Micellar Delivery System Research Articles

Healing efficacy of fracture-targeted GSK3β inhibitor-loaded micelles for improved fracture repair.

To evaluate the fracture healing capabilities of a GSK3β inhibitor, 6-bromoindirubin-3'-oxime, coupled with an aspartic acid octapeptide in a micellar delivery system. The efficacy of the intravenously administered micelles to accelerate healing of femoral fracture in mice was evaluated. Micro-computed tomography analysis was employed to obtain bone density, total volume, relative volume, trabecular thickness and trabecular spacing. Both fracture bone mineral density and volume were significantly higher in the micelle treatment groups when compared with controls. The fracture-targeted micelle demonstrates fracture-specific bone anabolism and biocompatibility in off-target tissues. Accelerated fracture healing in mice was achieved by targeting the GSK3β inhibitor, 6-bromoindirubin-3'-oxime, to the fracture site.

Ascorbyl palmitate/d-α-tocopheryl polyethylene glycol 1000 succinate monoester mixed micelles for prolonged circulation and targeted delivery of compound K for antilung cancer therapy in vitro and in vivo.

The roles of ginsenoside compound K (CK) in inhibiting tumor have been widely recognized in recent years. However, low water solubility and significant P-gp efflux have restricted its application. In this study, CK ascorbyl palmitate (AP)/d-α-tocopheryl polyethylene glycol 1000 succinate monoester (TPGS) mixed micelles were prepared as a delivery system to increase the absorption and targeted antitumor effect of CK. Consequently, the solubility of CK increased from 35.2±4.3 to 1,463.2±153.3 μg/mL. Furthermore, in an in vitro A549 cell model, CK AP/TPGS mixed micelles significantly inhibited cell growth, induced G0/G1 phase cell cycle arrest, induced cell apoptosis, and inhibited cell migration compared to free CK, all indicating that the developed micellar delivery system could increase the antitumor effect of CK in vitro. Both in vitro cellular fluorescence uptake and in vivo near-infrared imaging studies indicated that AP/TPGS mixed micelles can promote cellular uptake and enhance tumor targeting. Moreover, studies in the A549 lung cancer xenograft mouse model showed that CK AP/TPGS mixed micelles are an efficient tumor-targeted drug delivery system with an effective antitumor effect. Western blot analysis further confirmed that the marked antitumor effect in vivo could likely be due to apoptosis promotion and P-gp efflux inhibition. Therefore, these findings suggest that the AP/TPGS mixed micellar delivery system could be an efficient delivery strategy for enhanced tumor targeting and antitumor effects.

Co-assembly of doxorubicin and curcumin targeted micelles for synergistic delivery and improving anti-tumor efficacy

Chemotherapeutic drugs have a series of limitations in anti-tumor treatment, mainly including multidrug resistance (MDR) and serious adverse reactions. Co-delivery system with two or more synergistic therapeutic drugs is an effective strategy to settle these limitations. In this study, active tumor-targeted co-delivery micelles (DOX+Cur)-PMs, with two synergistic drugs of a therapeutic drug of doxorubicin (DOX) and a chemosensitizer of curcumin (Cur) co-encapsulated into hyaluronic acid-vitamin E succinate (HA-VES) graft copolymer, were prepared and delivered simultaneously into tumor cells for improving therapeutic effects of DOX. (DOX+Cur)-PMs had uniform particle size, high encapsulation efficacy, sustained release profile and good colloidal stability. In vitro cytotoxicity study, (DOX+Cur)-PMs exerted the strongest cytotoxicity and highest cell apoptosis-inducing activities against DOX-resistant MCF-7/Adr cells. Moreover, (DOX+Cur)-PMs more efficiently internalized into cancer cells and enhanced the cellular uptake of DOX via energy-dependent and caveolae-mediated endocytosis, and significantly reversed MDR effects via CD44 targeting delivery and the synergic effect of released Cur. More importantly, in vivo results illustrated that (DOX+Cur)-PMs not only displayed better tumor accumulation and tumor targeting, and more efficiently inhibited the growth of tumor in 4T1 tumor-bearing mice, but also induced significantly less pathological damage to the cardiac tissue in comparison with free DOX, even DOX-PMs and DOX-PMs+Cur. In summary, this targeted combinational micellar delivery system with DOX and Cur could be a promising vehicle in tumor therapy.

