Polymeric Prodrug Research Articles

Optimized aptamer functionalization for enhanced anticancer efficiency in vivo

Nucleic acid aptamers (Apt) are RNA or DNA fragments that can bind specifically to a target molecule or to a target substrate with great affinity, thus has attracted great attention for diagnosis and treatment of various malignant diseases. Two primary strategies reported for efficient incorporation of Apt into a nanocarrier include physical encapsulation via electrostatic interactions and chemical conjugation via covalent bonds. Generally, physical encapsulation offers an easier approach for Apt functionalization than covalent bonding that involves sophisticated chemical design as well as synthesis and purification procedures. However, the effect of Apt’s incorporation strategies on the property and performance of Apt-functionalized nanocarriers, to our knowledge, remains unclear, which clearly hampers the biomedical applications and potential clinical translations of Apt-decorated delivery systems. To clarify this critical issue toward better performance of Apt for biomedical applications, an Apt moiety with a specific targeting property to liver cancer cells was introduced to a previously fabricated polymeric prodrug, chitosan-5-fluorouracil-1-acetic acid (CS-FU) via either an amide link or electrostatic interactions to afford two types of Apt-functionalized polymeric prodrugs, i.e., Apt/CS-FU and Apt-CS-FU with an equivalent amount of incorporated Apt, respectively. The in vivo and in vitro anti-tumor efficacy and targeting properties of these two Apt-functionalized polymeric prodrugs were investigated and further compared in detail. Interestingly, the two self-assembled micelles showed almost identical in vitro targeting and antitumor efficiency, but Apt-CS-FU mediated 1.5-fold greater tumor inhibition rate (TIR) than Apt/CS-FU in murine tumor models. The better performance of Apt-CS-FU than that of Apt/CS-FU was substantially attributed to the smaller size of Apt-CS-FU than that of Apt/CS-FU in the presence of serum for prolonged in vivo circulation. The first disclosed Apt incorporation strategy effects on the performance and property of Apt-decorated nanocarriers is believed to promote rational design and future clinical translations of Apt-functionalized nanoplatforms with greater therapeutic efficiency.

Pegylated Curcumin Derivative: Water-Soluble Conjugates with Antitumor and Antibacterial Activity.

During the past years, the synthesis of polymer prodrug structures, based on natural phytochemical compounds with a great range of valuable biological properties, has become a promising solution in cancer prevention, imaging, and detection. Curcumin (Curc) remains one of the most studied natural products, due to the impressive palette of biological properties and the possibility to be easily loaded in various micro- and nanostructures and chemically modified. In this study, pegylated curcumin derivatives were prepared by a direct esterification reaction between poly(ethylene glycol)diacid (PEG of 600 g/mol molar mass, PEG600) and Curc in the presence of N,N′-dicyclohexylcarbodiimide (PEG600-Curc). The successful reaction resulted in a water-soluble stable product that was characterized by infrared spectroscopy (Fourier transform infrared (FT-IR)) and proton (1H) and carbon (13C) NMR. The effect of the pH values of buffer solutions on PEG600-Curc spectral properties (absorption and photoluminescence) was investigated by UV–vis and fluorescence spectrophotometry. Based on the biological tests, it was confirmed that PEG600-Curc exhibits cytotoxic activity against Graffi cell lines, as a function of the Curc concentration in the conjugate and the incubation time. PEG600-Curc antibacterial activity was validated in microbiological tests against pathogenic microorganisms such as Staphylococcus aureus. Most importantly, despite the covalent attachment of Curc to PEG and the slight reduction in the therapeutic index of the conjugate, both the anticancer and antimicrobial activities remain the highest reported, thus opening the gate for further, more clinically oriented studies.

A Polymer Prodrug Strategy to Switch from Intravenous to Subcutaneous Cancer Therapy for Irritant/Vesicant Drugs.

