Formulations Of Anticancer Drugs Research Articles

Development of lipoprotein-drug conjugates for targeted drug delivery

Tumour targeting approaches used in cancer chemotherapy offers prolonged, localized, and protected drug interaction with the diseased tissue with minimal side effects and systemic toxicity, which are accountable for the failure of chemotherapy using conventional delivery systems. The purpose of the present study is to develop an anticancer targeted drug delivery system using synthesized lipoproteins with the integration of quality by design approach. Lipoprotein structures were designed, and quality by design approach was implemented to select variables for optimization. Further, the lipoproteins were synthesized and characterized by physicochemical properties. Physical composites of synthesized lipoproteins with the drug (tablets) were prepared and evaluated for post-compression parameters. Moreover, drug-lipoprotein chemical conjugates were synthesized and characterized for physicochemical properties, including cellular drug uptake and cytotoxicity study on HaCaT cancer cells. Synthesized lipoproteins showed good swelling capacity but poor flowability. Nuclear magnetic resonance and infrared spectroscopy of conjugates showed characteristic peaks. Tablets from all batches extended the drug release up to 12 h. All synthesized conjugates showed improved cellular drug uptake (up to 86.1%) and inhibition (87.39%) of HaCat cancer cells. These findings explored the possible use of synthesized lipoproteins in the development of anti-cancer drug formulation against HaCat cancer cells. Communicated by Ramaswamy H. Sarma

Abstract 1741: Single protein encapsulation as a drug delivery platform for developing efficacious anticancer therapeutics

Abstract Small molecule anticancer drugs are potent and effective agents against a variety of malignancies. However, severe side effects are often associated with their application due to systemic toxicities caused by their indiscriminate infiltration into normal tissues, organs, and cells. Using natural human serum albumin (HSA) as the carrier, Sunstate Biosciences LLC has recently invented the SPE platform for anticancer drug formulation. The SPE technology employs only FDA-approved components to form HAS-encapsulated product SPE-DRUG. Unlike HSA nanoparticles that usually contain a number of HSA molecules through chemical conjugation/crosslinking or aggregation, the SPE-DRUG has a single HSA molecule that encloses a variable number of DRUG molecules via noncovalent interactions, and importantly it retains the molecular size of HSA. Both the DRUG/HSA ratio and the binding strength can be tuned precisely to allow controlled release of the DDRUG during circulation. The SPE platform is versatile and can be applied to the formulation of a variety of single- and multiple-anticancer drugs. We have successfully prepared the following formulated drugs: SPEDOX, SPEEPI, SPEDAU, SPEMIT, SPEIDA, SPEVIC, SPEVIB, SPEVIL, and SPEDOC. All SPE-DRUGS are highly water soluble to form clear and stable solutions. Their size distribution profiles determined by DLS are almost identical to that of HSA, suggesting no disruption of the structure and properties of native HSA. Pharmacokinetic properties of SPEDOX were evaluated. Mouse heart tissues harvested at 2/24 h were analyzed. Antitumor efficacy using a breast cancer model (MDA-MB-231) were also evaluated at various doses. Key findings include 1) ~ 47 fold increase in AUC, 2) ~ 4-8 fold decrease in free DOX in the mouse heart tissue, and 3) fivefold increase in MTD and substantial enhancement of tumor efficacy (34/88% TGI for DOX/SPEDOX). Drug release studies in pH 7.4 PBS and pH 5.2 acetate buffer revealed that SPEDOX, SPEEPI, SPEDAU, SPEMIT, SPEDA, SPEVIC, SPEBIB, SPEVIL released their drug molecules twice as fast in acetate buffer than in PBS. The enhanced drug release in acidic media provides a possible mechanism for targeting tumors due to their acidic environment, thereby leading to increased antitumor efficacy. Separate antitumor efficacy studies with SPEMIT also showed enhanced antitumor efficacy against MDA-MB-231 (16/56% TGI for MIT/SPEMIT). In conclusion, Sunstate Biosciences' novel SPE drug formulation and delivery platform can significantly enhances the pharmacokinetics and antitumor efficacy and, at the same time, reduces the side effect of the drug, leading to increased therapeutic indexes. SPE-DRUGS have the potential to revolutionize cancer treatment regimens and save lives of difficult-to-treat cancer patients. Citation Format: C. J. Yu. Single protein encapsulation as a drug delivery platform for developing efficacious anticancer therapeutics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1741.

