Doxorubicin Conjugates Research Articles

Safety and pharmacokinetics of MM-302, a HER2-targeted antibody\u2013liposomal doxorubicin conjugate, in patients with advanced HER2-positive breast cancer: a phase 1 dose-escalation study

BackgroundThis phase 1 dose-escalation trial studied MM-302, a novel HER2-targeted PEGylated antibody–liposomal doxorubicin conjugate, in HER2-positive locally advanced/metastatic breast cancer.MethodsPatients were enrolled in four cohorts: MM-302 monotherapy (8, 16, 30, 40, and 50 mg/m2 every 4 weeks [q4w]); MM-302 (30 or 40 mg/m2 q4w) plus trastuzumab (4 mg/kg q2w); MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) q3w; MM-302 (30 mg/m2) plus trastuzumab (6 mg/kg) and cyclophosphamide (450 mg/m2) q3w.ResultsSixty-nine patients were treated. The most common adverse events (AEs) were fatigue and nausea. Grade 3/4 AEs of special interest included neutropenia, fatigue, mucosal inflammation, anemia, thrombocytopenia, febrile neutropenia, and palmar-plantar erythrodysesthesia. The MTD was not reached. With MM-302 ≥ 30 mg/m2, overall response rate (ORR) was 13% and median progression-free survival (mPFS) 7.4 months (95% CI: 3·5–10·9) in all arms. In 25 anthracycline-naïve patients, ORR was 28·0% and mPFS 10·9 months (95% CI: 1·8–15·3). Imaging with 64Cu-labeled MM-302 visualized tumor-drug penetrance in tumors throughout the body, including the brain.ConclusionMM-302 monotherapy, in combination with trastuzumab, or trastuzumab plus cyclophosphamide, was well tolerated and showed promising efficacy. The selected phase 2 MM-302 dose was 30 mg/m2 plus 6 mg/kg trastuzumab q3w.

Improved anticancer efficacy of doxorubicin mediated by human-derived cell-penetrating peptide dNP2

Although cell penetrating peptides (CPPs) have been extensively studied as an approach to deliver anti-cancer drugs into the tumor cells for the last 30 years, no FDA-approved CPP-based drugs are available, implying that the existing CPPs may have less efficiency in human or have side effects such as toxicity. Herein, we established a tumor targeting drug delivery system by attaching a human-derived cell-penetrating peptide dNP2 (CKIKKVKKKGRKKIKKVKKKGRK) to N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymer doxorubicin conjugates. Firstly, in vitro cytotoxicity of free dNP2 peptide and dNP2-modified blank HPMA copolymer were examined. A classic CPP-R8 (CRRRRRRRR) was chosen for comparison and the results showed that 200 μM free R8 reduced cell viability to 68.4% but dNP2 did not induce any toxicity at the same concentration. After conjugation to HPMA copolymer, a similar trend was also observed which indicated the excellent biocompatibility of dNP2. Next, effect of dNP2 modification on cellular uptake, DNA damage, apoptosis and anticancer activity of HPMA copolymer doxorubicin conjugates were evaluated. It was excited that dNP2 modified HPMA copolymer (P-(dNP2)-DOX) not only had a higher uptake by HeLa cell compared with non-modified copolymer (P-DOX) but resulted in an enhanced drug distribution in nuclei. Furthermore, P-(dNP2)-DOX exhibited greater DNA damage ability (10.5 folds higher than P-DOX) in comet assay and induced more apoptosis cells (46.0%). P-(dNP2)-DOX also showed a stronger cell cytotoxicity (3-fold to P-DOX) as well as in 3D tumor spheroid assay (inhibition rate 78%). All these results suggested that the human-derived cell-penetrating peptide dNP2 could facilitate tumor nuclear-accumulation of anti-cancer drugs and improve anticancer efficacy. More importantly, dNP2 has less toxicity compared with classic CPP-R8 thus shows the potential for the clinic cancer therapy.

