Electroporation and Electrochemotherapy in Gynecological and Breast Cancer Treatment

Gynecological carcinomas affect an increasing number of women and are associated with poor prognosis. The gold standard treatment plan is mainly based on surgical resection and subsequent chemotherapy with cisplatin, 5-fluorouracil, anthracyclines, or taxanes. Unfortunately, this treatment is becoming less effective and is associated with many side effects that negatively affect patients’ physical and mental well-being. Electroporation based on tumor exposure to electric pulses enables reduction in cytotoxic drugs dose while increasing their effectiveness. EP-based treatment methods have received more and more interest in recent years and are the subject of a large number of scientific studies. Some of them show promising therapeutic potential without using any cytotoxic drugs or molecules already present in the human body (e.g., calcium electroporation). This literature review aims to present the fundamental mechanisms responsible for the course of EP-based therapies and the current state of knowledge in the field of their application in the treatment of gynecological neoplasms.     

Doxorubicin Encapsulated in TPGS-Modified 2D-Nanodisks Overcomes Multidrug Resistance

Multidrug resistance (MDR) is regarded as a main obstacle for effective chemotherapy, and P-glycoprotein (P-gp)-mediated drug efflux has been demonstrated to be the key factor responsible for MDR. In this study, a novel pH-responsive hybrid drug delivery system was developed by conjugating d -α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a kind of P-gp inhibitor, on the surface of laponite nanodisks to overcome MDR. The prepared LM-TPGS display excellent colloidal stability, a high encapsulation efficiency of doxorubicin (DOX), and a pH-responsive drug release profile. In vitro experiments verified that LM-TPGS/DOX could exhibit significantly enhanced therapeutic efficacy in treating DOX-resistant breast cancer cells (MCF-7/ADR) through inhibiting the activity of P-gp-mediated drug efflux and effectively accumulating DOX within cancer cells. In vivo results revealed that LM-TPGS/DOX outstandingly suppressed MCF-7/ADR tumors with low side effects. Therefore, the high drug payload, enhanced inhibition efficacy to drug-resistant cells, and low side effects make the LM-TPGS/DOX a promising nanoplatform to reverse MDR for effective chemotherapy.     

Reversal of Multidrug Resistance by Apolipoprotein A1-Modified Doxorubicin Liposome for Breast Cancer Treatment

Multidrug resistance (MDR) remains a major problem in cancer therapy and is characterized by the overexpression of p-glycoprotein (P-gp) efflux pump, upregulation of anti-apoptotic proteins or downregulation of pro-apoptotic proteins. In this study, an Apolipoprotein A1 (ApoA1)-modified cationic liposome containing a synthetic cationic lipid and cholesterol was developed for the delivery of a small-molecule chemotherapeutic drug, doxorubicin (Dox) to treat MDR tumor. The liposome-modified by ApoA1 was found to promote drug uptake and elicit better therapeutic effects than free Dox and liposome in MCF-7/ADR cells. Further, loading Dox into the present ApoA1-liposome systems enabled a burst release at the tumor location, resulting in enhanced anti-tumor effects and reduced off-target effects. More importantly, ApoA1-lip/Dox caused fewer adverse effects on cardiac function and other organs in 4T1 subcutaneous xenograft models. These features indicate that the designed liposomes represent a promising strategy for the reversal of MDR in cancer treatment.     

Lysinated Multiwalled Carbon Nanotubes with Carbohydrate Ligands as an Effective Nanocarrier for Targeted Doxorubicin Delivery to Breast Cancer Cells