Mucoadhesive nanoparticles based on ROS activated gambogic acid prodrug for safe and efficient intravesical instillation chemotherapy of bladder cancer

Chemotherapy is the standard of care for bladder cancer after transurethral resection of the tumor. However, the rapid excretion of clinically used formulations of anticancer drugs make the common intravesical instillation chemotherapy far from efficient. Therefore, improving the muco-adhesion and penetrability of chemotherapeutic drugs became the key factors in the post-surgery treatment of superficial bladder cancers. Here, a reduction sensitive vehicle was developed to deliver the reactive oxygen species activated prodrug of gambogic acid for treatment of orthotopic bladder cancer. The positively charged chitosan can significantly enhance the adhesion and permeability of prodrug within the bladder wall. Moreover, by utilizing the different glutathione and ROS level between cancer cells and normal cells, the dual responsive nanoparticle can selectively and rapidly deliver drug in bladder cancer cells, and thus can significantly inhibit the proliferation of bladder cancer cells in an orthotopic superficial bladder cancer model without causing damage to normal cells. This work demonstrates that the smart prodrug nanomedicine may act as a promising drug-delivery system for local chemotherapy of bladder cancer with unprecedented clinical benefits.

Recent strategies towards the surface modification of liposomes: an innovative approach for different clinical applications.

Liposomes are very useful biocompatible tools used in diverse scientific disciplines, employed for the vehiculation and delivery of lipophilic, ampiphilic or hydrophilic compounds. Liposomes have gained the importance as drug carriers, as the drugs alone have limited targets, higher toxicity and develop resistance when used in higher doses. Conventional liposomes suffer from several drawbacks like encapsulation inefficiencies and partially controlled particle size. The surface chemistry of liposome technology started from simple conventional vesicles to second generation liposomes by modulating their lipid composition and surface with different ligands. Introduction of polyethylene glycol to lipid anchor was the first innovative strategy which increased circulation time, delayed clearance and opsonin resistance. PEGylated liposomes have been found to possess higher drug loading capacity up to 90% or more and some drugs like CPX-1 encapsuled in such liposomes have increased the disease control up to 73% patients suffering from colorectal cancer. The surface of liposomes have been further liganded with small molecules, vitamins, carbohydrates, peptides, proteins, antibodies, aptamers and enzymes. These advanced liposomes exhibit greater solubility, higher stability, long-circulating time and specific drug targeting properties. The immense utility and demand of surface modified liposomes in different areas have led their way to the modern market. In addition to this, the multi-drug carrier approach of targeted liposomes is an innovative method to overcome drug resistance while treating ceratin tumors. Presently, several second-generation liposomal formulations of different anticancer drugs are at various stages of clinical trials. This review article summarizes briefly the preparation of liposomes, strategies of disease targeting and exclusively the surface modifications with different entities and their clinical applications especially as drug delivery system.

DEVELOPMENT AND IN VITRO EVALUATION OF 5-FLUOROURACIL NANOPARTICLES BY SALTING OUT TECHNIQUE

Objectives: At the current miserable state of the prevalence of cancers, there is a need for the development of simple technologies to prepare formulations of anticancer drugs with less economy and investment. Hence, the aim of the present work is to prepare nanoparticles of 5-fluorouracil (5-FU) by simple technique, such as salting out method.
 Methods: Nanoparticles containing 10 mg of 5-FU were prepared by salting out method using Eudragit-100 as polymer. The prepared nanoparticles were evaluated by particle size, zeta potential, in vitro drug release studies, and drug-excipient interaction studies.
 Results: Nanoparticles prepared by salting out methods showed higher dissolution rate for formulation F3 and F5 revealed high percentage release of 98.6±0.24 in 60 min and 86.5±0.39% in 120 min. Fourier transform infrared (FTIR) spectra revealed no interaction between drug and excipients used for preparation.
 Conclusion: 5-FU nanoparticles can be produced successfully by salting out method using drug to polymer (Eudragit S-100) ratio of 1:3 to possess ideal drug release characteristics and average particle size of 205.1 nm.