Modified Poly(T-Butyl Methacrylate) as a Doxorubicin Carrier for Targeted Delivery

Poly(t-butyl methacrylate) (PTBMA) was selected as a doxorubicin carrier for targeted delivery because it can hydrolyze to form water-soluble polymers. A chain-transfer reaction with thioglycolic acid was used. The thioglycolic acid concentration was 1 mass%, at which a polymer with the optimal biocompatibility (molecular mass ~12 kDa, polydispersion index Mw/Mn ≈ 1.5) was obtained. The polymer was chemically modified by a folate vector. The resulting polymer was converted via acid hydrolysis into a water-soluble copolymer. Then, a conjugate of doxorubicin (DOX) with the copolymer of t-butyl methacrylate and methacrylic acid modified by the folate vector on the terminal carboxylates was prepared. The degree of DOX conjugation to the polymer was 62.7 ± 11.8%. DOX was released from the polymer system almost three times faster at pH 4.6 than at pH 7.4. The cytotoxicity of the polymer conjugate was 1.52 μM.

Synthesis and Antiproliferative Activity of Conjugates of Anthracycline Antibiotics with Sesquiterpene Lactones of the Elecampane

The daunorubicin and doxorubicin anthracycline antibiotics were modified with the Inula helenium L. sesquiterpene lactones (alantolactone, isoalantolactone, and alloalantolactone) and with their epoxy derivatives. Antiproliferative properties of these conjugates were studied on tumor and normal cell lines. The daunorubicin conjugates with the sesquiterpene lactones (isoalantolactone, allantolactone, and alloalantolactone) and with their epoxy derivatives were found to exhibit the higher activity against human tumor cell lines than the corresponding doxorubicin conjugates. The daunorubicin conjugate with epoxyisoalantolactone proved to be the most effective compound, because it was more cytotoxic than daunorubicin towards a number of cell lines, including those daunorubicin-resistant, and did not affect normal human cells.

Synthesis of a Reactive Oxygen Species-Responsive Doxorubicin Derivative.

A heterobifunctional reactive oxygen species (ROS)-responsive linker for directed drug assembly onto and delivery from a quantum dot (QD) nanoparticle carrier was synthesized and coupled to doxorubicin using N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC)/sulfo–NHS coupling. The doxorubicin conjugate was characterized using 1H NMR and LC-MS and subsequently reacted under conditions of ROS formation (Cu2+/H2O2) resulting in successful and rapid thioacetal oxidative cleavage, which was monitored using 1H NMR.

Tumor microenvironment-labile polymer–doxorubicin conjugate thermogel combined with docetaxel for in situ synergistic chemotherapy of hepatoma

Topical chemotherapy with complementary drugs is one of the most promising strategies to achieve an effective antitumor activity. Herein, a synergistic strategy for hepatoma therapy by the combination of tumor microenvironment-sensitive polymer–doxorubicin (DOX) conjugate thermogel, containing a DNA intercalator DOX, and docetaxel (DTX), a microtubule-interfering agent, was proposed. First, cis-aconitic anhydride-functionalized DOX (CAD) and succinic anhydride-modified DOX (SAD) were conjugated onto the terminal hydroxyl groups of poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA–PEG–PLGA), yielding the acid-sensitive CAD-PLGA–PEG-PLGA–CAD and the insensitive SAD-PLGA–PEG–PLGA-SAD conjugates, respectively. The prodrug aqueous solution exhibited a thermoreversible sol–gel transition between room and physiological temperature. Meantime, appropriate mechanical property, biodegradability, as well as a sustained release profile were revealed in such prodrug thermogels. More importantly, the addition of DTX to the DOX-conjugated thermogels (i.e., Gel-CAD and Gel-SAD) was verified with enhanced curative effect against tumor, where the antitumor efficacy of Gel-CAD+DTX was obviously higher than the other groups. A reliable security in vivo was also showed in the Gel-CAD+DTX group. Taken together, such combination of tumor microenvironment-labile prodrug thermogel and a complementary drug exhibited fascinating prospect for local synergistic antineoplastic therapy. Statement of SignificanceMultidrug chemotherapy with synergistic effect has been proposed recently for hepatoma treatment in the clinic. However, the quick release, fast elimination, and unselectivity of multidrugs in vivo always limit their further application. To solve this problem, a synergistic combination of tumor microenvironment-sensitive polymeric doxorubicin (DOX) prodrug thermogel for DNA intercalation and a microtubule-interfering agent docetaxel (DTX) is developed in the present study for the local chemotherapy of hepatoma. Interestingly, a pH-triggered sustained release behavior, an enhanced antitumor efficacy, and a favorable security in vivo are observed in the combined dual-drug delivery platform. Therefore, effectively combining tumor microenvironment-labile polymeric prodrug thermogel with a complementary drug provides an advanced system and a promising prospect for local synergistic hepatoma chemotherapy.