Chemotherapy is almost exclusively administered via the intravenous (IV) route, which has serious limitations (e.g., patient discomfort, long hospital stays, need for trained staff, high cost, catheter failures, infections). Therefore, the development of effective and less costly chemotherapy that is more comfortable for the patient would revolutionize cancer therapy. While subcutaneous (SC) administration has the potential to meet these criteria, it is extremely restrictive as it cannot be applied to most anticancer drugs, such as irritant or vesicant ones, for local toxicity reasons. Herein, we report a facile, general, and scalable approach for the SC administration of anticancer drugs through the design of well-defined hydrophilic polymer prodrugs. This was applied to the anticancer drug paclitaxel (Ptx) as a worst-case scenario due to its high hydrophobicity and vesicant properties (two factors promoting necrosis at the injection site). After a preliminary screening of well-established polymers used in nanomedicine, polyacrylamide (PAAm) was chosen as a hydrophilic polymer owing to its greater physicochemical, pharmacokinetic, and tumor accumulation properties. A small library of Ptx-based polymer prodrugs was designed by adjusting the nature of the linker (ester, diglycolate, and carbonate) and then evaluated in terms of rheological/viscosity properties in aqueous solutions, drug release kinetics in PBS and in murine plasma, cytotoxicity on two different cancer cell lines, acute local and systemic toxicity, pharmacokinetics and biodistribution, and finally their anticancer efficacy. We demonstrated that Ptx-PAAm polymer prodrugs could be safely injected subcutaneously without inducing local toxicity while outperforming Taxol, the commercial formulation of Ptx, thus opening the door to the safe transposition from IV to SC chemotherapy.

Bortezomib prodrug catalytic nanoreactor for chemo/chemodynamic therapy and macrophage re-education.

Chemodynamic therapy (CDT), an emerging tumor-specific therapeutic modality, is frequently restrained by insufficient intratumoral Fenton catalysts and increasingly inefficient catalysis caused by the continuous consumption of limited H2O2 within tumors. Herein, we engineered a pH-responsive bortezomib (BTZ) polymer prodrug catalytic nanoreactor (HeZn@HA-BTZ) capable of self-supplying Fenton catalyst and H2O2. It is aimed for tumor-specific chemo/chemodynamic therapy via oxidative stress and endoplasmic reticulum (ER) stress dual-amplification and macrophage repolarization. A catechol‑boronate bond-based hyaluronic acid-BTZ prodrug HA-DA-BTZ was modified on Hemin and Zn2+ coordination nanoscale framework (HeZn), an innovative CDT inducer, to construct He-Zn@HA-BTZ. He-Zn@HA-BTZ with good stability and superior peroxidase-like activity preferentially accumulated at tumor sites and be actively internalized by tumor cells. Under the cleavage of catechol‑boronate bond in acidic endo/lysosomes, pre-masked BTZ was rapidly released to induce ubiquitinated protein aggregation, robust ER stress and elevated H2O2 levels. The amplified H2O2 was further catalyzed by HeZn via Fenton-catalytic reactions to produce hypertoxic •OH, enabling cascaded oxidative stress amplification and long-lasting effective CDT, which in turn aggravated BTZ-induced ER stress. Eventually, a dual-amplification of oxidative stress and ER stress was achieved to initiate cell apoptosis/necrosis with reduced BTZ toxicity. Intriguingly, He-Zn@HA-BTZ could repolarize macrophages from M2 to antitumor M1 phenotype for potential tumor therapy. This "all in one" prodrug nanocatalytic reactor not only enriches the CDT inducer library, but provides inspirational strategy for simultaneous oxidative stress and ER stress based excellent cancer therapy.

Highly Branched Betulin Based Polyanhydrides for Self-Assembled Micellar Nanoparticles Formulation.