Multiwalled carbon nanotubes (MWCNTs) are elongated, hollow cylindrical nanotubes made of sp2 carbon. MWCNTs have attracted significant attention in the area of drug delivery due to their high drug-loading capacity and large surface area. Furthermore, they can be linked to bioactive ligands molecules via covalent and noncovalent bonds that allow for the targeted delivery of anticancer drugs such as doxorubicin. The majority of methodologies reported for the functionalization of MWCNTs for drug delivery are quite complex and use expensive linkers and ligands. In the present study, we report a simple, cost-effective approach for functionalizing MWCNTs with the carbohydrate ligands, galactose (GA), mannose (MA) and lactose (LA), using lysine as a linker. The doxorubicin (Dox)-loaded functionalized MWCNTs were characterized using FT-IR, NMR, Raman, XRD and FE-SEM. The drug–loaded MWCNTs were evaluated for drug loading, drug release and cell toxicity in vitro, in breast cancer cells. The results indicated that the carbohydrate-modified lysinated MWCNTs had greater Dox loading capacity, compared to carboxylated MWCNTs (COOHMWCNTs) and lysinated MWCNTs (LyMWCNTs). In vitro drug release experiments indicated that the carbohydrate functionalized LyMWCNTs had higher Dox release at pH 5.0, compared to the physiological pH of 7.4, over 120 h, indicating that they are suitable candidates for targeting the tumor microenvironment as a result of their sustained release profile of Dox. Doxorubicin-loaded galactosylated MWCNTs (Dox-GAMWCNTs) and doxorubicin loaded mannosylated MWCNTs (Dox-MAMWCNTs) had greater anticancer efficacy and cellular uptake, compared to doxorubicin–loaded lactosylated MWCNTs (Dox-LAMWCNTs) and pure Dox, in MDA-MB231 and MCF7 breast cancer cells. However, neither the ligand conjugated multiwall blank carbon nanotubes (GAMWCNTs, MAMWCNTs and LAMWCNTs) nor the lysinated multiwalled blank carbon nanotubes produced significant toxicity in the normal cells. Our results suggest that sugar-tethered multiwalled carbon nanotubes, especially the galactosylated (Dox-GAMWCNTs) and mannosylated (Dox-MAMWCNTs) formulations, may be used to improve the targeted delivery of anticancer drugs to breast cancer cells.     

Targeted Drug Delivery Biopolymers Effectively Inhibit Breast Tumor Growth and Prevent Doxorubicin-Induced Cardiotoxicity

The anticancer agent doxorubicin(dox) has been widely used in the treatment of a variety of hematological malignancies and solid tumors. Despite doxorubicin’s efficiency in killing tumor cells, severe damage to healthy tissues, along with cardiotoxicity, limits its clinical use. To overcome these adverse side effects, improve patient safety, and enhance therapeutic efficacy, we have designed a thermally responsive biopolymer doxorubicin carrier that can be specifically targeted to tumor tissue by locally applying mild hyperthermia (41 °C). The developed drug vehicle is composed of the following: a cell penetrating peptide (SynB1) to promote tumor and cellular uptake; thermally responsive Elastin-like polypeptide (ELP); and the (6-maleimidocaproyl) hydrazone derivative of doxorubicin (DOXO-EMCH) containing a pH-sensitive hydrazone linker that releases doxorubicin in the acidic tumor environment. We used the in vivo imaging system, IVIS, to determine biodistribution of doxorubicin-delivered ELP in MDA-MB-231 xenografts in nude mice. Tumor bearing mice were treated with a single IV injection of 10 mg/kg doxorubicin equivalent dose with free doxorubicin, thermally responsive SynB1 ELP 1-DOXO, and a thermally nonresponsive control biopolymer, SynB1 ELP 2-DOXO. Following a 2 h treatment with hyperthermia, tumors showed a 2-fold higher uptake when treated with SynB1 ELP 1-DOXO compared to free doxorubicin. Accumulation of the thermally non-responsive control SynB1 ELP2 –DOXO was comparable to free doxorubicin, indicating that an increase in dox accumulation with ELP is due to aggregation in response to thermal targeting. Higher levels of SynB1 ELP1–DOXO and SynB1 ELP2 –DOXO with respect to free doxorubicin were observed in kidneys. Fluorescence intensity from hearts of animals treated with SynB1 ELP1–DOXO show a 5-fold decrease in accumulation of doxorubicin than the same dose of free doxorubicin. SynB1-ELP1-DOXO biopolymers demonstrated a 6-fold increase in tumor/heart ratio in comparison to free doxorubicin, indicating preferential accumulation of the drug in tumors. These results demonstrate that thermally targeted polymers are a promising therapy to enhance tumor targeting and uptake of anticancer drugs and to minimize free drug toxicity in healthy tissues, representing a great potential for clinical application.     