Synthesis and characterization of biocompatible hydrogel based on hydroxyethyl cellulose-g-poly(hydroxyethyl methacrylate)

A novel polymeric hydrogel composed of hydroxyethyl cellulose-g-poly(2-hydroxyethyl methacrylate) was prepared via graft polymerization of hydroxyethyl methacrylate on the surface of hydroxyethyl cellulose. N,Nʹ-Methylenebisacrylamide was used as a cross-linker. In this work, we changed the ratio of hydroxyethyl cellulose to the monomer, while the potassium persulfate and the cross-liker were used in amounts proportional to the wt% of both the matrix and monomer. The copolymers formation was confirmed by infrared spectroscopy and X-ray diffraction pattern, while the changes in the surface morphology of the hydrogel were examined by scanning electron microscopy. The increase in the monomer ratio gradually improved the thermal stability of the resultant hydrogels. Finally, the cytotoxicity of the new polymeric hydrogels was evaluated using HCT-116, HepG2, MCF-7 human cancer cell lines and RPE-1 normal cell line. The cytotoxicity studies showed that the hydrogels were selectively toxic against the tested human cancer cell lines in a dose-dependent manner, whereas their cytotoxic activity was significantly reduced when they incubated with human RPE-1 normal cell lines, suggesting their possible utility in the formulation of anticancer drugs.

Formulation and Evaluation of Anticancer Drug (Tamoxifen) Loaded Nanosponges

Formulation and Evaluation of Anticancer Drug (Tamoxifen) Loaded Nanosponges

Passive and Active Drug Targeting: Role of Nanocarriers in Rational Design of Anticancer Formulations.

Cancer is the major public health problem in developing countries. The treatment of cancer requires a multimodal approach and chemotherapy is one of them. Chemotherapeutic drug is administered to cancer patients in the form of a formulation which is prepared by mixing an active ingredient (drug) with the excipient. The role of excipient in a formulation is to regulate the release, bio-distribution, and selectivity of drug within the body. In this context, selectivity of an anticancer formulation is achieved through two mechanisms like passive and active targeting. The passive targeting of a formulation is generally through enhanced permeation retention (EPR) effect which is dictated by physical properties of the carrier such as shape and size. On the contrary, active targeting means surface functionalization of excipient with target-specific ligands and/or receptors to increase its selectivity. Over the past several decades, remarkable progress has been made in the development and application of an engineered excipient or carrier to treat cancer more effectively. Especially nanoparticulate systems composed of metal/liposomes/polymeric material/proteins have received significant attention in the rational design of anticancer drug formulations; for example, therapeutic agents have been integrated with nanoparticles of optimal sizes, shapes and surface properties to improve their solubility, circulation half-life, and bio-distribution. In this review article, recent literature is included to discuss the role of physicochemical properties of excipients in achieving tumour targeting through passive and active approaches. The selection of an excipient/carrier and targeting ligand plays a very important role in rational design and development of anticancer drug formulations.

Doxorubicin Loaded Liposomal Nanoparticles Containing Quantum Dot for Treatment of Breast Cancer

In addition to increasing the efficacy of various drugs, Nanoparticles reduce their side effects. In this study, different nanoparticle formulations of Doxorubicin anticancer drugs were prepared. The efficacy of the formulations produced in the cell culture medium was studied compared with the free drug. Reverse phase evaporation was used to form the liposome containing doxorubicin. The graphite nanoparticles were prepared. These nanoparticles were mixed with the liposome containing doxorubicin, and the related Nano-complex was conjugated. Spectroscopy methods for visible light-ultraviolet, light and light dynamics differentiation were used to describe nanoparticles. For the toxicity of different formulation, MTT and MCF-7 cells were used. The amount of drug loading in the liposomes was 72%. The largest amount was related to the Nano-conjugated complex and the smallest size was related to the graphene-oxide nanoparticle with a nanometer size. The controlled release in 96 hours and the amount of drug release was 95.43%. Doxorubicin-containing liposome toxicity was 75% and Nano- conjugated complex was 85%, at the lowest drug concentration (10µM). The free drug created 35% cell toxicity in 10µM and 89% in 2500µM. The results of the study showed Liposomes act as a suitable nanoparticle for doxorubicin. It was found that the effect of nanoparticles of graphene oxide is very important. In the presence of this nanoparticle in the complex, toxicity increased significantly.