The reversal of multidrug resistance in ovarian carcinoma cells by co-application of tariquidar and paclitaxel in transferrin-targeted polymeric micelles

In this study, a transferrin (Tf)-modified polyethylene glycol-phosphatidyl ethanolamine (PEG-PE)-based micellar delivery system containing paclitaxel (PTX) and tariquidar (TRQ), a potent third generation P-gp inhibitor, was prepared. The nanoformulation was evaluated by targeting efficiency, cellular association, cellular internalization pathway and cytotoxicity for reversal of PTX resistance on two multidrug resistant (MDR) ovarian carcinoma cell lines, SKOV-3TR and A2780-Adr. PTX and TRQ are both hydrophobic compounds. They were successfully encapsulated into the micellar structure containing vitamin E as the encapsulation enhancer. The Tf-targeted micelles were internalized mainly via clathrin-dependent endocytosis by both cell lines. For SKOV-3TR, additional mechanisms including caveolin-dependent endocytosis and macropinocytosis were found to play a significant role. The PTX cytotoxicity against the SKOV-3TR and A2780-Adr MDR cells was increased significantly in the presence of micellar encapsulation. However, unlike the A2780-Adr cell line, the Tf-targeting effect was significant on SKOV-3TR cells when co-administrated with TRQ. Penetration of the Tf-targeted micelles in a cancer cell spheroid culture was also investigated.

Cyclosporine Amicellar delivery system for dry eyes.

BackgroundThe objectives of this study were to develop stable cyclosporine A (CsA) ophthalmic micelle solutions for dry-eye syndrome and evaluate their physicochemical properties and therapeutic efficacy.Materials and methodsCsA-micelle solutions (MS-CsA) were created by a simple method with Cremophor EL, ethanol, and phosphate buffer. We investigated the particle size, pH, and osmolarity. In addition, long-term physical and chemical stability for MS-CsA was observed. To confirm the therapeutic efficacy, tear production in dry eye-induced rabbits was evaluated using the Schirmer tear test (STT). When compared to a commercial product, Restasis, MS-CsA demonstrated improvement in goblet-cell density and conjunctival epithelial morphology, as demonstrated in histological hematoxylin and eosin staining.ResultsMS-CsA had a smaller particle size (average diameter 14–18 nm) and a narrow size distribution. Physicochemical parameters, such as particle size, pH, osmolarity, and remaining CsA concentration were all within the expected range of 60 days. STT scores significantly improved in MS-CsA treated groups (P<0.05) in comparison to those of the Restasis-treated group. The number of goblet cells for rabbit conjunctivas after the administration of MS-CsA was 94.83±8.38, a significantly higher result than the 65.17±11.51 seen with Restasis. The conjunctival epithelial morphology of dry eye-induced rabbits thinned with loss of goblet cells. However, after 5 days of treatment with drug formulations, rabbit conjunctivas recovered epithelia and showed a relative increase in the number of goblet cells.ConclusionThe results of this study indicate the potential use of a novel MS for the ophthalmic delivery of CsA in treating dry eyes.

In vitro controlled release of clove essential oil in self-assembly of amphiphilic polyethylene glycol-block-polycaprolactone

In this study, a micellar delivery system with an amphiphilic diblock copolymer of poly (ethylene glycol) and poly (ɛ-caprolactone) was synthesised and used to incorporate hydrophobic clove essential oil (CEO). To determine an optimal delivery system, the effects of the copolymer’s hydrophobic block length and the CEO-loading content on the encapsulation of CEO were investigated. Percentages of entrapment efficiency (%EE), CEO loading (%CEO), and in vitro release profiles were determined. The size, size distribution, zeta potential, and morphology of the obtained micelles were determined by DLS, FE-SEM, and TEM. The %EE, %CEO, and in vitro release profiles of CEO incorporated in micelles were analysed by HPLC. The study revealed a sustained release profile of CEO from CEO-loaded micelles. The results indicate the successful formulation of CEO-loaded PEG-b-PCL micelle nanoparticles. It is suggested that this micelle system has considerably potential applications in the sustained release of CEO in intravascular drug delivery.