Synthesis and Characterization of Sterculia Gum Based pH Responsive Drug Delivery System for Use in Colon Cancer

The present study deals with the modification of sterculia gum to develop the novel colon specific delivery system for use in colon cancer. The sterculia and acrylic acid based hydrogels were synthesized and characterized with FTIR, SEMs, TGA and swelling behavior. Swelling studies of the hydrogels were carried out as a function of reaction parameters such as monomer concentration, initiator concentration, amount of sterculia gum and crosslinker concentration and nature of swelling mediums. Swelling kinetics of the hydrogels and in vitro release dynamics of anticancer model drug methotrexate from the hydrogels were studied to evaluate the swelling mechanism and drug release mechanism from the drug-loaded hydrogels. The values of diffusion exponent for the release of drug were 0.883, 0.910 and 0.787 in distilled water, pH 2.2 buffer and pH 7.4 buffer, respectively. The release of drug from the polymer matrix occurred through a non -Fickian type diffusion mechanism.     

Mixed Micelles for Targeted and Efficient Doxorubicin Delivery to Multidrug‐Resistant Breast Cancer Cells

For efficient treatment of multidrug‐resistance (MDR) breast cancer cells, design of biocompatible mixed micelles with diverse functional moieties and superior stability is needed for targeted delivery of chemical drugs. In this study, polypropylene glycol (PPG)‐grafted hyaluronic acid (HA) copolymers (PPG‐g‐HA) are used to make mixed micelles with different amounts of pluronic L61, named PPG‐g‐HA/L61 micelles. Optimized PPG‐g‐HA/L61 micelles with 3% pluronic L61 exhibit great stability in aqueous solution, superior biocompatibility, and significantly increased uptake into MCF‐7 MDR cells via HA–CD44‐specific interactions when compared to free doxorubicin (DOX) and other types of micelles. In addition, DOX in PPG‐g‐HA/L61 micelles with 3% pluronic L61 have toxicity in MCF‐7 MDR cells but significantly lower toxicity in fibroblast L929 cells compared to free DOX. Thus, PPG‐g‐HA/L61 micelles with 3% pluronic L61 content can be a promising nanocarrier to overcome MDR and release DOX in a hyaluronidase‐sensitive manner without any toxicity to normal cells.

     

Maleimide-Functionalized Liposomes: Prolonged Retention and Enhanced Efficacy of Doxorubicin in Breast Cancer with Low Systemic Toxicity

Cell surface thiols can be targeted by thiol-reactive groups of various materials such as peptides, nanoparticles, and polymers. Here, we used the maleimide group, which can rapidly and covalently conjugate with thiol groups, to prepare surface-modified liposomes (M-Lip) that prolong retention of doxorubicin (Dox) at tumor sites, enhancing its efficacy. Surface modification with the maleimide moiety had no effect on the drug loading efficiency or drug release properties. Compared to unmodified Lip/Dox, M-Lip/Dox was retained longer at the tumor site, it was taken up by 4T1 cells to a significantly greater extent, and exhibited stronger inhibitory effect against 4T1 cells. The in vivo imaging results showed that the retention time of M-Lip at the tumor was significantly longer than that of Lip. In addition, M-Lip/Dox also showed significantly higher anticancer efficacy and lower cardiotoxicity than Lip/Dox in mice bearing 4T1 tumor xenografts. Thus, the modification strategy with maleimide may be useful for achieving higher efficient liposome for tumor therapy.     

Enhanced Anti-Tumor Effect of Folate-Targeted FA-AMA-hyd-DOX Conjugate in a Xenograft Model of Human Breast Cancer

Folate-aminocaproic acid-doxorubicin (FA-AMA-hyd-DOX) was firstly synthesized by our group. It was indicated that FA-AMA-hyd-DOX was pH-responsive, and had strong cytotoxicity on a folate receptor overexpressing cell line (KB cells) in vitro. The aim of our study was to further explore the potential use of FA-AMA-hyd-DOX as a new therapeutic drug for breast cancer. The cellular uptake and the antiproliferative activity of the FA-AMA-hyd-DOX in MDA-MB-231 cells were measured. Compared with DOX, FA-AMA-hyd-DOX exhibited higher targeting ability and cytotoxicity to FR-positive tumor cells. Subsequently, the tissue distribution of FA-AMA-hyd-DOX was studied, and the result confirmed that DOX modified by FA can effectively increase the selectivity of drugs in vivo. After determining the maximum tolerated dose (MTD) of FA-AMA-hyd-DOX in MDA-MB-231 tumor-bearing nude mice, the antitumor effects and the in vivo safety of FA-AMA-hyd-DOX were systematically evaluated. The data showed that FA-AMA-hyd-DOX could effectively increase the dose of DOX tolerated by tumor-bearing nude mice and significantly inhibit MDA-MB-231 tumor growth in vivo. Furthermore, FA-AMA-hyd-DOX treatment resulted in almost no obvious damage to the mice. All the positive data suggest that FA-targeted FA-AMA-hyd-DOX is a promising tumor-targeted compound for breast cancer therapy.     