PEG-conjugated triacontanol micelles as docetaxel delivery systems for enhanced anti-cancer efficacy.

PEGylated triacontanol (mPEG2k-b-TRIA) was developed as a dual-functional polymer with remarkable biocompatibility. The polymer could self-assemble to micelles with critical micelle concentration (CMC) 17.62μgmL-1. Docetaxel-loaded mPEG2k-b-TRIA micelles (DTX PMs) were fabricated to evaluate the feasibility of mPEG2k-b-TRIA as drug delivery system. DTX PMs achieved desirable particle size of 93.7nm, drug loading of 6.66%, and drug encapsulation efficiency of 89.87%. The drug release was based on first-order kinetics model, thus enabling prolonged release. Meanwhile, pharmacokinetic study also revealed that DTX PMs could improve the exposure level of DTX and prolong its systemic circulation time. Furthermore, DTX PMs demonstrated significantly enhanced cytotoxicity and cellular uptake in vitro compared with DTX solution. The in vivo tumor inhibition study carried out on MCF-7 bearing BALB/c mice model also validated that DTX PMs exhibited stronger anti-tumor activity but low toxicity. Notably, mPEG2k-b-TRIA made some contribution to inhibit the growth of breast cancer cells in vitro and in vivo, indicating the potential as anti-tumor complementary agents. All the results suggested that mPEG2k-b-TRIA polymer as a vehicle in the formulation of anti-cancer drugs may provide an effective way to improve their therapeutic efficacy. Consequently, the mPEG2k-b-TRIA polymers would be another promising carrier for hydrophobic anti-cancer drugs delivery.

Preparation, characterization and cytotoxic evaluation of inclusion complexes between celastrol with polyamine-modified β-cyclodextrins

Celastrol (CSL), the major constituent from traditional Chinese medicine Tripterygium wilfordii Hook, has attracted considerable interest in the medicinal society due to its multiple biological activities. However, poor solubility and obvious toxic side effect have limited its application in the pharmaceutical field. To address the problems, the inclusion complexes of mono polyamine-modified β-CD (H1) and the polyamine-brideged bis(β-CD) (H2) with CSL were prepared. The characterization of inclusion complexes was investigated by NMR, XRD FT-IR and SEM, and the binding behaviors of H1-2 with CSL were investigated by UV. The results showed that the H2 gave the binding constant (Ks) towards CSL up to 1.7 times higher than that of H1, through cooperative binding of two hydrophobic CD cavities with one guest. Remarkably, complexation with H1 and H2 improved CSL solubility in water from 0.044 mg/mL up to 2.31 and 2.68 mg/mL, respectively. The in vitro anticancer activity of H1/CSL inclusion complex was better than that of cisplatin (positive control). Meanwhile, the toxicity of CSL was slightly reduced after the formation of the inclusion complex with H1. Therefore, the complexes of CSL with H1-2 favor their use in anticancer drug formulations, broadening the field of application in clinic.

Comparison of safety and toxicity of liposomal versus conventional Doxorubicin: an updated review

Cancer persists to be a major cause of hospitalization and death every year. With the passage of time, new formulations of anticancer drugs are being introduced to the market and are drawing the concern of healthcare professionals in terms of the superiority, toxicology, and cost-effectiveness of the new formulations in comparison to the conventional formulation of the same drugs. Doxorubicin, a highly potent chemotherapeutic agent, it comes with three formulations (pegylated liposomal, nonpegylated liposomal and non-liposomal conventional formulations). English-language literature of the three formulations of Doxorubicin has been reviewed to inform the healthcare professionals regarding the differences between these formulations. Liposomal Doxorubicin promotes better toxicology profile than non-liposomal conventional Doxorubicin with an increased cost. Due to very limited studies, the cost-effectiveness of liposomal Doxorubicin is not well defined. Apart from that, this review highlights the inter patient variability in regard to the clearance and volume of distribution following the administration of liposomal Doxorubicin. In conclusion, further studies regarding the superiority of liposomal formulation of Doxorubicin , efficacy and dose standardization of liposomal Doxorubicin should be sought in the near future in a more better way.