Sulforaphane delivery using mPEG–PCL co-polymer nanoparticles to breast cancer cells

Purpose: Among the potent anticancer agents, d,l-sulforaphane (SF) is very effective against many different types of cancer cells. Its clinical application is restricted because of its hydrophobicity, low gastrointestinal absorption and poor bioavailability. In the present study, a reliable micellar delivery system using monomethoxypoly (ethylene glycol)–poly (ɛ-caprolactone) (mPEG–PCL) was established. The encapsulation of SF inside mPEG–PCL as a nano-carrier was established and the cytotoxicity assay against human breast cancer cell line was evaluated.Methods: In this study, SF was encapsulated within mPEG–PCL micelles through a single-step nano-precipitation method, leading to creation of SF-loaded mPEG–PCL (SF/mPEG–PCL) micelles. Di-block mPEG–PCL copolymers were synthesized and used to prepare micelles. MPEG-PCL copolymer was characterized by HNMR, FTIR, differential scanning calorimetry and gel permeation chromatography techniques. Characterization, stability of micelles, the particle size and morphology were determined. The release profile of the SF from the micelles which prepared by the drug-loaded copolymer, was evaluated. The cytotoxicity of free SF, mPEG–PCL and SF-loaded mPEG–PCL micelles was compared with each other by performing MTT assay of the treated MCF-7 cell line. Expression levels of BCL-2, MMP-9, BCL-XL, BAK, BAX and GAPDH (endogenous gene) as control were quantified by real time PCR. To evaluate the apoptotic effects of Free SF compared with SF-loaded mPEG–PCL micelles, flow cytometry analysis was done using the annexin V-FITC apoptosis detection kit.Results: Our studies resulted in a successful establishment of uniformity and spherical SF-loaded mPEG–PCL micelles. The encapsulation efficiency of SF was 86 ± 1.58%. The results of atomic force microscopy revealed that the micelles have spherical shapes with size of 107 nm. In vitro release of SF from SF-entrapped micelles was remarkably sustained. The mPEG–PCL micelle showed little cytotoxicity in the case of MCF-7 cell line with concentration up to 1.5 mg/ml, whereas the SF-loaded mPEG–PCL micelles at all concentrations significantly was cytotoxic in the case of MCF-7 cell line. Finally, real-time PCR and flow cytometry were used to demonstrate that the SF-loaded mPEG–PCL could be efficiently inducing apoptosis in MCF-7 cell line.Conclusion: We achieved to a successful formulation of SF-loaded m-PEG/PCL micelles in this study. Based on the cytotoxicity results of mPEG–PCL micelles against human breast cancer cell line (MCF-7) in this study, it suggested that SF/mPEG–PCL micelles can be an effective breast cancer treatment strategy in the future.

Hydrophobically modified inulin as an amphiphilic carbohydrate polymer for micellar delivery of paclitaxel for intravenous route

Micellization offers several advantages for the delivery of water insoluble drugs including a nanoparticulate ‘core–shell’ delivery system for drug targeting. Recently, hydrophobically modified polysaccharides (HMPs) are gaining recognition as micelle forming polymers to encapsulate hydrophobic drugs. In this manuscript, for the first time, we have evaluated the self-assembling properties of a lauryl carbamate derivative of the poly-fructose natural polymer inulin (Inutec SP1® (INT)) to form paclitaxel (PTX) loaded micelles. INT self-assembled into well-defined micellar structures in aqueous environment with a low critical micellar concentration of 27.8μg/ml. INT micelles exhibited excellent hemocompatibility and low toxicity to cultured cells. PTX loaded INT micelles exhibited a mean size of 256.37±10.45nm with excellent drug encapsulation efficiency (95.66±2.25%) and loading (8.69±0.22%). PTX loaded micelles also displayed sustained release of PTX and enhanced anti-cancer efficacy in-vitro in mouse melanoma cells (B16F10) compared to Taxol formulation with Cremophor EL as solvent. In addition, PTX loaded INT micelles exhibited comparable in-vivo antitumor activity in B16F10 allograft mouse model at half the dose of Taxol. In conclusion, INT offers safe, inexpensive and natural alternative to widely used PEG-modified polymers for the formulation of micellar delivery systems for paclitaxel.