Smart Nanodrug with Nuclear Localization Sequences in the Presence of MMP-2 To Overcome Biobarriers and Drug Resistance

A series of physiological barriers have impeded nanoparticle-based drug formulations (NDFs) from reaching their targeted sites and achieving therapeutic outcomes. In this study, we develop size-controllable stealth doxorubicin-loaded nanodrug coated with CD47 peptides (DOX/sNDF-CD47) based on supramolecular chemistry to overcome multiple biological barriers. The smart DOX/sNDF-CD47 can efficiently decrease sequestration by macrophages and disassemble into poly(amidoamine) dendrimers with nuclear localization sequences (DOX/PAMAM-NLS) in the presence of matrix metalloproteinase-2 (MMP-2). Such structure transformation endows DOX/sNDF-CD47 with the ability of deep penetration in multicellular tumor spheroid, lysosomal escape, and nucleus localization, resulting in excellent cytotoxicity and drug resistance combating. In vivo experiments further confirmed that DOX/sNDF-CD47 has good tumor-targeting ability and can significantly improve therapeutic efficacy of DOX on xenograft tumor model. The ability to overcome multiple biological barriers makes sNDF-CD47 a promising NDFs to treat cancer expressing MMP-2 and combating drug resistance.     

Self‐assembled Lipid Nanoparticles for Ratiometric Codelivery of Cisplatin and siRNA Targeting XPF to Combat Drug Resistance in Lung Cancer

DNA damage repair through the nucleotide excision repair (NER) pathway is one of the major reasons for the decreased antitumor efficacy of platinum‐based anticancer drugs that have been widely applied in the clinic. Inhibiting the intrinsic NER function may enhance the antitumor activity of cisplatin and conquer cisplatin resistance. Herein, we report the design, optimization, and application of a self‐assembled lipid nanoparticle (LNP) system to simultaneously deliver a cisplatin prodrug together with siRNA targeting endonuclease xeroderma pigmentosum group F (XPF), a crucial component in the NER pathway. The LNP is able to efficiently encapsulate both the platinum prodrug and siRNA molecules with a tuned ratio. Both platinum prodrug and XPF‐targeted siRNA are efficiently carried into cells and released; the former damages DNA and the latter specifically downregulates both mRNA and protein levels of XPF to potentiate the platinum drug, leading to enhanced expression levels of apoptosis markers and improved cytotoxicity in both cisplatin‐sensitive and ‐resistant human lung cancer cells. Our results demonstrate an effective approach to utilize a multi‐targeted nanoparticle system that can specifically silence an NER‐related gene to promote apoptosis induced by cisplatin, especially in cisplatin‐refractory tumors.     

MUC1 Aptamer-Capped Mesoporous Silica Nanoparticles for Navitoclax Resistance Overcoming in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. In the last years, navitoclax has emerged as a possible treatment for TNBC. Nevertheless, rapid navitoclax resistance onset has been observed thorough Mcl-1 overexpression. As a strategy to overcome Mcl-1-mediated resistance, herein we present a controlled drug co-delivery system based on mesoporous silica nanoparticles (MSNs) targeted to TNBC cells. The nanocarrier is loaded with navitoclax and the Mcl-1 inhibitor S63845 and capped with a MUC1-targeting aptamer ( apMUC1-MSNs(Nav/S63845) ). The apMUC1-capped nanoparticles effectively target TNBC cell lines and successfully induce apoptosis, overcoming navitoclax resistance. Moreover, navitoclax encapsulation protects platelets against apoptosis. These results point apMUC1-gated MSNs as suitable BH3 mimetics nanocarriers in the targeted treatment of MUC1-expressing TNBC.     