Abstract 4663: Lysosomal targeting from a gelatin-doxorubicin conjugate produces evidence of both nuclear and lysosomal cytotoxcity pathways in mcf-7 breast cancer cells

Abstract Background: Intra-lysosomal targeting has been investigated for the treatment of cancer but details of the cytotoxicity pathways remain unclear. A high molecular weight gelatin - doxorubicin conjugate (GDox) has been synthesized to target acidic lysosomes for intra-lysosomal drug release. The purpose of this investigation was to explore GDox feasibility for drug delivery and to make a preliminary determination of a cytotoxic pathway. Methods: GDox was synthesized in formamide using the carbodiimide, EDC. Drug load was determined spectroscopically, drug release at pH 4.8 was determined by HPLC, and molecular weight and its reduction in FBS was determined by HPSEC. Cellular localization was determined for free Dox and GDox at 10 µM or its equivalent Dox concentration using fluorescence microscopy with appropriate subcellular stains. Three to four independent trials (n=3-4) were examined with 200 to 700 cells per time point. Cytotoxicity was determing by the MTT procedure (n=3). Viabilities, growth inhibition profiles and their IC50 values were calculated with GraphPad Prism 7. The nucleus content of free Dox or Dox released from GDox after incubation was determined by UHPLC using fluorescent detection (n=3-4). Results: A typical GDox contained 5.6% w/w Dox, had a molecular weight of ~ 160 kDa, and released 58+2.3% Dox at pH 4.8 representing lysosomal pH. After incubation in FBS at 37°C for 24 hr the low molecular weight species increased a relatively small 16%. Fluorescent images with LysoTracker Green confirmed GDox localization to the lysosome which was detectable by 2 hr but substantial in swollen lysosomes by 24 and 48 hrs. No released Dox was observed in the nucleus, but a slight red nucleus haze at later times suggested this possibility. Cell debri from GDox was not observed from free Dox. As expected, free Dox rapidly accumulated in the nucleus by 2 hr. Viability determinations at 0.1, 1, and 10 µM for 2 to 48 hr showed no effect from either agent before 24 hr. By 48 hr at 10 µM, the viability of Dox (30+12%) and GDox (36+13%) were indistinguishable (p=0.68). However, by 72 hr, IC50 values varied 10-fold at 0.094 and 0.96 µM, respectively. The nucleus drug content after incubation at 10 µM for 2 to 48 hr was 0.27+0.07 to 1.39+0.6 µg/106 cells (p&lt0.01) for free Dox, and 0.014+0.01 to 0.11+0.06 µg/106 cells (p&lt0.01) for released Dox. Conclusions: Taken together these results suggest good feasibility of GDox lysosomal targeting and Dox release in MCF7 breast cancer cells. Of note, after 48 hr incubation GDox produced the same cytotoxicity as the free drug but with 13-fold less Dox in the nucleus. This striking nucleus difference and the substantial lysosomal GDox content suggest a lysosomal pathway of GDox cytotoxicity in addition to a nuclear pathway. Support: NIH/NCI R15CA135421 and the Agnes Varis Trust for Women's Leadership and Health. Citation Format: Mohammed Alvi, Bayan Eshmawi, Rachel Nicoletto, Hyun Kate Kim, Christopher Cammarata, Clyde Ofner. Lysosomal targeting from a gelatin-doxorubicin conjugate produces evidence of both nuclear and lysosomal cytotoxcity pathways in mcf-7 breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4663.

