007.jpg

The search for drug nanocarriers with stimuli-responsive properties and high payloads for targeted drug delivery and precision medicine is currently a focal point of biomedical research, but this endeavor still encounters various challenges. Herein, a porous organic cage (POC) is applied to paclitaxel (PTX) drug delivery for cancer therapy for the first time. Specifically, water-soluble, stable, and biocompatible POC-based nanocapsules (PTX@POC@RH40) with PTX encapsulation efficiency over 98% can be synthesized by simply grafting nonionic surfactant (Polyoxyl 40 hydrogenated castor oil, RH40) on the POC surface. These PTX@POC@RH40 nanocapsules demonstrate remarkable stability for more than a week without aggregation and exhibit pH-responsive behavior under acidic conditions (pH 5.5) and display sustained release behavior at both pH 7.4 and pH 5.5. Intravenous administration of PTX@POC@RH40 led to a 3.5-fold increase in PTX bioavailability compared with the free PTX group in rats. Moreover, in vivo mouse model experiments involving 4T1 subcutaneous breast cancer tumors revealed that PTX@POC@RH40 exhibited enhanced anticancer efficacy with minimal toxicity compared with free PTX. These findings underscore the potential of POCs as promising nanocarriers for stimuli-responsive drug delivery in therapeutic applications.

Keywords: porous organic cages, pH-responsive delivery, paclitaxel, nanocarrier drug delivery, tumor therapy

1. Introduction

Cancer remains a leading cause of mortality among humans, with its incidence progressively rising over recent years.1 However, efficient treatment methods that can entirely eradicate tumor cells without inflicting harm on normal cells or organs are currently lacking.2 This scenario underscores the urgent need for the development of in situ responsive therapy for tumors. The enhanced permeability and retention (EPR) effect is a pivotal characteristic of tumors.3 Normal tissues have cellular connectivity of blood vessels less than 6 nm, whereas solid tumor blood vessels range from 200 to 600 nm. Consequently, nanoparticles with diameters under 200 nm can accumulate passively in the bloodstream, delivering drugs specifically to cancer cells.4 In addition, the extracellular pH of tumors is approximately 6.8, contrasting with the intracellular pH range of 4.5 to 6.5. Thus, the development of pH-responsive smart nanoscale drug carriers exploiting the pH disparities between tumor and normal tissues represents a burgeoning area of research.5 However, the complex design process for such delivery systems frequently hinders their clinical application,6 necessitating simplified approaches for fabricating pH-responsive nanoscale drug delivery systems.

Over the past few decades, a variety of synthetic nanoscopic delivery platforms, including cell-permeable peptides,7 metal nanoparticles,8 small dendrimers,9 carbon nanotubes,10 and artificial nanosized porous materials, such as metal–organic frameworks (MOFs),11,12 covalent organic frameworks (COFs),13 porous organic polymers (POPs),14 hydrogen-bonded organic frameworks (HOFs),15 porous coordination cages (PCCs),16,17 and porous organic cages (POCs),18,19 have been investigated for their potential as drug nanocarriers. Artificial nanosized porous materials have recently seen rapid development and use in targeted drug delivery, due to their unique properties such as a large surface area, high pore volume, and controllable pore size.20 Nevertheless, the design and production of responsive nanocarriers based on nanosized porous materials to enhance antitumor efficacy remain significant challenges.

