The effect of lengths of branched-chain fatty alcohols on the efficacy and safety of docetaxel-prodrug nanoassemblies.

The self-assembly prodrugs are usually consisted of drug modules, activation modules, and assembly modules. Keeping the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug nanoassemblies. This study designed four docetaxel (DTX) prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules (C16, C18, C20, and C24). The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules' sensitivity. The extension of the carbon chains improved the prodrugs' self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative toxicity. The use of C20 can balance efficacy and safety. These results provide a great reference for the rational design of prodrug nanoassemblies.

Copper-gallate metal-organic framework encapsulated multifunctional konjac glucomannan microneedles patches for promoting wound healing.

An ideal chronic wound dressing needs to have some properties, such as antibacterial, antioxidant, regulating macrophage polarization and promoting angiogenesis. This work presents a microneedle patch fabricated from oxidized konjac glucomannan (OKGM-MNs), in which Copper-gallate metal-organic framework (CuGA-MOF) is encapsulated for wound healing (denoted as CuGA-MOF@OKGM-MNs). CuGA-MOF is composed of Cu2+ and gallic acid (GA), which are released through microneedles in the deep layer of the dermis. The released Cu2+ is able to act as an antibacterial agent and promote angiogenesis, while GA as a reactive oxygen species scavenger displays antioxidant activity. More attractively, the material OKGM used to prepare the microneedle patch is not only a drug carrier but also plays a role in promoting macrophage polarization M2 phenotype. In vitro experiments showed that CuGA-MOF@OKGM-MNs had good antibacterial and antioxidant properties. The therapeutic effect on wound healing has been confirmed in full-thickness skin wounds of diabetes mice models, which showed that the wound could be completely healed within 21 days under the treatment of CuGA-MOF@OKGM-MNs, and the healing effect was better than other groups. These indicated that the proposed CuGA-MOF@OKGM-MNs could be applicable in the treatment of clinical wound healing.

Functional Microneedle Patch for Wound Healing and Biological Diagnosis and Treatment.

Wound healing, especially chronic wounds, has been one of the major challenges in the field of biomedicine. Drug therapy alone is not effective, so a variety of functional wound healing dressings have been developed. Microneedles have attracted more and more attentions in the field of wound healing dressings due to their penetration and high drug delivery efficiency. In this review, all the studies on the application of microneedles in wound healing in recent years are summarized, classify different microneedles according to their functions in the process of wound healing, discuss the current challenges in the transformation of microneedle technology toward clinical applications, and finally look forward to the future design and development directions of microneedles in this field.

Multifunctional hydrogel wound dressing with rapid on-demand degradation property based on aliphatic polycarbonate and chitosan.

The multifunctional hydrogel dressings are effective strategy to treat chronic wounds of diabetes. In addition, the ability of selective degradation on demand to change dressings could provide better patient compliance. Here, an injectable, self-healing hydrogel with rapid degradability on-demand is designed to promote the healing of diabetes wounds. The block copolymer formed by aldehyde modified aliphatic cyclic carbonate monomer with polyethylene glycol (MBP) and chitosan (CS) were crosslinked through the Schiff base bond to obtain a hydrogel with excellent injectability and self-healing ability. Due to the presence of carbonate bonds in MBP, it showed the rapid on-demand degradation characteristics triggered by N-acetylcysteine (NAC). At the same time, gallic acid (GA) was loaded into the hydrogel, giving the hydrogel dressing antioxidant. In vivo and in vitro experiments showed that the hydrogel wound dressing possesses good natures, such as antibacterial, antioxidant, and friendly cell compatibility, which could promote wound healing. Overall, the multifunctional hydrogel wound dressings with rapid on-demand degradation characteristics are more practical for clinical applications.

ROS scavenging and immunoregulative EGCG@Cerium complex loaded in antibacterial polyethylene glycol-chitosan hydrogel dressing for skin wound healing.