Core-Cross-Linking Accelerates Antitumor Activities of Paclitaxel-Conjugate Micelles to Prostate Multicellular Tumor Spheroids: A Comparison of 2D and 3D Models.

The 2D monolayer cell culture model is often the first step in the prediction of the success or failure of a nanoparticle-based drug delivery system. However, there is often poor translation between the 2D monolayer in vitro results and the nanoparticle-drug performance in vivo. One possible way of bridging this gap is the use of multicellular tumor spheroids (MCTSs) as an intermediate in vitro model due to its 3D structure. This paper aims to quantify and compare the results obtained from traditional 2D monolayer cell cultures and 3D MCTS by studying the cytotoxic effects of free paclitaxel (PTX) and paclitaxel, which has been conjugated to a poly(ethylene glycol methyl ether acrylate)-b-poly(carboxyethyl acrylate) (POEGMEA-b-PCEA-PTX) block copolymer and self-assembled to give a micellar delivery system. The core of the micelle was cross-linked with a diamino nondegradable cross-linker to compare the effects of micelle stability on the results. Although the 2D prostate tumor cell culture results indicated that all micellar variants (IC50: 193-271 nM) were significantly less toxic than free paclitaxel (IC50: 15.2 nM), the micelles showed faster and higher cytotoxicity than free PTX in the 3D prostate MCTS. The cross-linking of micelles even showed accelerated antitumor activities to the MCTS compared with un-cross-linked micelles. The results indicate that DAO-cross-linked POEGMEA-b-PCEA-PTX conjugate micelles will be a useful nanodrug carrier for prostate cancer therapy. MCTS offers a very promising method of incorporating 3D structures into in vitro testing.

Biodegradable m-PEG/PCL Core-Shell Micelles: Preparation and Characterization as a Sustained Release Formulation for Curcumin.

Among the potent anticancer agents, curcumin is known as a very efficacious against many different types of cancer cells, but its clinical applications has been limited because of hydrophobicity, low gastrointestinal absorption, poor bioavailability and rapid metabolism. In this way, a novel micellar delivery system with mPEG-PCL was synthesized and the release profile of the curcumin from the drug-loaded micelles was evaluated. In this study, curcumin was encapsulated within monomethoxypoly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) micelles through a single-step nano-precipitation method, leading to creation of curcumin-loaded mPEG-PCL (Cur/mPEG-PCL) micelles. Di-block mPEG-PCL copolymers were synthesized and used to prepare micelles. mPEG-PCL copolymer was characterized in vitro by HNMR, FTIR, DSC and GPC techniques. Then, mPEG-PCL copolymers with curcumin were self-assembled into micelles in aqueous solution. The resulting micelles were characterized further by various techniques such as dynamic light scattering (DLS) and atomic force microscopy (AFM). The findings showed the successful formation of smooth and spherical curcumin-loaded micelles. The encapsulation efficiency of curcumin was 88 ± 3.32%. The results of AFM revealed that the micelles have spherical shapes with size of 73.8 nm. The release behavior of curcumin from micelles was compared in different media. In vitro release of curcumin from curcumin-entrapped micelles was followed remarkably sustained profile. The sustained release of drug was hypothetically due to the entrapment of curcumin in core of micelles. The results indicate the successful formulation of curcumin loaded m-PEG/PCL micelles. From the results, iIt can be concluded that curcumin m-PEG-PCL micelles may be considered as an effective treatment strategy for cancer in the future.

Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics.

Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic d-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data.