Periodic Mesoporous Organosilica Nanoparticles with Controlled Morphologies and High Drug/Dye Loadings for Multicargo Delivery in Cancer Cells

Despite the worldwide interest generated by periodic mesoporous organosilica (PMO) bulk materials, the design of PMO nanomaterials with controlled morphology remains largely unexplored and their properties unknown. In this work, we describe the first study of PMO nanoparticles (NPs) based on meta‐phenylene bridges, and we conducted a comparative structure–property relationship investigation with para‐phenylene‐bridged PMO NPs. Our findings indicate that the change of the isomer drastically affects the structure, morphology, size, porosity and thermal stability of PMO materials. We observed a much higher porosity and thermal stability of the para‐based PMO which was likely due to a higher molecular periodicity. Additionally, the para isomer could generate multipodal NPs at very low stirring speed and upon this discovery we designed a phenylene–ethylene bridged PMO with a controlled Janus morphology. Unprecedentedly high payloads could be obtained from 40 to 110 wt % regardless of the organic bridge of PMOs. Finally, we demonstrate for the first time the co‐delivery of two cargos by PMO NPs. Importantly, the cargo stability in PMOs did not require the capping of the pores, unlike pure silica, and the delivery could be autonomously triggered in cancer cells by acidic pH with nearly 70 % cell killing.     

Selective Killing of Breast Cancer Cells by Doxorubicin‐Loaded Fluorescent Gold Nanoclusters: Confocal Microscopy and FRET

Fluorescent gold nanoclusters (AuNCs) capped with lysozymes are used to deliver the anticancer drug doxorubicin to cancer and noncancer cells. Doxorubicin‐loaded AuNCs cause the highly selective and efficient killing (90 %) of breast cancer cells (MCF7) (IC₅₀=155 nm ). In contrast, the killing of the noncancer breast cells (MCF10A) by doxorubicin‐loaded AuNCs is only 40 % (IC₅₀=4500 nm ). By using a confocal microscope, the fluorescence spectrum and decay of the AuNCs were recorded inside the cell. The fluorescence maxima (at ≈490–515 nm) and lifetime (≈2 ns), of the AuNCs inside the cells correspond to Au_10–13. The intracellular release of doxorubicin from AuNCs is monitored by Förster resonance energy transfer (FRET) imaging.     

Conjugates of Antibody‐Targeted PEG Multiblock Polymers with Doxorubicin in Cancer Therapy

The synthesis and physico‐chemical characterisation of biodegradable multiblock polymer drug carriers based on poly(ethylene glycol) (PEG) are described. The blocks of PEG ( = 2 000) are interconnected by an enzymatically degradable tripeptide derivative consisting of one Lys and two Glu residues. An anticancer drug, doxorubicin (Dox), was attached to the polymer carrier by a Gly‐Phe‐Leu‐Gly tetrapeptide spacer, which is also susceptible to degradation by lysosomal enzymes. A targeting polyclonal antibody was covalently linked to the polymer‐Dox conjugate by the aminolytic reaction of reactive sulfosuccinimidyl ester groups of the polymer with the protein. The resulting antibody‐polymer‐drug conjugates were characterised by SEC, UV/VIS spectrophotometry and amino acid analysis. Although the studied polymers show only a moderate antiproliferative activity against concanavalin A‐stimulated murine splenocytes and a murine T‐cell EL 4 lymphoma in vitro, they exhibited significant antitumour efficiency against murine T‐cell EL 4 lymphoma in vivo.

     

Synthesis of HPMA Copolymers Containing Doxorubicin Bound via a Hydrazone Linkage. Effect of Spacer on Drug Release and in vitro Cytotoxicity