The elevation of oxidative stress and inflammatory response after injury remains a substantial challenge that can deteriorate the wound microenvironment and compromise the success of wound healing. Herein, the assembly of naturally derived epigallocatechin-3-gallate (EGCG) and Cerium microscale complex (EGCG@Ce) was prepared as reactive oxygen species (ROS) scavenger, which was further loaded in antibacterial hydrogels as wound dressing. EGCG@Ce shows superior antioxidation capacity towards various ROS including free radical, O2- and H2O2 through superoxide dismutase-like or catalase-mimicking catalytic activity. Importantly, EGCG@Ce could provide mitochondrial protective effect against oxidative stress damages, reverse the polarization of M1 macrophages and reduce the secretion of pro-inflammatory cytokines. Furtherly, EGCG@Ce was loaded into the PEG-chitosan hydrogel with dynamic, porous, injectable and antibacterial properties as wound dressing, which accelerated the regeneration of both epidermal layer and dermis, resulting in improved healing process of full-thickness skin wounds in vivo. Mechanistically, EGCG@Ce re-shaped the detrimental tissue microenvironment and augmented the pro-reparative response through reducing ROS accumulation, alleviating inflammatory response, enhancing the M2 macrophage polarization and angiogenesis. Collectively, antioxidative and immunomodulatory metal-organic complex-loaded hydrogel is a promising multifunctional dressing for the repair and regeneration of cutaneous wounds without additional drugs, exogenous cytokines, or cells. STATEMENT OF SIGNIFICANCE: (1) We reported an effective antioxidant through self-assembly coordination of EGCG and Cerium for managing the inflammatory microenvironment at the wound site, which not only showed high catalytic capacity towards multiple ROS, but also could provide mitochondrial protective effect against oxidative stress damage, reverse the polarization of M1 macrophages and downregulate pro-inflammatory cytokines. EGCG@Ce was further loaded into porous and bactericidal PEG-chitosan (PEG-CS) hydrogel as a versatile wound dressing, which accelerated wound healing and angiogenesis. (2) The applicability of alleviating sustainable inflammation and regulating macrophage polarization through ROS scavenging is a promising strategy for tissue repair and regeneration without additional drugs, cytokines, or cells.

Rational Engineering Docetaxel Prodrug Nanoassemblies: Response Modules Guiding Efficacy Enhancement and Toxicity Reduction.

Prodrug-based nanoassemblies have been developed to solve the bottlenecks of chemotherapeutic drugs. The fabricated prodrugs usually consist of active drug modules, response modules, and modification modules. Among three modules, the response modules play a vital role in controlling the intelligent drug release at tumor sites. Herein, various locations of disulfide bond linkages were selected as response modules to construct three Docetaxel (DTX) prodrugs. Interestingly, the small structural difference caused by the length of response modules endowed corresponding prodrug nanoassemblies with unique characteristic. α-DTX-OD nanoparticles (NPs) possessed the advantages of high redox-responsiveness due to their shortest linkages. However, they were too sensitive to retain the intact structure in the blood circulation, leading to severe systematic toxicity. ß-DTX-OD NPs significantly improved the pharmacokinetics of DTX but may induce damage to the liver. In comparison, γ-DTX-OD NPs with the longest linkages greatly ameliorated the delivery efficiency of DTX as well as improved DTX's tolerance dose.

Self-Assembly of a Linear-Dendritic Polymer Containing Cisplatin and Norcantharidin into Raspberry-like Multimicelle Clusters for the Efficient Chemotherapy of Liver Cancer.

Combination chemotherapy has been proved to be an effective strategy in the clinic, and nanoformulations have drawn much attention in the field of drug delivery. However, conventional nanocarriers suffer from shortcomings such as inefficient coloading and undesired molar ratios of the combined drugs, preleakage of cargos during systemic circulation, and lack of cancer-selective drug release. To achieve tumor-specific codelivery of cisplatin (CDDP) and norcantharidin (NCTD) for synergistic treatment of liver cancer, a novel linear-dendritic polymer, termed as G1(PPDC)x, was designed and synthesized, where a prodrug consisting of cisplatin (CDDP) and norcantharidin (NCTD) was conjugated to PEG2000 via ester bonds to fabricate linear polymer-drug conjugates, and the conjugates were subsequently grafted to the terminal hydroxyls of a dendritic polycarbonate core. Benefiting from the hydrogen bond interactions, G1(PPDC)x could spontaneously self-assemble into a unique type of raspberry-like multimicelle clusters in solution (G1(PPDC)x-PMs). G1(PPDC)x-PMs possessed an optimal synergistic ratio of CDDP and NCTD, without obvious premature release or disassembly in biological environments. Intriguingly, upon extravasation into the interstitial tumor tissues, G1(PPDC)x-PMs (132 nm in diameter) could disassemble and reassemble into smaller micelles (40 nm in diameter) in response to the mildly acidic tumor microenvironment, which would enhance the deep tumor penetration and cellular accumulation of drugs. In vivo delivery of G1(PPDC)x-PMs led to a significantly prolonged blood circulation half-life, which is beneficial to achieve sufficient tumor accumulation through the enhanced permeability and retention (EPR) effect. G1(PPDC)x-PMs displayed the best antitumor activity in H22 tumor-bearing mice with a tumor inhibition rate of 78.87%. Meanwhile, G1(PPDC)x-PMs alleviated both myelosuppression toxicities of CDDP and vascular irritation of NCTD. Our results demonstrated that G1(PPDC)x-PMs could serve as an effective drug delivery system for codelivery of CDDP and NCTD to treat liver cancer efficiently.