Polyanhydrides based on betulin are promising materials for use in controlled drug delivery systems. Due to the broad biological activity of betulin derivatives and lack of toxicity in vitro and in vivo, these polymers can be used both as polymeric prodrug and as carriers of other biologically active compounds. In this study, we develop a novel amphiphilic branched polyanhydrides synthesized by the two-step melt polycondensation of betulin disuccinate (DBB) and a tricarboxylic derivative of poly(ethylene glycol) (PEG_COOH). DBB and PEG_COOH were used as the hydrophobic and hydrophilic segments, respectively. The content of DBB in copolymers was from 10 to 95 wt%. Copolymers were assessed for their cytostatic activity against various cancer cell lines. Compared to linear DBB and PEG-based polyanhydrides, the branched polyanhydrides exhibited higher anticancer activity. The obtained polymers were able to self-assemble in water to form micelles with hydrodynamic diameters from 144.8 to 561.8 nm. and are stable over a concentration range from 12.5 µg/mL to 6.8 mg/mL. The formed micelles were found to be spherical in shape using a scanning electron microscope. It was found that the structure and composition of polyanhydrides affected the hydrodynamic diameter of the micelles. The branched betulin-based polyanhydrides have the potential to serve as biodegradable polymer prodrugs or carriers for other bioactive compounds.

PH-Responsive non-antibiotic polymer prodrugs eradicate intracellular infection by killing bacteria and regulating immune response

Intracellular bacterial infections pose enormous challenges to food safety and public health. Antibiotic-based polymer prodrugs have been used to treat intracellular bacterial infection. However, the overuse of antibiotics may lead to the emergence of antibiotic resistance. In this work, we aimed to develop antibiotic-free pH-responsive polymeric prodrugs to combat intracellular S. aureus infection. Amphiphilic poly(ethylene glycol)-b-poly[(3-phenylprop-2-ene-1,1-diyl)bis(oxy)bis(enthane-2,1-diyl)diacrylate] (PEG-b-PCAE) was obtained by radical polymerization and they could self-assemble to form micelles. PEG-b-PCAE micelles could uptake by macrophage. Upon exposure to the acidic phagolysosome, PEG-b-PCAE micelles could release cinnamaldehyde (CA) through hydrolysis of the acetal linkage. PEG-b-PCAE could kill intracellular bacteria by damaging the bacterial membrane. Furthermore, PEG-b-PCAE micelles could generate reactive oxygen species (ROS) in macrophages and subsequently activate immune system to clear bacteria by inducing macrophages differentiation to M1 phenotype. PEG-b-PCAE micelles could accelerate the wound healing process of the S. aureus-infected model in vivo. It is anticipated that multifunctional antibiotic-free PEG-b-PCAE micelles with intrinsic antibacterial activities hold promise for improved outcomes in intracellular S. aureus infections.

Intelligent Drug Delivery by Peptide-Based Dual-Function Micelles.

To endow the polymeric prodrug with smart properties through a safe and simple method, matrix metalloproteinase (MMPs) responsive peptide GPLGVRGDG was introduced into the block copolymer to prepare TPGS3350-GPLGVRGDG-DOX&DOX micelles, where TPGS3350 is D-α-tocopheryl polyethylene glycol 3350 succinate. During the doxorubicin delivery, the cleavage of the peptide chain triggers de-PEGylation, and the remaining VRGDG sequence was retained on the surface of the micelles, which can act as a ligand to facilitate cell uptake. Moreover, the cytotoxicity of TPGS3350-GPLGVRGDG-DOX&DOX micelles against 4T1 cells was significantly improved, compared with TPGS3350-GPLGVRG-DOX&DOX micelles and TPGS3350-DOX&DOX micelles. During in vivo studies, TPGS3350-GPLGVRGDG-DOX&DOX micelles exhibited good anticancer efficacy with long circulation in the body and more efficient accumulation at the tumor site. Therefore, TPGS3350-GPLGVRGDG-DOX&DOX micelles have improved antitumor activity and reduced toxic side effects. This work opens new potential for exploring the strategy of drug delivery in clinical applications.