Redox-sensitive hydroxyethyl starch-doxorubicin conjugate for tumor targeted drug delivery

Doxorubicin (DOX) is one of the most potent anticancer agents in cancer chemotherapy, but the clinical use of DOX is restricted by its severe side effects caused by nonspecific delivery. To alleviate the side effects and improve the antitumor efficacy of DOX, a novel redox-sensitive hydroxyethyl starch–doxorubicin conjugate, HES-SS-DOX, with diameter of 19.9 ± 0.4 nm was successfully prepared for tumor targeted drug delivery and GSH-mediated intracellular drug release. HES-SS-DOX was relatively stable under extracellular GSH level (∼2 μM) but released DOX quickly under intracellular GSH level (2–10 mM). In vitro cell study confirmed the GSH-mediated cytotoxicity of HES-SS-DOX. HES-SS-DOX exhibited prolonged plasma half-life time and enhanced tumor accumulation in comparison to free DOX. As a consequence, HES-SS-DOX exhibited better antitumor efficacy and reduced toxicity as compared to free DOX in the in vivo antitumor activity study. The redox-sensitive HES-SS-DOX was proved to be a promising prodrug of ...

Pharmacokinetics and pharmacodynamics of pH responsive hydroxyethyl starch doxorubicin conjugate

Pharmacokinetics and pharmacodynamics of pH responsive hydroxyethyl starch doxorubicin conjugate

Doxorubicin Conjugation and Drug Linker Chemistry Alter the Intravenous and Pulmonary Pharmacokinetics of a PEGylated Generation 4 Polylysine Dendrimer in Rats

PEGylated polylysine dendrimers have demonstrated potential as inhalable drug delivery systems that can improve the treatment of lung cancers. Their treatment potential may be enhanced by developing constructs that display prolonged lung retention, together with good systemic absorption, the capacity to passively target lung tumors from the blood and highly selective, yet rapid liberation in the tumor microenvironment. This study sought to characterize how the nature of cathepsin B–cleavable peptide linkers, used to conjugate doxorubicin (Dox) to a PEGylated (PEG570) G4 polylysine dendrimer, affects drug liberation kinetics and intravenous and pulmonary pharmacokinetics in rats. The construct bearing a self-emolative diglycolic acid-V-Citrulline linker exhibited faster Dox release kinetics compared to constructs bearing self-emolative diglycolic acid-glycine-leucine-phenylalanine-glycine (GLFG), or non-self-emolative glutaric acid-GLFG linkers. The V-Citrulline construct exhibited slower plasma clearance, but faster absorption from the lungs than a GLFG construct, although mucociliary clearance and urinary elimination were unchanged. Dox-conjugation enhanced localization in the bronchoalveolar lavage fluid compared to lung tissue, suggesting that projection of Dox from the dendrimer surface reduced tissue uptake. These data show that the linker chemistry employed to conjugate drugs to PEGylated carriers can affect drug release profiles and systemic and lung disposition.

Tumor Specific and Renal Excretable Star-like Triblock Polymer-Doxorubicin Conjugates for Safe and Efficient Anticancer Therapy.

Efficient tumor accumulation and body clearance are two paralleled requirements for ideal nanomedicines. However, it is hard for both to be met simultaneously. The inefficient clearance often restrains the application of drug delivery systems (DDSs), especially for high-dosage administration. In this study, the star-like and block structures are combined to enhance the tumor specific targeting of the parent structures and obtain additional renal excretion property. The influences of polymer architectures and chemical compositions on the physicochemical and biological properties, particularly the simultaneous achievement of tumor accumulation and renal clearance, have been investigated. Among the tested conjugates, an eight-arm triblock star polymer based on poly(ethylene glycol) (PEG) and poly( N-(2-hydroxyl) methacrylamide) (PHPMA) is found to simultaneously fulfill the requirements of superior tumor accumulation and efficient renal clearance due to the appropriate micelle size and reversible aggregation process. On the basis of this conjugate, 60 mg/kg of Dox equivalent (much higher than the maximum tolerated dose (MTD) of Dox) can be administered to efficiently suppress tumor growth without causing any obvious toxicity. This work provides a new approach to design polymer-drug conjugates for tumor specific application, which can simultaneously address the efficacy and safety concerns.