Probing the Role of Connecting Bonds and Modifying Chains in the Rational Design of Prodrug Nanoassemblies.

Prodrug-based self-assembled nanoparticles combined with the merits of nanotechnology and prodrugs strategies have gradually become a research trending topic in the field of drug delivery. These prodrugs usually consist of parent drugs, connecting bonds, and modifying chains. The influences of the connecting bonds and modifying chains on the pharmaceutical characteristics, in vivo delivery fate, and antitumor activity of prodrug nanoassemblies remain elusive. Herein, three docetaxel (DTX) prodrugs were designed using sulfur bonds (thioether bond or disulfide bond) as connecting bonds and fatty alcohols (straight chain or branched chain) as modifying chains. Interestingly, the difference between connecting bonds and modifying chains deeply influenced the colloidal stability, redox responsive drug release, cytotoxicity, pharmacokinetic properties, tumor accumulation, and antitumor effect of prodrug nanoassemblies. DTX conjugated with branched chain fatty alcohols via disulfide bonds (HUA-SS-DTX) significantly improved the antitumor efficiency of DTX and reduced the systematic toxicity. Our study elaborates on the vital role of connecting bonds and modifying chains in the rational design of prodrug nanoassemblies.

Emerging platinum(0) nanotherapeutics for efficient cancer therapy.

Platinum (Pt)-based chemotherapy has been necessary for clinical cancer treatment. However, traditional bivalent drugs are hindered by poor physicochemical properties, severe toxic side effects, and drug resistance. Currently, elemental Pt(0) nanotherapeutics (NTs) have emerged to tackle the dilemma. The inherent acid-responsiveness of Pt(0) NTs could help to improve tumor selectivity and alleviate toxic effects. Moreover, the metal nature of Pt facilitates the great combination of Pt(0) NTs with photothermal and photodynamic therapy and imaging-guided diagnosis. Based on recent important researches, this review provides an updated introduction to Pt(0) NTs. First, the challenges of traditional Pt-based chemotherapy have been outlined. Then, Pt(0) NTs with multiple applications of tumor theranostics have been overviewed. Furthermore, the combinations of Pt(0) NTs with other therapeutical modalities are introduced. Last but not least, we envision the possible challenges and prospects associated with Pt(0) NTs.

Endocytosis-mediated triple-activable prodrug nanotherapeutics potentiating therapeutic efficacy and security towards solid tumors.

Self-assembling prodrug nanotherapeutics have emerged as a promising nanoplatform for anticancer drug delivery. The specific and efficient activation of prodrug nanotherapeutics inside tumor cells is vital for the antitumor efficacy and security. Herein, a triple-activable prodrug polymer (TAP) is synthesized by conjugating polyethylene glycol-poly-(caprolactone)-paclitaxel (PTX) polymer with two tumor-responsive bonds, disulfide and acetal. TAP could self-assemble into nanotherapeutics (TAP NTs) free of surfactant with a high drug loading (32.6%). In blood circulation, TAP NTs could remain intact to efficiently accumulate in tumor sites. Thereafter, tumor cells would internalize TAP NTs through multiple endocytosis pathways. Inside tumor cells, TAP NTs could be activated to release PTX and induce tumor cell apoptosis in triple pathways: (i) lysosomal acidity rapid activation; (ii) ROS-acidity tandem activation and (iii) GSH-acidity tandem activation. Compared with Taxol and non-activable control, TAP NTs significantly potentiate the antitumor efficacy and security of PTX against solid tumors including breast cancer and colon cancer.

Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy.

Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.

Inhibition of post-surgery tumour recurrence via a sprayable chemo-immunotherapy gel releasing PD-L1 antibody and platelet-derived small EVs.