Preparation of cisplatin delivery calcium phosphate nanoparticles using poly(Pt(IV) prodrug) as the payload

Directly encapsulating cisplatin in calcium phosphate nanoparticles (CPNPs) is a challenge because of the low water-solubility and weak binding affinity with calcium phosphate (CaP) of the cisplatin. In this work, we present a unique strategy using a polymer (poly(Pt(IV) prodrug)) bearing numerous carboxyl side groups and incorporating redox-sensitive cisplatin Pt(IV) prodrugs in its backbone as the payload for encapsulation in CPNPs. The poly(Pt(IV) prodrug) was efficiently encapsulated in CPNPs (>90 %), attributing to its improved solubility in alkaline water and strong binding affinity with CaP deriving from the plenty of carboxyl side groups. The CPNPs were stable and almost entirely inhibited the premature release of platinum drugs in the medium mimicking the pH condition of the bloodstream, whether there were reduction agents or not. While in an acidic condition with reduction agents, they released platinum drugs rapidly due to simultaneous reduction and hydrolysis of the poly(Pt(IV) prodrug). Further bioactivity experiments demonstrated the poly(Pt(IV) prodrug) encapsulated CPNPs were of higher efficacy against cancerous cells than free cisplatin and poly(Pt(IV) prodrug) owing to the enhanced platinum drugs uptake by cancerous cells via the CPNPs.

H2O2-Activatable Antioxidant Polymeric Prodrug Nanoparticles for the Prevention of Renal Ischemia/Reperfusion Injury.

Renal ischemia-reperfusion (IR) injury is an inevitable complication in various clinical settings including kidney transplantation and major vascular surgeries. Renal IR injury is a major risk factor for acute kidney injury, which still remains a major clinical challenge without effective therapy. The main cause of renal IR injury is the massive production of reactive oxygen species (ROS) including hydrogen peroxide (H2O2) that initiate inflammatory signaling pathways, leading to renal cell death. In this study, we developed fucoidan-coated polymeric prodrug (Fu-PVU73) nanoparticles as renal IR-targeting nanotherapeutics that can rapidly eliminate H2O2 and exert anti-inflammatory and antiapoptotic effects. Fu-PVU73 nanoparticles were composed of H2O2-activatable antioxidant and anti-inflammatory polymeric prodrug (PVU73) that incorporated H2O2-responsive peroxalate linkages, ursodeoxycholic acid (UDCA), and vanillyl alcohol (VA) in its backbone. Fu-PVU73 nanoparticles rapidly scavenged H2O2 and released UDCA and VA during H2O2-triggered degradation. In the study of renal IR injury mouse models, Fu-PVU73 nanoparticles preferentially accumulated in the IR injury-induced kidney and markedly protected the kidney from IR injury by suppressing the generation of ROS and the expression of proinflammatory cytokines. We anticipate that Fu-PVU73 nanoparticles have tremendous therapeutic potential for not only renal IR injury but also various ROS-associated inflammatory diseases.

Enzymatic drug release cascade from polymeric prodrug nanoassemblies enables targeted chemotherapy.

Cancer drug delivery systems often suffer from premature drug leakage during transportation and/or inefficient drug release within cancer cells. We present here a polymeric prodrug nanoassembly that addresses these problems simultaneously. This nanoassembly comprises a polymeric prodrug with novel trivalent phenylboronate moieties for drug conjugation via ether linkages, as well as β-lapachone (Lapa). While the ether linkage enables nearly no drug release under physiological conditions, the Lapa molecules can induce the reactive oxygen species (ROS) burst specifically in cancer cells via NAD(P)H: quinone oxidoreductase-1 catalysis, which triggers the cleavage of the ether bonds and thus cascade amplification drug release in cancer cells. As a result, the nanoassemblies exhibit much higher cytotoxicity against cancer cells than normal cells, and also increased therapeutic efficacy and reduced side effects compared to the clinically used irinotecan. We anticipate that this strategy can be applied to other drug delivery platforms to enable more precise drug release.