The aim of this study was the synthesis, physico‐chemical characterization and preliminary evaluation of biological activity of novel polymer drugs based on conjugates of anti‐cancer drug doxorubicin (Dox) with water‐soluble polymer drug carriers based on N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymers. In the conjugates, Dox is attached to the polymer via a pH‐sensitive linkage susceptible to hydrolysis at pH ≈ 5–6, thus enabling intracellular Dox release. Seven Dox‐containing polymer conjugates differing in the length and structure of the single‐amino‐acid or oligopeptide spacer were synthesized (Gly, β‐Ala, 6‐aminohexanoyl, 4‐aminobenzoyl, GlyGly, GlyLeuGly, Gly‐DL ‐PheLeuGly) and the relationship between the spacer structure and the rate of in vitro Dox release was studied at various pH. The rate of Dox release at pH 5 (close to lysosomal pH) ranged from 70 to 96% of total Dox/48 h, depending on the spacer structure and being the highest for the conjugate containing the 6‐aminohexanoyl spacer. The rate of Dox release from most conjugates incubated at pH 7.4 (blood pH) was more than 10 times slower, ca. 4–10% of total Dox/48 h. Molecular weight of the polymer (25 000–115 000 g/mol) did not significantly influence the rate. The presence of lysosomal enzyme cathepsin B in incubation media increased the rate of Dox release from the conjugates with oligopeptide GlyLeuGly and Gly‐DL ‐PheLeuGly spacers by 15–30%, whereas the release from conjugates with other spacers remained unchanged. Cytotoxicity of all hydrazone conjugates for mouse EL‐4 T cell lymphoma cells was much higher and close to that of free Dox (IC₅₀ ≈ 0.1–0.34 μg Dox/mL), in contrast to cytotoxicity of similar classic conjugates bearing Dox attached via an amide bond (IC₅₀ ≈ 19 μg Dox/mL).     

PLGA-Lipid Hybrid Nanoparticles for Overcoming Paclitaxel Tolerance in Anoikis-Resistant Lung Cancer Cells

Drug resistance and metastasis are two major obstacles to cancer chemotherapy. During metastasis, cancer cells can survive as floating cells in the blood or lymphatic circulatory system, due to the acquisition of resistance to anoikis—a programmed cell death activated by loss of extracellular matrix attachment. The anoikis-resistant lung cancer cells also develop drug resistance. In this study, paclitaxel-encapsulated PLGA-lipid hybrid nanoparticles (PLHNPs) were formulated by nanoprecipitation combined with self-assembly. The paclitaxel-PLHNPs had an average particle size of 103.0 ± 1.6 nm and a zeta potential value of −52.9 mV with the monodisperse distribution. Cytotoxicity of the nanoparticles was evaluated in A549 human lung cancer cells cultivated as floating cells under non-adherent conditions, compared with A549 attached cells. The floating cells exhibited anoikis resistance as shown by a lack of caspase-3 activation, in contrast to floating normal epithelial cells. Paclitaxel tolerance was evident in floating cells which had an IC₅₀ value of 418.56 nM, compared to an IC₅₀ value of 7.88 nM for attached cells. Paclitaxel-PLHNPs significantly reduced the IC₅₀ values in both attached cells (IC₅₀ value of 0.11 nM, 71.6-fold decrease) and floating cells (IC₅₀ value of 1.13 nM, 370.4-fold decrease). This report demonstrated the potential of PLHNPs to improve the efficacy of the chemotherapeutic drug paclitaxel, for eradicating anoikis-resistant lung cancer cells during metastasis.     

新型结合阿霉素的聚乙二醇嵌段共聚树枝状聚赖氨酸的合成及其药物缓释行为的研究

采用液相多肽合成方法, 成功制备得到窄分子量分布、结构确定的聚乙二醇嵌段共聚四代树枝状聚赖氨酸 (MPEG-block-DPL4). 在此基础上, 进一步将其DPL4的端氨基转化为端肼基, 并通过其与抗肿瘤药物阿霉素(DOX) C＝O的反应形成C＝N键, 实现在DPL4表面的阿霉素药物分子化学结合, 最终得到新型pH敏感性的高分子药物MPEG-block-DPL4-CONHN＝DOX. 运用紫外分光光度(UV-Vis)法, 对MPEG-block-DPL4-CONHNH₂与阿霉素的负载效率进行了定量分析. 高分子药物MPEG-block-DPL4-CONHN＝DOX在生理条件(pH＝7.4)下相对稳定, 而弱酸性条件(pH＝4.5, 5.5)下, C＝N键能较快水解, 释放阿霉素药物分子. 体外细胞毒性评价结果表明(细胞株SMMC-7721和SPCA-1), 所得新型高分子药物MPEG-block-DPL4-CONHN＝DOX的细胞毒性显著地低于游离阿霉素药物分子, 因此, 可进一步研究发展成为新型pH敏感性可控缓释高分子抗肿瘤药物载体体系.