BACKGROUND: Melanoma is the most serious type of skin cancer, and surgery is an effective method to treat melanoma. Unfortunately, local residual micro-infiltrated tumour cells and systemic circulating tumour cells (CTCs) are significant causes of treatment failure, leading to tumour recurrence and metastasis. METHODS: Small EVs were isolated from platelets by differential centrifugation, and doxorubicin-loaded small EVs (PexD) was prepared by mixing small EVs with doxorubicin (DOX). PexD and an anti-PD-L1 monoclonal antibody (aPD-L1) were co-encapsulated in fibrin gel. The synergistic antitumour efficacy of the gel containing PexD and aPD-L1 was assessed both in vitro and in vivo. RESULTS: Herein, we developed an in situ-formed bioresponsive gel combined with chemoimmunotherapeutic agents as a drug reservoir that could effectively inhibit both local tumour recurrence and tumour metastasis. In comparison with a DOX solution, PexD could better bind to tumour cells, induce more tumour immunogenic cell death (ICD) and promote a stronger antitumour immune response. PexD could enter the blood circulation through damaged blood vessels to track and eliminate CTCs. The concurrent release of aPD-L1 at the tumour site could impair the PD-1/PD-L1 pathway and restore the tumour-killing effect of cytotoxic T cells. This chemoimmunotherapeutic strategy triggered relatively strong T cell immune responses, significantly improving the tumour immune microenvironment. CONCLUSION: Our findings indicated that the immunotherapeutic fibrin gel could "awaken" the host innate immune system to inhibit both local tumour recurrence post-surgery and metastatic potential, thus, it could serve as a promising approach to prevent tumour recurrence.

Zwitterion-Driven Shape Program of Prodrug Nanoassemblies with High Stability, High Tumor Accumulation, and High Antitumor Activity.

Prodrug nanoassemblies have emerged as a promising platform for the delivery of anticancer drugs. PEGylation is a "gold standard" to improve colloidal stability and pharmacokinetics of nanomedicines. However, the clinical application of PEG materials is challenged by in vivo oxidative degradation and immunogenicity. Rational design of advanced biomaterials for the surface modification of nanomedicines is the hot spot of research. Here, a zwitterionic sulfobetaine surfactant is constructed as a novel surface modifier to coassemble with 10-hydroxycamptothecin-linoleic acid conjugate, with the classical PEGylated material as control. Interestingly, both the type and ratio of surfactants have profound impacts on the molecular mechanisms of the assembly of prodrugs, thereby affecting the pharmaceutical properties. Compared with PEGylated spherical prodrug nanoassemblies, zwitterion-modified prodrug nanoassemblies have distinct rod shape and superhydrophilic surface, and exhibit potent antitumor activity due to the combination of multiple advantages in terms of colloidal stability, cellular uptake, and pharmacokinetics. The findings illustrate the crucial role of zwitterionic surfactants as the surface modifier in the determination of in vivo fate of the prodrug nanoassemblies, and pave the way for the development of advanced nanomedicines.

The length of disulfide bond-containing linkages impacts the oral absorption and antitumor activity of paclitaxel prodrug-loaded nanoemulsions.

The rational design of oral paclitaxel (PTX) preparations is still a challenge. Many studies focus on developing PTX-loaded nanoemulsions (NEs) for oral administration. Unfortunately, PTX has poor affinity with the commonly used oil phases, leading to low encapsulation efficiency, poor colloidal stability, and premature drug leakage of PTX-loaded NEs. Herein, three lipophilic PTX prodrugs are synthesized by conjugating PTX with citronellol (CIT), using different lengths of disulfide bond-containing linkages. Interestingly, compared with PTX, the prodrugs exhibit higher affinity with the oil phase, effectively improving the encapsulation efficiency, colloidal stability, and sustained-release behavior of NEs. In addition, the disulfide bond-bridged prodrugs could specifically release PTX in tumor cells, reducing unnecessary systemic exposure of PTX. As a result, all three prodrug NEs exhibited improved oral bioavailability and antitumor effects compared to oral Taxol. Moreover, the length of disulfide bond-containing linkages exhibits great impacts on the oral absorption, drug release, and antitumor behaviors of NEs. It is found that the prodrug NEs with the shortest linkages show comparable antitumor effects with intravenous Taxol, but with less systemic and gastrointestinal toxicity.