Inhaled Micro/Nanoparticulate Anticancer Drug Formulations: An Emerging Targeted Drug Delivery Strategy for Lung Cancers.

Local delivery of drug to the target organ via inhalation offers enormous benefits in the management of many diseases. Lung cancer is the most common of all cancers and it is the leading cause of death worldwide. Currently available treatment systems (intravenous or oral drug delivery) are not efficient in accumulating the delivered drug into the target tumor cells and are usually associated with various systemic and dose-related adverse effects. The pulmonary drug delivery technology would enable preferential accumulation of drug within the cancer cell and thus be superior to intravenous and oral delivery in reducing cancer cell proliferation and minimising the systemic adverse effects. Site-specific drug delivery via inhalation for the treatment of lung cancer is both feasible and efficient. The inhaled drug delivery system is non-invasive, produces high bioavailability at a low dose and avoids first pass metabolism of the delivered drug. Various anticancer drugs including chemotherapeutics, proteins and genes have been investigated for inhalation in lung cancers with significant outcomes. Pulmonary delivery of drugs from dry powder inhaler (DPI) formulation is stable and has high patient compliance. Herein, we report the potential of pulmonary drug delivery from dry powder inhaler (DPI) formulations inhibiting lung cancer cell proliferation at very low dose with reduced unwanted adverse effects.

Development of Nanostructured Liquid Crystalline Formulation of Anti-Cancer Drug as a New Drug Delivery System

This study is concerned with encapsulation of the anti-cancer drug (berberine hydrochloride (BH)) in nanocarriers as cubosomes, which is, then, formulated in solid form to ease its incorporation into different drug delivery systems, improve its solubility, and improve its anti-cancer activity. BH cubosomes were prepared using glyceryl mono-oleate (GMO) and poloxamer 407 (PF127). Polyvinyl alcohol (PVA) was added as a stabilizer. The well-characterized cubosome formula via particle size, entrapment efficiency, and in vitro release study was converted into free-flowing powder (S-BH) using sugar carriers at different mass ratios. The prepared powdered cubosome S-BH was subjected to in vitro characterization, such as flowability, compressibility, drug solubility, and drug release studies. The prepared formula’s cytotoxic effects on human breast cancer cell line (MCF-7) were studied. The prepared cubosome formula has an average particle size of 220.8 nm with a polydispersity index (PdI) < 1 and a high drug EE value (64.75%). The BH release rate begins relatively fast followed by a slower release rate. S-BH has good flowability and compressibility as evidenced by decreased repose angle (31.53 ± 0.31) and lowered required pressure for compression (60.07 ± 6.16). Enhanced dissolution rate and increased drug solubility relate to the increased particle surface area as a result of decreased particle size. It also provides high anti-proliferative and apoptotic activities against breast cancer cells. The prepared solid cubosomal BH can be utilized for the preparation of different solid dosage forms, like tablets and capsules.

Synthesis, Spectroscopic Characterization and Biological Applications of Novel Zinc Complexes with Schiff Bases

Schiff base ligands, having nitrogen and oxygen donor sites and their zinc (II) complexes have been prepared by using methanol as a solvent. Purity of the compounds has been tested by TLC and are characterized by FT-IR, multinuclear NMR (1H and13C). FT-IR spectra suggested the binding of precursors and their chelation with zinc (II) moieties by showing characteristics peaks in particular regions.1H-NMR also approves the synthesis of compounds by showing characteristics peaks of azomethine proton (HC=N) and phenolic proton (-OH). On complexation phenolic proton was disappeared while a down field shift was observed in azomethine proton.13C-NMR data further supports the formation of compounds by the displaying and shifting of characteristic peaks of azomethine carbon (HC=N).The DNA binding ability of all the synthesized ligands was studied by UV-Visible spectroscopy. A hypochromic affect was observed showing that ligands interacted with DNA by intercalation. The results implied that these synthesized compounds can be employed for the formulation of Anticancer and Antitumor drugs in future with less toxic side effects to normal cells (unlike toxic drugs presently used) .Moreover they were found to have antifungal and antibacterial activity by Disc Diffusion method. Zinc containing complexes have been investigated a lot recently for the treatment of Diabetes Mellitus. Thus, these synthesized compounds are potential drug candidates for research if explored .