Porous organic cages (POCs) are an emerging class of nanosized porous materials. These self-assemble from covalently bonded organic building blocks into discrete organic macromolecules with inherent specific cavity sizes.21−31 These macromolecules form an ordered structure via weak interactions with porosity encompassing both internal cavities and external stacking pores. Besides their favorable properties, such as low density, high surface area, high porosity, and exceptional chemical and thermal stability, POCs also display vital characteristics necessary for therapeutic drug delivery. First, the absence of heavy and toxic metal ions in POCs ensures excellent biocompatibility. Second, the ultrasmall size of POCs (typically under 10 nm) facilitates their penetration into tumor tissue, overcoming the obstacles of high interstitial fluid pressure and dense extracellular matrix, while enhancing their accumulation in cancer tissue via the EPR effect. Third, the discrete nature of POCs confers unique advantages in terms of solution processing, regeneration, and straightforward functionalization.32−35 Lastly, POCs can be synthesized using dynamic covalent chemistry (DCC) methods, allowing for disassembly through specific external stimuli.36−40 Given these merits, POCs have shown promising applications in selective guest encapsulation and separation,41−43 species stabilization,44−46 and nanoscale reaction vessels for catalysis,47−49 among others.50−62 However, the utilization of POCs as nanodrug carriers in biomedicine remains relatively unexplored. Moreover, to the best of our knowledge, no prior studies have examined the effect of anticancer drug delivery using POCs in an in vivo model. Herein, we present a straightforward approach employing POCs as nanocarriers for the anticancer drug paclitaxel (PTX; Figure 1b) to fabricate drug-loaded nanocapsules (namely, PTX@POC@RH40) with excellent biocompatibility, tailored particle size, high drug loading capacity, acidic pH-responsive characteristics, and sustained release behavior (Figure 1a). Furthermore, PTX@POC@RH40 showed enhanced anticancer efficacy in a subcutaneous breast cancer (4T1) in vivo mouse model, surpassing the effectiveness of free PTX while exhibiting minimal toxicity. This approach offers a more effective strategy for precision tumor treatment based on POC materials.

Figure 1.

Figure 1

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(a) Schematic diagram of POC as pH-responsive anticancer drug deliver for precise tumor therapy. (b) Design and synthesis of [6 + 12] calix[4]resorcinarene-based POC. Carbon is yellow, oxygen red, nitrogen blue, hydrogen white, and cavity gray. (c) Chemical structure of PTX.

2. Experimental Section

The POC (CPOC-301) was synthesized following a slightly modified procedure previously published by our research group,63 and the structure has been determined by 1H NMR (Figure S1). Other organic solvents and commercially obtained drugs were utilized without further purification. The POC@RH40 was prepared by combining POC and RH40 in water, followed by stirring. The PTX@POC was synthesized using a straightforward immersion method, while the PTX@POC@RH40 was prepared by combining PTX@POC with RH40 and stirring in water. The effect of POC@RH40 on cellular uptake was investigated by using coumarin-6 (C6) as a fluorescent probe. Ex vivo tissue distribution of POC@RH40 was assessed by quantifying the concentration of Dir (a fluorescent dye) in major organs and tumors using in vivo imaging analysis. The antitumor efficacy of free PTX and PTX@POC@RH40 was evaluated in a mouse model of breast cancer (4T1 tumor). The ultraviolet–visible (UV–vis) spectra of PTX@POC, POC, and PTX were measured by using a UV-2600i UV–vis spectrophotometer (SHIMADZU, Japan). In vivo imaging was conducted using an IVIS Spectrum system (PerkinElmer, USA). Particle size, particle size distribution (polydispersity index, PDI), and zeta potential were determined with a laser particle size analyzer (Anton-Paar, Austria). High-resolution transmission electron microscopy (TEM) images were obtained by using a Hitachi HT7800 transmission electron microscope (Japan). Real-time drug release behavior was monitored using high-performance liquid chromatography (HPLC, 1260 Infinity, Agilent, USA) with an Amethyst C18-H column. Absorbance values for cell viability were measured at a wavelength of 570 nm using a microplate reader (Thermo Fisher, Multiskan FC, USA). Additional experimental details and characterization can be found in the Supporting Information.