Cellular delivery of doxorubicin mediated by disulfide reduction of a peptide-dendrimer bioconjugate

In this study, we developed a peptide-dendrimer-drug conjugate system for the pH-triggered direct cytosolic delivery of the cancer chemotherapeutic doxorubicin (DOX) using the pH Low Insertion Peptide (pHLIP). We synthesized a pHLIP-dendrimer-DOX conjugate in which a single copy of pHLIP displayed a generation three dendrimer bearing multiple copies of DOX via disulfide linkages. Biophysical analysis showed that both the dendrimer and a single DOX conjugate inserted into membrane bilayers in a pH-dependent manner. Time-resolved confocal microscopy indicate the single DOX conjugate may undergo a faster rate of membrane translocation, due to greater nuclear localization of DOX at 24 h and 48 h post delivery. At 72 h, however, the levels of DOX nuclear accumulation for both constructs were identical. Cytotoxicity assays revealed that both constructs mediated ∼80% inhibition of cellular proliferation at 10 µM, the dendrimer complex exhibited a 17% greater cytotoxic effect at lower concentrations and greater than three-fold improvement in IC50 over free DOX. Our findings show proof of concept that the dendrimeric display of DOX on the pHLIP carrier (1) facilitates the pH-dependent and temporally-controlled release of DOX to the cytosol, (2) eliminates the endosomal sequestration of the drug cargo, and (3) augments DOX cytotoxicity relative to the free drug.

Redox-responsive microbeads containing thiolated pectin-doxorubicin conjugate inhibit tumor growth and metastasis: An in vitro and in vivo study

The objective of this study was to investigate the in vitro cytotoxicity and in vivo anticancer efficacy of redox-responsive microbeads containing thiolated pectin–doxorubicin (DOX) conjugate. Oral microbeads were coated with an enteric polymer to protect the drug from release in the upper gastrointestinal (GI) tract and allow redox-triggered drug release in the colon. Morphology, particle size, drug content, and in vitro drug release behavior of the microbeads were characterized; in vitro cytotoxicity was tested on mouse colon carcinoma, human colorectal adenocarcinoma, and human bone osteosarcoma cell lines. In vivo anticancer efficacy of coated microbeads was examined in BALB/c mice with murine colon carcinoma. These coated microbeads significantly inhibited the growth of all cell lines. The in vivo study confirmed delivery of DOX to the colorectal tumor site, redox-responsiveness, and anticancer efficacy of coated microbeads. Coated microbeads also effectively inhibited primary tumor growth and suppressed tumor metastases without gross toxicity to the non-target tissue. No noticeable damage was found in mouse GI tissues, indicating lack of DOX toxicity. These novel coated microbeads containing thiolated pectin–DOX conjugate may be a promising vehicle for targeted clinical delivery of DOX to the colorectal cancer site by oral administration.

Heteronanoparticles by Self-Assembly of Ecdysteroid and Doxorubicin Conjugates To Overcome Cancer Resistance.

Heteronanoparticles (H-NPs) consisting of conjugates characterized by a squalene tail linked to doxorubicin and ecdysteroid derivatives are presented. Biological evaluation on A2780ADR cell line confirms not only the maintenance of the activity of the parental drug but also the ability to overcome cancer resistance. The in vitro cell uptake was demonstrated, and the involvement of an endosomal-mediated pathway was suggested.

In vitro cytotoxicity of GO-DOx on FaDu squamous carcinoma cell lines.