WITHDRAWN: Fabrication of Dual-Responsive pH and Reduction of Dual Anticancer Drugs Conjugates Dextran Self-Assembly for Osteosarcoma Cancer Treatment

Polymeric prodrugs, fabricated by coupling anticancer drugs to functional copolymers, have undergone substantial research and are now being used to treat cancer more safely and effectively. Covalent conjugation of methotrexate (MTX) and cisplatin (Pt) to an oxidized dextran (O-Dex@Pt/MTX) was used to deliver a pH and reduction of dual-responsive oxidized Dextran (O-Dex)-dual drugs conjugates (O-Dex@Pt/MTX-NPs). MTX and Pt(IV) prodrugs were conjugated by esterification and Schiff base reactions. Transmission electron microscopy (TEM) analysis reveals that the O-Dex@Pt/MTX-NPs with an average size of ~180 nm could be self-assembled. The degradation and drug release profile of the O-Dex@Pt/MTX-NPs was studied in vitro using optical and in vitro drug release experiments. The human osteosarcoma carcinoma OS-732 cells used confocal laser scanning microscopy to determine if the O-Dex@Pt/MTX-NPs effectively uptake the cells. O-Dex@Pt/MTX-NPs showed comparable antiproliferative activity to the simple combination of MTX/PT as the extension of time. The morphological changes of the OS-732 osteosarcoma cells were confirmed by the dual staining (AO-EB) and nuclear damage staining DAPI. The flow cytometry analysis confirmed the apoptosis of cells by using OS-732 cells. The apoptosis staining cells show that the nanoparticles effectively killed cancer cells without affecting non-cancerous cells. If this intelligent polymer-dual-drug hybrid can take advantage of the tumor's acidic and reductive milieu, it might be helpful in combination chemotherapy. All data generated or analyzed during this study are included in this submitted article. The raw data shall be made available upon request to the corresponding author. A Convergent Fabrication of Dual-Responsive pH and Reduction of Dual Anticancer Drugs Conjugates Dextran Self-Assembly for Osteosarcoma Cancer Therapy • We developed the conjugation of methotrexate and cisplatin to an oxidized dextran. • O-Dex@Pt/MTX-NPs effectively uptake the OS-732 cells. • The O-Dex@Pt/MTX-NPs effectively kill OS-732 cancer cells. • Various biochemical methods determined the morphological changes of OS-732 cells. • The flow cytometry analysis confirmed the apoptosis of the OS-732 cells.

PH/redox-responsive core cross-linked based prodrug micelle for enhancing micellar stability and controlling delivery of chemo drugs: An effective combination drug delivery platform for cancer therapy.

Core-crosslinking of micelles (CCMs) appears to be a favorable strategy to enhance micellar stability and sustained release of the loaded drug. In this study, the DOX-conjugated pH-sensitive polymeric prodrug Methoxy Poly (ethylene oxide)-b-Poly (Aspartate-Hydrazide) (mPEG-P [Asp-(Hyd-DOX)] was created using ring-opening polymerization. To further enhance the micellar system, 3,3'-diselanediyldipropanoic acid (DSeDPA) was applied to link the hydrophobic segment via click reaction to form pH/redox-responsive CCMs. Dual anti-cancer drugs, DOX as a pro-drug and SN-38 as a targeting drug, were used to enhance inhibition. DLS confirmed that the non-cross-linked micelle (NCMs) showed a higher (96.43nm) particle size compared to the CCMs (72.63nm). Due to micellar shrinkage after crosslinking, CCMs displayed SN-38 drug loading (7.32%) and encapsulation efficiency (86.23%). The mPEG-P(Asp-Hyd) copolymer's in vitro cytotoxicity on HeLa and HaCaT cell lines found that 84.52% of the cells are alive, and zebrafish (Danio rerio) embryos and larvae are highly biocompatible. The DOX/SN-38@CCMs had a sustained discharge profile in vitro, unlike the DOX/SN-38@NCMs. In DOX/SN-38@CCMs, HeLa cells were inhibited 50.90% more than HaCaT (14.25%) at the maximum drug dose (10μg/mL). The CCMs successfully targeted and supplied DOX/SN-38 in HeLa cells rather than HaCaT cells, based on cellular uptake of 2D cell culture. CCMs, unlike NCMs, inhibit the growth of spheroids for extended periods of time due to the prolonged release of the loaded drug. Overall, CCMs are good-looking for use as regulated delivery of DOX/SN-38 in cancer cells because of all of these appealing characteristics.