3. Results and Discussion

3.1. Synthesis of POC and Enhancement of Its Water Solubility by RH40 Surfactant

A predesignable POC with chemical formula of C360H384N24O48 was synthesized through [6 + 12] imine condensation reactions between one equivalent of tetraformyl-functionalized calix[4]resorcinarene and two equivalents of p-phenylenediamine (Figures 1b).63−65 The single X-ray crystal structure suggested that the [6 + 12] POC is a truncated octahedron-shaped cage with eight trigonal ports with edge lengths and diameters of about 1.2 and 0.7 nm, and a large cavity with inner diameters and volumes of ∼1.7 and ∼4.3 nm3, respectively, which can be a promising drug nanocarrier. However, the presence of 24 pendant alkyl chains on the outer surface of POC makes it insoluble in water, which limits its potential biomedical application. Therefore, the POC was modified with nonionic surfactants, such as polysorbate 80 (Tween 80) with hydrophilic–lipophilic balance (HLB) value of about 15, poly(ethylene glycol) 12-hydroxystearate (Solutol HS15) with HLB = ∼14–16, and polyoxyl 40 hydrogenated castor oil (RH40) with HLB = ∼14–16 (Figure S2), to increase its water solubility.66,67 When these nonionic surfactants were incubated with POC in a weight ratio of 100:1, a reduction in surface tension was observed compared to their corresponding nonionic surfactant solutions (Figure 2). Notably, incubation of POC with RH40 demonstrated a significant decrease in surface tension compared to RH40 alone, making RH40 the preferred choice for the formation of POC-based nanocapsules. These nanocapsules could self-assemble to form clear colloidal solutions in aqueous environments (Figure 2), while the same concentration of POC precipitated in water under identical conditions. By utilizing POC@RH40 nanocapsules, we successfully achieved substantial improvement in the solubility of POC up to 5 mg/mL.

Figure 2.

Figure 2

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Surface tension variation with different concentrations of nonionic surfactants and their corresponding concentrations incubated with POC. The photos of POC in H2O and POC@RH40 in H2O.

3.2. Excellent Biocompatibility In Vivo and In Vitro

The biocompatibility of POC@RH40 was initially investigated for its potential in biological applications. First, the cell viability of POC@RH40 was assessed using 3-(4,5-dimethylthiazol-2-y1)-3,5-diphenyltetrazolium bromide (MTT) assay, incubating it with cancer cells (MCF-7) and normal cells (MCF-10A). Even at POC concentrations up to 34.5 μmoL/L, the cell viability of MCF-7, MCF-10A, HepG2 and B16-F10 incubated with POC@RH40 for 24 h was approximately 80%, indicating minimal cytotoxicity (Figures 3a and S3). Furthermore, POC@RH40 was added to 2% rat serum and incubated at 37 °C for 4 h. The hemolysis rate in the presence of POC@RH40 consistently remained below 5% even at a concentration of 69 μmoL/L, demonstrating excellent biocompatibility (Figure 3b and eq S1). Additionally, an in vivo acute toxicity test on mice was conducted by intraperitoneal injection of POC@RH40 nanocapsules at a cumulative dose of 2000 mg/kg over 48 h. Following administration, the mice exhibited a 100% survival rate, and no significant changes in body weight were observed over a seven day period, confirming its favorable biocompatibility and high safety profile (Figure S4).

Figure 3.

Figure 3

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(a) Cell viability of POC@RH40 nanocapsules after 24 h of incubation with either cancer cells (MCF-7) or normal cells (MCF-10A). (b) Hemolysis assay on POC@RH40 nanocapsules.