We have synthesized graphene oxide (GO) nanosheets using modified Hummer’s method and conjugated it with doxorubicin (DOx), an anticancer drug. Drug release kinetics from GO–DOx conjugate indicated the drug release at acidic pH. MTT assay performed on FaDu hypopharyngeal cancer cell lines revealed that the GO–DOx nanoconjugate inhibited cell proliferation more efficiently compared with pure DOx. Preliminary results indicate the potential of designed GO–DOx drug conjugate for head and neck cancer.

Chemotherapeutic Effect of CD147 Antibody-labeled Micelles Encapsulating Doxorubicin Conjugate Targeting CD147-Expressing Carcinoma Cells.

CD147 (basigin/emmprin) is expressed on the surface of carcinoma cells. For studying the efficacy of CD147-targeting medicine on CD147-expressing cells, we studied the effect of anti-CD147-labeled polymeric micelles (CD147ab micelles) that encapsulated a conjugate of doxorubicin with glutathione (GSH-DXR), with specific accumulation and cytotoxicity against CD147-expressing A431 human epidermoid carcinoma cells, Ishikawa human endometrial adenocarcinoma cells, and PC3 human prostate carcinoma cells. By treatment of each cell type with CD147ab micelles for 1 h, a specific accumulation of CD147ab micelles in CD147-expressing cells was observed. In addition, the cytotoxicity of GSH-DXR-encapsulated micelles against each cell type was measured by treatment of the micelles for 1 h. The cytotoxic effect of CD147ab micelles carrying GSH-DXR was 3- to 10-fold higher for these cells than that of micelles without GSH-DXR. These results suggest that GSH-DXR-encapsulated CD147ab micelles could serve as an effective drug delivery system to CD147-expressing carcinoma cells.

Conjugate of PAMAM Dendrimer, Doxorubicin and Monoclonal Antibody-Trastuzumab: The New Approach of a Well-Known Strategy.

The strategy utilizing trastuzumab, a humanized monoclonal antibody against human epidermal growth receptor 2 (HER-2), as a therapeutic agent in HER-2 positive breast cancer therapy seems to have advantage over traditional chemotherapy, especially when given in combination with anticancer drugs. However, the effectiveness of single antibody or antibody conjugated with chemotherapeutics is still far from ideal. Antibody–dendrimer conjugates hold the potential to improve the targeting and release of active substance at the tumor site. In the present study, we developed and synthesized PAMAM dendrimer–trastuzumab conjugates carrying doxorubicin (dox) specifically to cells overexpressing HER-2. 1HNMR, FTIR and RP-HPLC were used to characterize the products and analyze their purity. Toxicity of PAMAM–trastuzumab and PAMAM–dox–trastuzumab conjugates compared with free trastuzumab and doxorubicin towards HER-2 positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines was determined using MTT assay. Furthermore, the cellular uptake and cellular localization were studied by flow cytometry and confocal microscopy, respectively. A cytotoxicity profile of above mentioned compounds indicated that conjugate PAMAM–dox–trastuzumab was more effective when compared to free drug or the conjugate PAMAM–trastuzumab. Moreover, these results reveal that trastuzumab can be used as a targeting agent in PAMAM–dox–trastuzumab conjugate. Therefore PAMAM–dox–trastuzumab conjugate might be an interesting proposition which could lead to improvements in the effectiveness of drug delivery systems for tumors that overexpress HER-2.

Imaging doxorubicin and polymer-drug conjugates of doxorubicin-induced cardiotoxicity with bispecific anti-myosin-anti-DTPA antibody and Tc-99m-labeled polymers