Combinatorial delivery of Crizotinib–Palbociclib–Sildenafil using TPGS-PLA micelles for improved cancer treatment

The co-delivery of multiple chemotherapeutics by micellar delivery systems is a valuable approach to improve cancer treatment since various disease hallmarks can be targeted simultaneously. However, the delivery of multiple drugs requires a nanocarrier structure that can encapsulate various bioactive molecules. In this study, we evaluate the simultaneous encapsulation of a novel triple drug combination in D-α-tocopheryl polyethylene glycol 1000 succinate-poly(lactic acid) (TPGS-PLA) amphiphilic micelles for cancer therapy. The drug mixture involves two anti-tumoral drugs, Crizotinib and Palbociclib combined with Sildenafil, a compound that is capable of increasing drug accumulation in the intracellular compartment. Such combination aims to achieve an enhanced cytotoxic effect in cancer cells. Our results demonstrated that TPGS-PLA copolymers self-assembled into stable nanosized micelles (158.3nm) capable of co-encapsulating the three drugs with high loading efficiency. Triple drug loaded TPGS-PLA micelles were internalized in A549 non-small lung cancer cells and exhibited an improved cytotoxic effect in comparison with single (Crizotinib) or dual (Crizotinib–Palbociclib) drug loaded micelles, indicating the therapeutic potential of the triple co-delivery strategy. These findings demonstrate that TPGS-PLA micelles are suitable carriers for multiple drug delivery and also that this particular drug combination may have potential to improve cancer treatment.

Miktoarm Star Micelles Containing Curcumin Reduce Cell Viability of Sensitized Glioblastoma

Glioblastoma multiforme (GBM) is the most common and lethal primary intracranial tumor in humans. Monotherapeutic interventions have not been successful. The objective of the current studies was to establish the effective combination therapy consisting of pifitrin as a sensitizer, and curcumin as therapeutic incorporated into miktoarm micelles. A2B type miktoarm stars were prepared using a combination of click chemistry with ring opening polymerization on a core with orthogonal functionalities. These self-assemble into spherical micelles with hydrophobic core and hydrophilic corona structure. Micellar delivery systems for curcumin based on these miktoarm star polymers were prepared, characterized and tested on cultures sensitized with pifitrin. The results show that: (1) pifitrin and temozolamide in combination with curcumin cause significant cell death compared with the individual therapeutics (incorporated or not in micelles), and (2) repeated exposure to the same treatments is necessary to fully prevent a re-growth of glioblastoma cells both in 2D and 3D cultures. Although the incorporation of curcumin into A2B star polymer micelles did not increase the extent of cell death compared with curcumin alone, the advantage of micelles is that they significantly increase the aqueous solubility of curcumin and sustain its release; this will likely reduce the frequency of its administration required to be effective in vivo. A2B miktoarm polymers could be a new viable delivery system for curcumin and other anticancer drugs with similar limitations.

P51 Polymeric micelles for controlled delivery of hydrogen sulfide

With the discovery of the important biological roles of hydrogen sulfide (H2S), therapeutic applications of this gas have attracted growing attention. For medical applications of H2S, an increasing number of H2S donors, compounds which release H2S under physiological conditions, have been developed to evaluate the therapeutic potential of H2S. However, these low molecular weight molecules have intrinsic pharmacokinetic problems including poorly-controlled tissue distribution and rapid elimination from the blood circulation which may result in adverse effects and low therapeutic efficiency for practical applications. To overcome these limitations, polymeric micelles, spherical supramolecular assemblies formed from amphiphilic block copolymers with a diameter of 10–100 nm, have been used to improve pharmacokinetics, bioavailability and stability of drugs. In view of these feature, we sought to develop a micellar H2S delivery system. Here we report on novel polymeric micelles carrying H2S-releasing anethole dithiolethione (ADT) moieties. We prepared diblock copolymers having a hydrophilic poly (ethylene glycol) block and a hydrophobic ADT-bearing H2S-releasing block using reversible addition-fragmentation transfer (RAFT) polymerization. The resulting polymers self-assembled into monodisperse micelles with a diameter of 40 nm according to dynamic light scattering (DLS). Further characterization by transmission electron microscopy (TEM) confirmed that the polymers formed spherical micelles with narrow size distributions. The in vitro experiments using murine macrophages showed that the micelles enhanced lipopolysaccharide-induced nuclear factor-κB (NF-κB) activation and proinflammatory cytokine production. MTT assay revealed that the micelles have much lower toxicity compared to the small H2S donor ADT. This micellar system may offer a safe and efficient delivery of H2S in immunotherapy.