3.3. PTX@POC@RH40 Nanocapsules with Excellent Encapsulation Efficiency and pH-Responsive Sustained Release Behavior

Due to its excellent biocompatibility, accessible windows, and large cavity volume, POC was further investigated as a potential nanocarrier for antitumor drug delivery systems. The widely used anticancer agent PTX is noted for its limited water solubility and pronounced toxic effects, making it a suitable drug model for a proof-of-concept POC-based drug delivery system for cancer therapy. In this study, the synthesis of PTX@POC material was successfully achieved by rotating the POC sample in a methanol solution. The encapsulation of PTX within PTX@POC (1.47/1, w/w) was confirmed through various analytical techniques such as UV–vis spectrum, Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffraction (PXRD) spectra, and N2 gas sorption isotherms (Figure 4a–d). The presence of both POC and PTX in PTX@POC was verified by observing their characteristic absorption peaks in the UV–vis and FT-IR spectra (Figure 4a,b). This was further supported by the retention of the PXRD patterns of POC after encapsulation of PTX, indicating that PTX was located within the cavities of the POC samples (Figure 4c). Additionally, the specific surface area as determined by Brunauer–Emmett–Teller (BET) analysis for PTX@POC was negligible (∼4 m2 g–1) and much lower than those of the pristine POC and physical mixture of POC and PTX with BET values of ∼1800 and ∼1210 m2 g–1, respectively (Figure 4d). These results suggest that PTX was successfully confined within the cavities of POC. The PTX loading of PTX@POC reached up to 24.63 wt % (Figure S5 and eq S2), which is remarkably higher than other drug delivery nanoplatforms based on porous materials.68 The high payload of this POC has also been confirmed with 5-fluorouracil (5-Fu), another kind of anticancer agent,13 with drug uptake capacity of 28.81 wt % (Figure S6).

Figure 4.

Figure 4

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(a) UV–vis spectrum of PTX@POC, POC, and PTX. (b) FT-IR spectra of PTX@POC, POC, PTX, and a physical mixture of POC and PTX. (c) PXED spectra of PTX@POC, POC, PTX, and physical mixture of POC and PTX. (d) N2 sorption isotherms of PTX@POC, POC, and physical mixture of POC and PTX at 77 K. (e) Particle size and distribution of POC@RH40 and PTX@POC@RH40. (f) Photos of PTX@POC@RH40 in H2O. TEM images of (g) POC@RH40 and (h) PTX@POC@RH40 nanocapsules. (i, j) Colloidal stability of POC@RH40 and PTX@POC@RH40 in (i) PBS solution at 4 °C for 7 days and (j) PBS containing 10 wt % FBS at 37 °C for 7 days. (k, l) Cumulative release of PTX from (k) PTX@POC and (l) PTX@POC@RH40.

Subsequently, the resultant PTX@POC was mixed with RH40 and magnetically stirred at 55 °C for 2 h. Water was slowly added dropwise to the final formulation (PTX@POC@RH40, 1.47/1/100, w/w/w). PTX@POC@RH40 could form clear colloidal solutions in aqueous solution and exhibited a strong visual Tyndall effect under the irradiation of a portable laser pointer pen (635 nm) (Figure 4f). The particle sizes of POC@RH40 and PTX@POC@RH40 were measured to be 18.03 ± 1.9 and 20.14 ± 2.7 nm, respectively (Figure 4e and Table S1). The slight increase in particle size may occur upon drug loading, which could potentially be attributed to the interaction between PTX and POC. Given the strong hydrophobicity of PTX, PTX@POC@RH40 demonstrated exceptional encapsulation efficiency, exceeding 98% (eq S3). The TEM images show that the POC@RH40 and PTX@POC@RH40 samples were monodispersed spherical particles (Figure 4g,h). Furthermore, the particle sizes of these samples were found to align well with the results from dynamic light scattering. Subsequent incubation of the PTX@POC@RH40 and POC@RH40 samples with phosphate buffered saline (PBS) and a PBS solution containing 10 wt % fetal bovine serum (FBS) at 37 °C for 7 days did not result in significant changes in particle size and polydispersity index (PDI) for either sample (Figures 4f,g). This demonstrates their excellent colloidal stability and potential for long-term storage, making it a promising candidate for easy industrial-scale production. The PTX@POC@RH40 nanocapsules exhibited an optimal particle size of approximately 20 nm, which is smaller than that of commercial PTX nanoformulations such as Abraxane (approximately 130 nm) and Genexol-PM (approximately 23 nm). This result implies that the PTX@POC@RH40 nanocapsule may exhibit superior permeability and enhanced EPR effect.69