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.

Oxidation and Reduction Dual-Responsive Polymeric Prodrug Micelles Co-delivery Precisely Prescribed Paclitaxel and Honokiol for Laryngeal Carcinoma Combination Therapy.

Laryngeal carcinoma is the most common head and neck malignancy globally, and chemotherapy is still the most common treatment for this type of carcinoma. Monotherapy has become powerless because of the lack of drugs in the anticancer agent library, the difficult process of new drug discovery, and the widespread drug resistance. Combination therapy with two agents, in particular Chinese herbal medicines with chemotherapy drugs, is a potential alternative to chemotherapy alone. However, combination therapy faces difficulties in delivering multiple drugs to tumor tissue in a precise ratio. Here, a cocktail polymeric prodrug micelle (PHPPM) was developed using an oxidation and reduction dual-responsive polymeric paclitaxel (PTX) and polymeric honokiol (HK) prodrugs. Both of them were obtained by covalently conjugating the drug to dextran via diselenium bonds. Following optimization and characterization, the PHPPM with the precise mass ratio of PTX and HK was obtained, enabling ratiometric drug loading, synchronized drug release in response to tumor high-level reactive oxygen species and glutathione environment, long blood circulation, and high tumor accumulation. This co-delivery system can effectively inhibit laryngeal carcinoma growth in vitro and in vivo. Codelivery of chemotherapy agents and Chinese herbal medicine with a precise ratio and controlled release of the two drugs at the tumor site provides an effective approach to clinical therapy for other laryngeal carcinomas.

Development of branched polyphenolic poly(beta amino esters) to facilitate post-synthesis processing.

Given their versatility and formability, polymers have proven to be a viable platform facilitating a controlled and tuned release for a variety of therapeutic agents. One growing area of polymer drug delivery is polymeric prodrugs, which covalently link active pharmaceutical ingredients to a polymeric form to enhance stability, delivery, and pharmacology. One such class of polymeric prodrugs, poly(beta amino esters) (PβAEs) can be synthesized into crosslinked, or "thermoset," networks which greatly limits their processability. An antioxidant-PβAE polymer prodrug that is soluble in organic solutions would permit enhanced processability, increasing their utility and manufacturability. Curcumin PβAEs were synthesized to be soluble in organic solvents while retaining the release and activity properties. To demonstrate the polymer processability, curcumin PβAEs were further synthesized into nanoparticles and thin films. Control over nanoparticle size and film thickness was established through variance of dope solution concentration and withdrawal speed, respectively. Layering of polymeric films was demonstrated through inkjet printing of thin films. Polymer function was characterized through curcumin release and antioxidant activity. The processing of the polymer had a drastic impact on the curcumin release profiles indicating the polymer degradation was influenced by surface area and porosity of the final product. Previously, release was controlled primarily through the hydrophobicity of the polymer. Here, we demonstrate a novel method for further tuning the degradation by processing the polymer.

Self-assembled amphiphilic copolymers–doxorubicin conjugated nanoparticles for gastric cancer therapy with low in vivo toxicity and high efficacy

Amphiphilic copolymers have long been utilized to turn hydrophobic anticancer drugs into nanoparticles administered to patients with cancer. A lack of stability in these monotherapies may be blamed for their poor clinical results in patients with cancer. We propose novel nanotherapies based on polymeric small prodrugs that preserve pharmacologic effectiveness while significantly reducing the toxicity of the fabricated drugs in animals to overcome this problem. Doxorubicin is attached to the end of the PLA fragments through a hydrolyzable ester bond utilizing methoxypolyethylene glycol-block-poly(d, l-lactic acid) (mPEG-PCL(2K)) with conjugates to mimic the self-assembly of colloidal nanotherapies. In a gastric cancer xenograft model, this nanotherapy displays a long-lasting suppression of tumor growth once a reasonable dosage is administered. Our findings imply that a toxic chemical and hydrophobic can be converted into therapeutic effective self-delivery nanotreatment.