Formulation and in vitro/in vivo Evaluation of Zidovudine Contained in Solidified Reverse Micellar Delivery System of Immune Compromised Rats

studies which was done using SGF and SIF. The in vivo study was done using Wistar albino rats and the in vitroin vivo correlation (IVIVC) was determined by plotting a graph of the fraction of drug absorbed in vivo versus the fraction of drug released in vitro. The yield of the goat fat extraction was 58 %. The particle size and yield of the solid lipid microparticle (SLM) containing 1 %w/w of AZT were 5.10 ± 0.10m and 86.3 ± 4.70% respectively. The fraction of drugs absorbed in vivo were 0.102 µg, 0.114 µg, 0.115 µg, 0.134 µg and 0.123 µg for 1 h, 3 h, 5 h, 8 h and 12 h respectively. A 1:1 ratio of goat fat and Phospholipon ® 90H with a high value of correlation coefficient (r 2 = 0.909) suggested good level-A correlation between the in vitro-in vivo data of the SLM obtained

α-Tocopherol succinate-modified chitosan as a micellar delivery system for paclitaxel: Preparation, characterization and in vitro/in vivo evaluations

α-Tocopherol succinate hydrophobically modified chitosan (CS-TOS) containing 17 α-tocopherol groups per 100 anhydroglucose units was synthesized by coupling reaction. The formation of CS-TOS was confirmed by 1H NMR and FT-IR analysis. In aqueous medium, the polymer could self-aggregate to form micelles, and the critical micelle concentration (CMC) was determined to be 5.8×10−3mg/ml. Transmission electron microscopy (TEM) observation revealed that both bare and paclitaxel-loaded micelles were near spherical in shape. The mean particle size and zeta potential of drug-loaded micelles were about 78nm and +25.7mV, respectively. The results of DSC and XRD analysis indicated that paclitaxel was entrapped in the micelles in molecular or amorphous state. In vitro cytotoxicity and hemolysis study revealed the effectiveness and safety of this delivery system, which was further confirmed by the in vivo antitumor evaluations. It can be concluded that the CS-TOS was a potential micellar carrier for paclitaxel.

Linoleic acid-grafted chitosan oligosaccharide micelles for intracellular drug delivery and reverse drug resistance of tumor cells

Intracellular drug delivery is an important rout to reverse drug resistance of tumor cells. In this study, the linoleic acid (LA)-grafted chitosan oligosaccharide (CSO) was synthesized to construct a micellar delivery system for intracellular delivery. The synthesized linoleic acid-grafted chitosan oligosaccharide (CSO-LA) with 10.3% graft ratio of LA could form micelles in aqueous with 86.69 μg/ml critical micellar concentration (CMC). The CSO-LA micelle had 46.2 ± 3.6 nm number average diameter and 36.0 ± 3.3 mV zeta potential. Taking doxorubicin base (DOX) as a model drug, the drug-loaded CSO-LA micelles (CSO-LA/DOX) was then prepared. The drug encapsulation efficiencies of CSO-LA/DOX were as high as 80%, and the drug loading capacity could be improved by increasing the charged DOX. Using MCF-7, Doxorubicin·HCl resistant MCF-7 (MCF-7/ADR), K562 and Doxorubicin·HCl resistant K562 (K562/ADR) cells as model drug sensitive and drug resistant tumor cells, the experiments demonstrated the CSO-LA had excellent cellular uptake ability by either drug sensitive tumor cells or drug resistance tumor cells. The CSO-LA micelles could deliver DOX into tumor cells, and the DOX in cells was increased with incubation time. As a result, the cytotoxicities of DOX encapsulated in CSO-LA micelles against drug resistance tumor cells were improved significantly, comparing to that of Doxorubicin·HCl solution.

Nanomicellar Formulations for Sustained Drug Delivery: Strategies and Underlying Principles

Micellar delivery systems smaller than 100 nm can be readily prepared. While micelles allow a great depth of tissue penetration for targeted drug delivery, they usually disintegrate rapidly in the body. Thus, sustained drug delivery from micellar nanocarriers is a challenge. This article summarizes various key strategies and underlying principles for sustained drug delivery using micellar nanocarriers. Comparisons are made with other competing delivery systems such as polymeric microparticles and nanoparticles. Amphiphilic molecules self-assemble in appropriate liquid media to form nanoscale micelles. Strategies for sustained release nanomicellar carriers include use of prodrugs, drug polymer conjugates, novel polymers with low critical micellar concentration or of a reverse thermoresponsive nature, reverse micelles, multi-layer micelles with layer by layer assembly, polymeric films capable of forming micelles in vivo and micelle coats on a solid support. These new micellar systems are promising for sustained drug delivery.