Development of Orally Applicable, Combinatorial Drug–Loaded Nanoparticles for the Treatment of Fibrosarcoma

Nanoparticulate systems have been receiving a significant attention especially for the treatment of cancer but one of the main hurdles is to produce these developed and high-tech nanosystems in large quantities. Anticancer drug formulations are generally designed for parenteral administrations but oral administration is still the most convenient route. In this study, orally applicable nano-sized chitosan nanoparticles (NPs) were successfully prepared using Nano Spray Dryer. It is possible to produce these NPs in large quantities by simply increasing the processing time using the machine without changing any parameter. A chemotherapeutic agent (imatinib mesylate; IMA) and nonsteroidal anti-inflammatory drug (dexketoprofen trometamol) were loaded together in these NPs. NPs were also functionalized with polyethylene glycol and folic acid to obtain long circulating NPs and tumor targeting. The antitumoral activities of formulations showed that these developed NPs can enhance the effectiveness. Animal experiments were performed on fibrosarcoma-bearing mice model, and the treatment with 0.8 mg/μL/kg IMA-loaded chitosan NPs was found to be successful to slow down the growth of tumors. The tumor tissues were removed from the animals and enzymatic activities were evaluated. The inhibitory effect of tyrosine kinase was found to be enhanced from 36.4% to 68.4% when IMA was used in combination with dexketoprofen trometamol. Furthermore, all dried NPs were found to be stable for more than a year at 25°C. Presented results show that these developed combinatorial drug–loaded NPs can be used for the treatment of fibrosarcoma, and these data can provide an insight, new strategies for productions or alternatives in cancer treatment.

Near-Infrared Activated Release of Doxorubicin from Plasmon Resonant Liposomes.

Precise control of drug release from nanoparticles can improve efficacy and reduce systemic toxicity associated with administration of certain medications. Here, we combined two phenomena, photothermal conversion in plasmon resonant gold coating and thermal sensitivity of liposome compositions, to achieve a drug delivery system that rapidly releases doxorubicin in response to external stimulus.Methods: Thermosensitive liposomes were loaded with doxorubicin and gold-coated to produce plasmon resonant drug delivery system. Plasmon resonance facilitates release of contents upon near-infrared laser illumination, thus providing spatial and temporal control of the process. This controlled delivery system was compared to thermosensitive liposomes without gold coating and to the FDA-approved Doxil that was gold-coated to create a plasmon resonant coating. Release of doxorubicin from the gold-coated thermosensitive liposomes was further confirmed by tests of cell viability.Results: Upon laser illumination at 760 nm and 88 mW/cm2 power density, permeability of plasmon resonant liposomes increased by three orders of magnitude, from 70×10-12 to 60,000x10-12 cm/s. In control experiments, mild hyperthermia (42°C) increased permeability of these thermosensitive liposomes to just 3,700×10-12 cm/s. Neither hyperthermia nor laser illumination elicit content release from Doxil or plasmon resonant Doxil obtained by gold coating. Laser-induced release of doxorubicin from plasmon resonant thermosensitive liposomes resulted in the loss of cell viability significantly greater than in any of the control groups.Conclusion: Combination of thermosensitive liposomes with plasmon resonant coating enables rapid, controlled release, not currently available in pharmaceutical formulations of anticancer drugs.

A novel controlled release formulation of the Pin1 inhibitor ATRA to improve liver cancer therapy by simultaneously blocking multiple cancer pathways

Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide largely due to lack of effective targeted drugs to simultaneously block multiple cancer-driving pathways. The identification of all-trans retinoic acid (ATRA) as a potent Pin1 inhibitor provides a promising candidate for HCC targeted therapy because Pin1 is overexpressed in most HCC and activates numerous cancer-driving pathways. However, the efficacy of ATRA against solid tumors is limited due to its short half-life of 45min in humans. A slow-releasing ATRA formulation inhibits solid tumors such as HCC, but can be used only in animals. Here, we developed a one-step, cost-effective route to produce a novel biocompatible, biodegradable, and non-toxic controlled release formulation of ATRA for effective HCC therapy. We used supercritical carbon dioxide process to encapsulate ATRA in largely uniform poly L-lactic acid (PLLA) microparticles, with the efficiency of 91.4% and yield of 68.3%, and ~4-fold higher Cmax and AUC over the slow-releasing ATRA formulation. ATRA-PLLA microparticles had good biocompatibility, and significantly enhanced the inhibitory potency of ATRA on HCC cell growth, improving IC50 by over 3-fold. ATRA-PLLA microparticles exerted its efficacy likely through degrading Pin1 and inhibiting multiple Pin1-regulated cancer pathways and cell cycle progression. Indeed, Pin1 knock-down abolished ATRA inhibitory effects on HCC cells and ATRA-PLLA did not inhibit normal liver cells, as expected because ATRA selectively inhibits active Pin1 in cancer cells. Moreover ATRA-PLLA microparticles significantly enhanced the efficacy of ATRA against HCC tumor growth in mice through reducing Pin1, with a better potency than the slow-releasing ATRA formulation, consistent with its improved pharmacokinetic profiles. This study illustrates an effective platform to produce controlled release formulation of anti-cancer drugs, and ATRA-PLLA microparticles might be a promising targeted drug for HCC therapy as PLLA is biocompatible, biodegradable and nontoxic to humans.

New Poly(3-hydroxybutyrate) Microparticles with Paclitaxel Sustained Release for Intraperitoneal Administration.

Poly(hydroxyalkanoates) (PHA) have recently attracted increasing attention due to their biodegradability and high biocompatibility, which makes them suitable for the development of new prolong drug formulations. This study was conducted to develop new prolong paclitaxel (PTX) formulation based on poly(3- hydroxybutyrate) (PHB) microparticles. PHB microparticles loaded with antitumor cytostatic drug PTX were obtained by spray-drying method using Nano Spray Dryer B-90. The PTX release kinetics in vitro from PHB microparticles and their cytotoxity on murine hepatoma cell line MH-22a were studied. Microparticles antitumor activity in vivo was studied using intraperitoneally (i.p.) transplanted tumor models: murine Lewis lung carcinoma and xenografts of human breast cancer RMG1. Uniform PTX release from PHB-microparticles during 2 months was observed. PTX-loaded PHB microparticles have demonstrated a significant antitumor activity versus pure drug both in vitro in murine hepatoma cells and in vivo when administered i.p. to mice with murine Lewis lung carcinoma and xenografts of human breast cancer RMG1. The developed technique of PTX sustained delivery from PHB-microparticles has therapeutic potential as prolong anticancer drug formulation.

Rational Design of Multifunctional Dendritic Mesoporous Silica Nanoparticles to Load Curcumin and Enhance Efficacy for Breast Cancer Therapy.

Breast cancer is the primary reason for cancer-related death in women worldwide and the development of new formulations to treat breast cancer patients is crucial. Curcumin (Cur), a natural product, exerts promising anticancer activities against various cancer types. However, its therapeutic efficacy is hindered as a result of poor water solubility, instability, and low bioavailability. The aim of this work is to assess the curative effect of a novel nanoformulation, i.e., Cur-loaded and calcium-doped dendritic mesoporous silica nanoparticles modified with folic acid (Cur-Ca@DMSNs-FA) for breast cancer therapy. The results manifested that Cur-Ca@DMSNs-FA dispersed very well in aqueous solution, released Cur with a pH-responsible profile, and targeted efficiently to human breast cancer MCF-7 cells. Further investigations indicated that Cur-Ca@DMSNs-FA effectively inhibited cell proliferation, increased intracellular ROS generation, decreased mitochondrial membrane potential, and enhanced cell cycle retardation at G2/M phase, leading to a higher apoptosis rate in MCF-7 compared to free Cur. Moreover, the Western blotting analysis demonstrated that Cur-Ca@DMSNs-FA were more active than free Cur through suppression of PI3K/AKT/mTOR and Wnt/β-catenin signaling, and activation of the mitochondria-mediated apoptosis pathway. In addition, hemolysis assay showed that the Ca@DMSNs-FA exhibited good biocompatibility. Last, in vivo studies indicated that when Cur was encapsulated in Ca@DMSNs-FA, the Cur concentration in blood serum and tumor tissues was increased after 1 h intraperitoneal injection. In conclusion, Cur-Ca@DMSNs-FA might act as a potential anticancer drug formulation for breast cancer therapy.