Given the inherent dynamic nature of POC’s bond linkages, we hypothesized that PTX@POC and PTX@POC@RH40 would exhibit pH responsiveness. Subsequently, we conducted an investigation of its release behavior in simulated tumor microenvironments (pH 5.5). We used the paddle dissolution method to evaluate the cumulative release of PTX from PTX@POC and the dialysis membrane method to assess the release of PTX from PTX@POC@RH40. PTX@POC demonstrated distinct drug release profiles in media with pH values of 7.4 and 5.5 (Figure 4k). At pH 7.4, the cumulative percentage of PTX released over 72 h was relatively low (53.4%), but this significantly increased to 82.6% at pH 5.5. Furthermore, PTX@POC displayed sustained-release characteristics, releasing 40.6% at pH 7.4 and 62.8% at pH 5.5 within the initial 12 h. As can be seen from Table S2, the in vitro release profiles of PTX@POC and PTX@POC@RH40 were analyzed using kinetic fitting, with the drug release for both being modeled following first-order kinetics. Notably, over 90% of raw PTX was released under both pH conditions. These results suggest that PTX@POC is sensitive to acidic environments and exhibits a sustained-release behavior, which is ascribed to the disassembly of POC’s bonds in such conditions. Similar patterns of drug release were observed in PTX@POC@RH40 (Figure 4l).

3.4. Enhanced Bioavailability and Extended Systemic Circulation in Rat Models

To evaluate whether PTX@POC@RH40 can enhance the relative bioavailability of PTX, an in vivo pharmacokinetic study using a rat model was performed. Both PTX@POC@RH40 and free PTX were administered intravenously at a dose of 15 mg/kg. The mean plasma concentration–time profile is depicted in Figure 5a, while the principal pharmacokinetic parameters are enumerated in Table S3. In comparison to free PTX, PTX@POC@RH40 demonstrated a significantly elongated mean residence time (MRT) and a markedly increased area under the curve (AUC). These values were respectively 2.1-fold and 3.5-fold greater than those observed in the group administered free PTX. These findings suggest that PTX@POC@RH40 can enhance drug bioavailability and effectively lengthen its circulation time within the body. The prolonged in vivo residence time of PTX@POC@RH40 can be attributed to its enhanced EPR effect, sustained release, and high encapsulation efficiency. Collectively, these results imply that PTX@POC@RH40 holds significant potential for substantially increasing the plasma concentration of PTX, which could lead to benefits such as improved therapeutic efficacy and reduced dosing frequency.

Figure 5.

Figure 5

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(a) Mean plasma concentration–time curves of free PTX and PTX@POC@RH40. (b) Inverted fluorescence microscope images of MCF-7 cells incubated with the C6@POC@RH40 and C6 solution, and (c) their fluorescence intensity data. Data are expressed as mean ± standard deviation. Scale bars represent 100 μm. **p < 0.01, ***p < 0.001. (d) Cell viability after incubation with MCF-7 cells for 48 and 72 h. (e) Cell viability after incubation with 4T1 cells for 48 and 72 h. (f, g) Colony formation assay conducted using (f) MCF-7 cells and (g) 4T1 cells. Data are expressed as mean ± standard deviation, *p < 0.05, **p < 0.01.