BackgroundRadiolabeled anti-myosin imaging is well-established for imaging doxorubicin-induced cardiotoxicity. However, to enable imaging of drug-induced cardiotoxicity in small experimental animals, pretargeting with bispecific anti-myosin-anti-DTPA-Fab-Fab’ and targeting with high-specific radioactivity Tc-99m-DTPA-succinylated-polylysine (DSPL) was developed. MethodsMice were injected biweekly with 10 mg/kg Dox or its equivalent as D-Dox-PGA. Tc-99m-DSPL myocardial activity after pretargeting with bsAb-Fab-Fab’ was determined after gamma imaging performed at day 7 for Dox-treated mice and day 39 for all others. ResultsMice treated with 10 mg/kg Dox lost 10% total body weight in 1 week and 20% after a second dose. Pretargeted mice treated with 30 mg/kg cumulative D-Dox-PGA dose showed no loss of body weight for the duration of the study. Cardiotoxicity was confirmed by gamma imaging and scintillation counting (1.9 ± 0.25 [mean% ID/g ± SD]) after 1 dose of Dox. Mice injected with 3 × 10 mg/kg Dox equivalent as D-Dox-PGA (0.4 ± 0.04, P < .01) and untreated 2 control groups (0.20 ± 0.05 and 0.19 ± 0.04, P < .01) showed significantly lower myocardial anti-myosin radioactivity relative to the 10 mg/kg Dox group. ConclusionPretargeting with bsAb-Fab-Fab’ and targeting with Tc-99m labeled high-specific activity polymers enabled early visualization of doxorubicin induce cardiotoxicity in mice. Tolerated dose of D-Dox-PGA was greater than to 30 mg/kg Dox-equivalent dose with minimal cardiotoxicity.

Polymeric nanovesicles as simultaneous delivery platforms with doxorubicin conjugation and elacridar encapsulation for enhanced treatment of multidrug-resistant breast cancer.

Multidrug resistance (MDR) is one of the major obstacles hindering the successful chemotherapy of cancer. Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) is an important factor responsible for MDR. In this study, a novel copolymer methoxy-poly(ethylene glycol)-poly[(N-(6-hydroxyhexyl)-g-doxorubicin-l-aspartamide)-(β-benzyl-l-aspartate)] (mPEG-P[Asp(HPA-g-DOX)-BLA)] was synthesized and utilized to assemble into nanovesicles with hydrophilic P-gp inhibitor elacridar hydrochloride (Ela) encapsulated into the aqueous lumen. Doxorubicin (DOX) was covalently conjugated onto the polymer chain via a pH-cleavable amide linkage, leading to a pH responsive DOX release as well as disintegration of the nanovesicles in the lysosome of tumor cells. In vitro studies demonstrated that the DOX and Ela co-delivered nanovesicles showed superior cytotoxicity and enhanced anti-tumor properties as compared to single DOX-delivery nanosystems in MCF-7/ADR cancer, which was attributed to the P-gp bioactivity inhibition as investigated by a cell immunofluorescence assay. In vivo studies showed that the polymeric nanovesicles effectively accumulated at the tumor site and the co-delivered DOX and Ela effectively suppressed the MCF-7/ADR tumor growth. All the results indicated that the acid-liable nanovesicles had a synergistic effect to enhance antitumor efficacy for multidrug-resistant breast cancer treatment.

Albumin as a "Trojan Horse" for polymeric nanoconjugate transendothelial transport across tumor vasculatures for improved cancer targeting.

Although polymeric nanoconjugates (NCs) hold great promise for the treatment of cancer patients, their clinical utility has been hindered by the lack of efficient delivery of therapeutics to targeted tumor sites. Here, we describe an albumin-functionalized polymeric NC (Alb-NC) capable of crossing the endothelium barrier through a caveolae-mediated transcytosis pathway to better target cancer. The Alb-NC is prepared by nanoprecipitation of doxorubicin (Doxo) conjugates of poly(phenyl O-carboxyanhydrides) bearing aromatic albumin-binding domains followed by subsequent surface decoration of albumin. The administration of Alb-NCs into mice bearing MCF-7 human breast cancer xenografts with limited tumor vascular permeability resulted in markedly increased tumor accumulation and anti-tumor efficacy compared to their conventional counterpart PEGylated NCs (PEG-NCs). The Alb-NC provides a simple, low-cost and broadly applicable strategy to improve the cancer targeting efficiency and therapeutic effectiveness of polymeric nanomedicine.