Dual chemotherapy and photodynamic therapy in an HT-29 human colon cancer xenograft model using SN-38-loaded chlorin-core star block copolymer micelles

Chlorin-core star-shaped block copolymer (CSBC) may self-assemble to form micelles, which act as nanosized photosensitizing agents for photodynamic therapy (PDT) and further encapsulate hydrophobic drugs. This functionalized micellar delivery system is a potential dual carrier for the synergistic combination of photodynamic therapy and chemotherapy for the treatment of cancer. In this study, SN-38 encapsulated CSBC micelles were successfully prepared using a lyophilization–hydration method. Our results show that the prolonged plasma residence time of SN-38/CSBC micelles as compared with free CPT-11 permit increased tumor accumulation and consequently, improved antitumor activity. The combined effects of SN-38/CSBC micelles with PDT were evaluated in an HT-29 human colon cancer xenograft model. Interesting, SN-38/CSBC-mediated PDT synergistically inhibited tumor growth, resulting in up to 60% complete regression of well-established tumors after 3 treatments. These treatments also decreased the microvessel density (MVD) and cell proliferation within the subcutaneous tumors. Therefore, this SN-38/CBSC delivery system has the potential to offer dual therapies for the synergistic combination of PDT and chemotherapy for the treatment of cancer.

Self-Associating Poly(ethylene oxide)-b-poly(α-cholesteryl carboxylate-ε-caprolactone) Block Copolymer for the Solubilization of STAT-3 Inhibitor Cucurbitacin I

An increase in the degree of chemical compatibility between drug and polymeric structure in the core has been shown to raise the encapsulation efficiency and lower the rate of drug release from polymeric micelles. In this study, to achieve an optimized polymeric micellar delivery system for the solubilization and controlled delivery of cucurbitacin I (CuI), the Flory-Huggins interaction parameter (chi(sc)) between CuI and poly(epsilon-caprolactone) (PCL), poly(alpha-benzylcarboxylate-epsilon-caprolactone) (PBCL) and poly(alpha-cholesteryl carboxylate-epsilon-caprolactone) (PChCL) structures was calculated by group contribution method (GCM) as an indication for the degree of chemical compatibility between different micellar core structures and CuI. The results pointed to a better compatibility between CuI and PChCL core rationalizing the synthesis of self-associating methoxy poly(ethylene oxide)-b-poly(alpha-cholesteryl carboxylate-epsilon-caprolactone) block copolymer (MePEO-b-PChCL). Novel block copolymer of MePEO-b-PChCL was synthesized through, first, preparation of substituted monomer, that is, alpha-cholesteryl carboxylate-epsilon-caprolactone, and further ring opening polymerization of this monomer by methoxy PEO (5000 g mol(-1)) using stannous octoate as catalyst. Synthesized block copolymers were characterized for their molecular weight and polydispersity by (1)H NMR and gel permeation chromatography. Self-assembled MePEO-b-PChCL micelles were characterized for their size, morphology, critical micellar concentration (CMC), capacity for the physical encapsulation of CuI, and mode of CuI release in comparison to MePEO-b-PCL and MePEO-b-PBCL micelles. Overall, the experimental order for the level of CuI encapsulation in different polymeric micellar formulations was consistent with what was predicted by the Flory-Huggins interaction parameter. Although MePEO-b-PChCL micelles exhibited the highest level of CuI loading, this structure did not show any significant superiority over MePEO-b-PCL in controlling CuI release. The most efficient control over the rate of CuI release was achieved by MePEO-b-PBCL micelles that had more viscous cores than that of MePEO-b-PChCL, instead. The results point to a potential for MePEO-b-PChCL micelles for the solubilization of cholesterol compatible drugs. It also highlights the inadequacy of the Flory-Huggins interaction parameter calculated by GCM in predicting the order of drug release from different polymeric micellar structures.