3.5. Improved Cellular Uptake in Breast Cancer Cell Lines and Augmented Inhibitory Effects on Cancer Cell Line Proliferation

Coumarin-6 (C6)-labeled POC@RH40 (C6@POC@RH40) was incubated with breast cancer MCF-7 cells for 0.5, 2, 12, and 24 h. The cellular uptake of the resultant nanocapsules was captured using an inverted fluorescence microscope at predetermined time points, followed by quantification of the intracellular C6 fluorescence intensity in the obtained images using ImageJ 1.46r software. After 0.5 h treatment with MCF-7 cells, a weak green fluorescence emitted by either C6@POC@RH40 or free C6 was observed surrounding the cell nucleus (Figure 5b), suggesting internalization of some drugs into the cytoplasm. Moreover, compared to free C6 solution, the fluorescence intensity inside the cells for C6@POC@RH40 at different time points (0.5, 1, 12, and 24 h) was significantly higher; it showed respective increases of 2.6-fold, 1.7-fold, 1.8-fold, and 1.7-fold compared to free C6 solution (Figure 5c). This suggests that POC-based nanocarriers can substantially enhance cellular drug uptake, thereby improving the inhibitory effects on cells treated with PTX@POC@RH40.

The inhibitory effects of both PTX@POC@RH40 and free PTX on the proliferation of breast cancer cell lines, including MCF-7 and 4T1 cells, were assessed by using the MTT assay and colony formation assay. Following incubation with the breast cancer cell lines, it was found that the cytotoxic effect of both free PTX and PTX@POC@RH40 was both dose- and time-dependent (Figures 5d,e). The half-maximum inhibitory concentration (IC50) of PTX@POC@RH40 at 48 or 72 h was significantly lower than that of free PTX at the corresponding time (Table S4), indicating superior inhibitory effects of PTX@POC@RH40 on breast cancer cell proliferation. Similar results were observed in other cancer cell lines, including HepG2 and B16-F10 (Figure S7), suggesting that POC enhances PTX’s inhibitory effects on cancer cell proliferation. The colony formation assay further confirmed the superior inhibitory effect of PTX@POC@RH40 on MCF-7 and 4T1 compared to that of free PTX (Figure 5f,g), consistent with the findings from the MTT assay.

3.6. Reinforced Targeting of the Tumor Microenvironment Ex Vivo and Improved In Vivo Antitumor Effects

The ex vivo tissue distribution and in vivo antitumor effects were investigated using a mouse model bearing tumors from subcutaneous inoculation of breast cancer 4T1 cells with a tumor volume reaching 100 mm3. The ex vivo tissue distribution of POC@RH40 was investigated using a fluorescent 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanineiodide (Dir) dye. Dir was incorporated into POC@RH40 (Dir@POC@RH40). Dir solution (Dir Sol) and Dir@POC@RH40 were administered at a dosage of 1.5 mg Dir/kg (n = 3) for the mice. In vivo imaging was carried out at 2, 4, 8, and 24 h postinjection using a in vivo imaging system with set excitation and emission wavelengths of 740 and 790 nm, respectively. The results revealed that, in comparison to free Dir, Dir@POC@RH40 displayed higher fluorescence intensity and greater tumor site accumulation after 2, 4, and 8 h (Figure 6a). Notably, 24 h postinjection, the fluorescence intensity of Dir@POC@RH40 in the tumor tissue was 4.1 times higher than that of free Dir (Figure 6b,c), suggesting selective tumor accumulation and prolonged residence time of PTX@POC@RH40 nanocapsules in comparison to free PTX. The enhanced tumor targeting effect may be attributed to the unique properties of the POC@RH40 nanocapsules, such as the EPR effect and acidic pH-responsive drug release properties. Collectively, these results suggest potential application of POC@RH40 in improving targeted drug delivery to tumors while minimizing harmful effects on normal tissues.

Figure 6.

Figure 6

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(a) Ex vivo images of mice after injection. (b) Ex vivo fluorescence images of excised organs and tumor at 24 h postinjection. (c) Quantitative fluorescence intensity of excised organs and tumor after 24 h postinjection. (d) Dosing regimen. (e) Tumor volume growth curve in mice during the entire treatment. (f) Tumor weight. (g) Tumor photographs. Data are expressed as mean ± standard deviation. ***p < 0.001; ****p < 0.0001. (h) Hematoxylin and eosin (H&E) staining for major organs and tumor. Magnification, ×200. (i) Liver and kidney function parameters of the treated mice: aspartate transaminase (AST), alanine transaminase (ALT), urea nitrogen (BUN), creatinine (CREA). (j) Body weight changes of mice during the entire treatment.