Polymeric dexamethasone prodrugs attenuate lupus nephritis in MRL/lpr mice with reduced glucocorticoid toxicity

Due to their potent immunosuppressive and anti-inflammatory effects, glucocorticoids (GCs) are the most widely used medications in treating lupus nephritis (LN). Long-term use of GCs, however, is associated with numerous off-target adverse effects. To reduce GCs' adverse effects, we previously developed two polymeric dexamethasone prodrug nanomedicines: N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based dexamethasone prodrug (P-Dex), and micelle-forming polyethylene glycol (PEG)-based dexamethasone prodrug (ZSJ-0228). Both P-Dex and ZSJ-0228 provided sustained amelioration of LN in lupus-prone NZB/W F1 mice with reduced GC-associated adverse effects. Here, we have extended our investigation to the MRL/lpr mouse model of LN. Compared to dose equivalent daily dexamethasone sodium phosphate (Dex) treatment, monthly P-Dex or ZSJ-0228 treatments were more effective in reducing proteinuria and extending the lifespan of MRL/lpr mice. Unlike the daily Dex treatment, ZSJ-0228 was not associated with measurable GC-associated adverse effects. In contrast, adrenal gland atrophy was observed in P-Dex treated mice.

Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis

The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases. Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment. However, only a limited number of nanotherapies have enter clinical trials or are clinically approved. Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system (MPS), resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors. Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy. Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages. Polymer conjugation revived the parent camptothecin agent (e.g., 7-ethyl-10-hydroxy-camptothecin), enabling lipid nanoparticle encapsulation. Furthermore, macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin, increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy. When tested in a preclinical murine model of breast cancer, macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles. Furthermore, intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity. Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity. This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers.

Use of Self-Assembled Colloidal Prodrug Nanoparticles for Controlled Drug Delivery of Anticancer, Antifibrotic and Antibacterial Mitomycin.

Herein we present the synthesis of a polymeric prodrug nanomaterial capable of spontaneous, self-assembled nanoparticle formation and of the conjugation (encapsulation) of drugs with amino and/or carboxyl and/or hydroxyl groups via ester and/or amide linkage. Mitomycin C (MMC) a versatile drug with antibiotic, antibacterial and antineoplastic properties, was used to prove this concept. The in vitro drug release experiments showed a fast release for the pure MMC (k = 49.59 h−n); however, a significantly lower MMC dissolution rate (k = 2.25, 1.46, and 1.35 h−n) was obtained for the nanoparticles with increased cross-link density (3, 10, 21%). The successful modification and conjugation reactions were confirmed using FTIR and EDX measurements, while the mucoadhesive properties of the self-assembled particles synthesized in a simple one-pot reaction were proved by rheological measurement. The prepared biocompatible polymeric prodrugs are very promising and applicable as a drug delivery system (DDS) and useful in the area of cancer treatment.

Acid-sensitive polymeric prodrug micelles for achieving enhanced chemo-photodynamic therapy

Multimodal combination therapy is considered more effective in cancer treatment than monotherapy, because it overcomes some limitations of monotherapy. In this study, acid-sensitive polymeric prodrugs consisting of photosensitizer (Hemin) and ortho ester-terminated PEG were synthesized and loaded with doxorubicin (DOX) to obtain a dual-modal therapeutic nanoplatform (Hemin/DOX-M). This nanoplatform demonstrated good drug encapsulation and stability. In vitro experiments have confirmed that Hemin/DOX-M can be effectively internalized by HepG2 cells, trigger rapid drug release via the cleavage of ortho ester and alleviate tumor hypoxia to amplify the PDT effect under laser irradiation. In vivo experiments revealed that Hemin/DOX-M caused decreased hemolysis and selective accumulation in the tumor tissue, thereby significantly reducing the side effects. Intriguingly, In vivo antitumor evaluation revealed that Hemin/DOX-M had stronger capability at tumor growth inhibition (TGI, 79.63%) than chemo- or photodynamic therapy alone. Overall, Hemin/DOX-M is a promising candidate to increase therapeutic efficacy by achieving combination therapy against tumors.