Acetal-linked polymeric prodrug micelles based on aliphatic polycarbonates for paclitaxel delivery: preparation, characterization, in vitro release and anti-proliferation effects.

Acidic tumor microenvironment has been extensively explored to design pH-responsive paclitaxel prodrug micelles for cancer therapy. The object of this study is to investigate the pH-responsive drug release behavior and the anti-proliferation capacity of acetal-linked paclitaxel polymeric prodrug micelles. The prodrug was synthesized and evaluated for paclitaxel content. The prodrug micelles were fabricated and characterized for morphology, size, in vitro pH-responsive paclitaxel release, cellular uptake, and anti-proliferation. Paclitaxel content was 33 wt%. The prodrug micelles exhibited spherical structure with the hydrodynamic diameter of 154 nm. Besides, the in vitro paclitaxel release behavior was verified to be pH-responsive, and 77%, 38%, and 17% of parent free paclitaxel was released from the nano-sized prodrug micelles in 13 h at pH 5.5, 6.5, and 7.4, respectively. The cellular uptake assessment demonstrated the time-dependent internalization of prodrug micelles. Meanwhile, CCK-8 analysis showed that prodrug micelles possessed the potent anti-proliferation effects. Prodrug micelles based on aliphatic polycarbonates present a promising platform for cancer chemotherapy due to the pH-responsive characteristics of acetal bond, potent anti-proliferation effects, and outstanding cytocompatibility of aliphatic polycarbonates.

Tumor Microenvironment Stimuli-Responsive Polymeric Prodrug Micelles for Improved Cancer Therapy.

PURPOSE: The discovery of nano drug delivery system has rendered a great hope for improving cancer therapy. However, there are some inevitable obstacles that constrain its development, such as the physical and biological barriers, the toxicity of carrier materials and the physiological toxicity of drugs. Here, we report a polymeric prodrug micelle (PPM) with pH/redox dual-sensitivity, which was prepared using methoxy poly (ethylene glycol) (mPEG) with favorable biosafety to improve cancer therapy. METHOD: The tumor microenvironment stimuli-responsive PPMs were prepared and characterized in vitro and in vivo. RESULTS: Our data displayed that the PPMs with excellent biocompatibility exhibited the stimuli-responsive drug release behavior under the microenvironment of cancer cells, superior cellular internalization and lower cytotoxicity. A new method to control drug release behavior was proposed by comparing the release behavior of PPMs formed by PEG of different molecular weight. Furthermore, the fabricated PPMs exhibited the "oral-like" blood concentration curve, improved biodistribution, reduced tissue toxicity and excellent antitumor efficiency in vivo. Consistently, these results indicated that PPMs improved chemotherapeutic efficiency and reduced side effects of the model drug doxorubicin (DOX). CONCLUSION: The prepared pH/redox dual-sensitive PPM enhanced the chemotherapy effect on the tumor site while reducing the physiological toxicity of DOX. Graphical Abstract.

High Co-loading Capacity and Stimuli-Responsive Release Based on Cascade Reaction of Self-Destructive Polymer for Improved Chemo-Photodynamic Therapy.

Photodynamic therapy (PDT) shows a promising synergy with chemotherapy in the therapeutic outcome of malignant cancers. The minimal invasiveness and nonsystemic toxicity are appealing advantages of PDT, but combination with chemotherapy brings in the nonselective toxicity. We designed a polymeric nanoparticle system that contains both a chemotherapeutic agent and a photosensitizer to seek improvement for chemo-photodynamic therapy. First, to address the challenge of efficient co-delivery, polymer-conjugated doxorubicin (PEG-PBC-TKDOX) was synthesized to load photosensitizer chlorin e6 (Ce6). Ce6 is retained with DOX by a π-π stacking interaction, with high loading (41.9 wt %) and the optimal nanoparticle size (50 nm). Second, light given in PDT treatment not only excites Ce6 to produce cytotoxic reactive oxygen species (ROS) but also spatiotemporally activates a cascade reaction to release the loaded drugs. Finally, we report a self-destructive polymeric carrier (PEG-PBC-TKDOX) that depolymerizes its backbone to facilitate drug release upon ROS stimulus. This is achieved by grafting the ROS-sensitive pendant thioketal to aliphatic polycarbonate. When DOX is covalently modified to this polymer via thioketal, target specificity is controlled by light, and off-target delivery toxicity is mostly avoided. An oral squamous cell carcinoma that is clinically relevant to PDT was used as the cancer model. We put forward a polymeric system with improved efficiency for chemo-photodynamic therapy and reduced off-target toxicity.