The antitumor effects of PTX@POC@RH40 were evaluated, as depicted in Figure 6d. Throughout the treatment period, both the saline and POC@RH40 groups exhibited an increase in tumor volume (eq S4), indicating negligible therapeutic effect of POC alone. However, both free PTX and PTX@POC@RH40 effectively inhibited tumor growth (Figure 6e). At the treatment’s end, free PTX resulted in a tumor weight inhibition rate of 69.5%, whereas PTX@POC@RH40 achieved a higher rate of 86.8% (Figure 6f,g and eq S5). Moreover, the PTX@POC@RH40 group displayed prominent tumor necrosis, nuclear shrinkage, and fragmentation, indicative of superior antitumor effects (Figure 6h). A comprehensive biosafety assessment of PTX@POC@RH40 in mice throughout the treatment duration revealed no significant alterations in body weight in the PTX@POC@RH40-treated groups as compared to those in the saline-treated groups (Figure 6j). Additionally, there were no significant changes detected in the liver and kidney functions of mice following administration of either POC@RH40 or PTX@POC@RH40 (Figure 6g). Consistent with these findings, histopathological examination showed no notable alterations in major organs of mice. These data suggest that PTX@POC@RH40 possesses enhanced anticancer efficacy with negligible toxicity.

4. Conclusions

In conclusion, we have successfully developed a pH-responsive and biocompatible POC-based nanocapsule (PTX@POC@RH40) to facilitate the delivery of poorly soluble PTX for cancer therapy. The POC’s drug loading capacity reaches up to 24.63%, outperforming most drug nanocarriers based on synthetic porous materials. Moreover, the resulting PTX@POC@RH40 nanocapsules show high PTX encapsulation efficiency (>98%), and exhibit remarkable stability (>1 week) without aggregation, making it excellent candidate for industrial-scale production. PTX@POC@RH40 exhibits pH-responsive release under acidic conditions (pH 5.5) and sustained-release of PTX, which enhance the tumor targeting, improve antitumor efficacy, and minimize toxic side effects on healthy tissue and organs. Furthermore, PTX@POC@RH40 exhibits superior pharmacokinetic behavior and in vivo antitumor effects compared to PTX alone. To our knowledge, this study represents the first reported use of POC-based material for practical biological applications in vivo. The design strategy introduced in this study not only provides a novel methodology for constructing drug nanocarriers using POCs but also broadens the research scope and application potential of POCs.

Acknowledgments

This work was financially supported by the National Nature Science Foundation of China (22071244, 22275191), Youth Innovation Promotion Association CAS (2022305), and Natural Science Foundation of Fujian Province of China (2022J01503, 2020J05087).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsabm.4c01123.

  • Additional experimental details regarding the preparation of POC, POC@RH40, PTX@POC@RH40, and their respective drug delivery performances. Additional figures including 1H NMR spectra of POC, the chemical structures of nonionic surfactants, cell viability data for POC@RH40, body weight changes in mice following the injection of POC@RH40, UV–vis spectra of PTX and 5-FU, and cytotoxicity assays for PTX@POC@RH40. Additional supplementary tables including the physicochemical characterization of PTX@POC@RH40 and POC@RH40, the kinetics of the in vitro release profile for PTX@POC@RH40 and PTX@POC, half-maximum inhibitory concentration (IC50) values for PTX and PTX@POC@RH40, as well as key pharmacokinetic parameters for PTX in rats (PDF)

Author Contributions

§ Y.D., Z.D., and S.D. contributed equally to this work.

The authors declare no competing financial interest.

Supplementary Material

mt4c01123_si_001.pdf (664.7KB, pdf)

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