Electrospun nanofibers as a wound dressing for treating diabetic foot ulcer.

Diabetes is one of the most prevalent diseases in the world with high-mortality and complex complications including diabetic foot ulcer (DFU). It has been reported that the difficulties in repairing the wound related to DFU has much relationship with the wound infection, change of inflammatory responses, lack of extracellular matrix (ECM), and the failure of angiogenesis. Following the development of medical materials and pharmaceutical technology, nanofibers has been developed by electrospinning with huge porosity, excellent humidity absorption, a better oxygen exchange rate, and some antibacterial activities. That is to say, as a potential material, nanofibers must be a wonderful candidate for the DFU treatment with so many benefits. Careful selection of polymers from natural resource and synthetic resource can widen the nanofibrous application. Popular methods applied for the nanofibrous fabrication consist of uniaxial electrospinning and coaxial electrospinning. Furthermore, nanofibers loading chemical, biochemical active pharmaceutical ingredient (API) or even stem cells can be wonderful dosage forms for the treatment of DFU. This review summarizes the present techniques applied in the fabrication of nanofibrous dressing (ND) that utilizes a variety of materials and active agents to offer a better health care for the patients suffering from DFU.

Amphiphilic block copolymer NPs obtained by coupling ricinoleic acid/sebacic acids and mPEG: Synthesis, characterization, and controlled release of paclitaxel.

Currently, nanoparticles (NPs) made of amphiphilic block copolymer are still an essential part of drug delivery system. Here, we report a novel amphiphilic block copolymer and paclitaxel (PTX)-loaded copolymer NPs for the controlled delivery of PTX. The block copolymer was synthesized via melt polycondensation method of methoxy poly(ethylene glycol) (mPEG), sebacic acid (SA) and ricinoleic acid (RA). A series of characterization approaches such as Fourier Transform Infrared Spectroscopy (FTIR), 1Hydrogen-Nuclear Magnetic Resonance (1H-NMR), Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD) and Gel Permeation Chromatography (GPC) applied have shown that the amphiphilic block copolymer was prepared as designed. NPs prepared by nanoprecipitation method consist of mPEG segments as the hydrophilic shell and RA-SA segments as the hydrophobic core, hydrophobic PTX was encapsulated as model drug. Subsequently, Transmission Electron Microscopy (TEM) analysis indicated that the spherical NPs have effective mean diameters ranging from 100 to 400 nm. Dynamic Light Scattering (DLS) analysis also revealed the controllable NPs diameter by modulating the mass ratio of RA to SA and drug loading amount (DLA). Besides, biphasic profile with zero order drug release was observed in general in vitro release behaviors of PTX from NPs. Further investigation confirmed that the release behaviors depend on the crystallinity of hydrophobic RA-SA segments. Results above suggest that NPs with amphiphlic block copolymer mPEG-b-P(RA-SA)-b-mPEG have a remarkable potential as a carrier for hydrophobic drug delivery in cancer therapy.

Design, Synthesis, and Characterization of Schiff Base Bond-Linked pH-Responsive Doxorubicin Prodrug Based on Functionalized mPEG-PCL for Targeted Cancer Therapy.

The side effects of doxorubicin (DOX) extremely limit its application in the treatment of malignant tumors. Nano-sized polymeric drugs based on the acidic microenvironment of tissular- or intra- tumor have attracted ample attention because of their potential in reducing side effects. In this research, an amphiphilic diblock copolymer based on poly (ethylene glycol) (PEG) and functionalized polycaprolactone (PCL) was synthesized and utilized as the drug carrier. DOX was chemically conjugated with the polymer via acid-cleavable imine bonds to obtain a novel pH-sensitive DOX prodrug (mPEG-PCL-Imi-DOX). mPEG-PCL-Imi-DOX (24.2 wt % DOX content) formed micelles with an average diameter of 125 nm through a simple solvent evaporation method. The in vitro release profile demonstrated that DOX release of the prodrug micelles was pH-responsive and able to be accelerated with the decrease of pH. In vitro cytotoxicity assay tests revealed that the pH-sensitive DOX prodrug micelles exhibited relatively lower toxicity and similar antitumor efficacy towards MCF-7 cells compared with free DOX. Hence, the DOX prodrug micelles with imine bonds can offer a carrier with great potential for chemo-therapeutics.