EQ-5D-5L Valuation for the Malaysian Population.

OBJECTIVES: The aim of this study was to develop an EQ-5D-5L value set reflecting the health preferences of the Malaysian adult population. METHODS: Respondents were sampled with quotas for urbanicity, gender, age, and ethnicity to ensure representativeness of the Malaysian population. The study was conducted using a standardized protocol involving the EuroQol Valuation Technology (EQ-VT) computer-assisted interview system. Respondents were administered ten composite time trade-off (C-TTO) tasks and seven discrete choice experiment (DCE) tasks. Both linear main effects and constrained non-linear regression models of C-TTO-only data and hybrid models combining C-TTO and DCE data were explored to determine an efficient and informative model for value set prediction. RESULTS: Data from 1125 respondents representative of the Malaysian population were included in the analysis. Logical consistency was present in all models tested. Using cross-validation, eight-parameter models for C-TTO only and C-TTO + DCE hybrid data displayed greater out-of-sample predictive accuracy than their 20-parameter, main-effect counterparts. The hybrid eight-parameter model was chosen to represent the Malaysian value set, as it displayed greater out-of-sample predictive accuracy over C-TTO data than the C-TTO-only model, and produced more precise estimates. The estimated value set ranged from - 0.442 to 1. CONCLUSIONS: The constrained eight-parameter hybrid model demonstrated the best potential in representing the Malaysian value set. The presence of the Malaysian EQ-5D-5L value set will facilitate its application in research and health technology assessment activities.

Psychometric performance assessment of Malay and Malaysian English version of EQ-5D-5L in the Malaysian population.

PURPOSE: To determine the psychometric properties and performance of Malay and English versions of the EQ-5D-5L descriptive instrument in the general Malaysian population. METHODS: 1137 members of the Malaysian general public were sampled in this national study. Respondents were recruited by quota sampling of urbanicity, gender, age, and ethnicity. In face-to-face interviews, respondents first answered the EQ-5D-5L questionnaire administered using the EQ-Valuation Technology software, and then completed the EQ-5D-3L questionnaire on paper. A subgroup of the respondents were given paper form of EQ-5D-5L for completion within 2 weeks for test-retest reliability. Ceiling effects, response redistribution, informativity, and convergent validity were compared between EQ-5D-5L and ED-5D-3L separately by Malay and English language versions. RESULTS: The proportion of 'full health' responses (11111) drastically decreased by 25.55% and 15.74% in the Malay and English language versions indicating lower ceiling effects in EQ-5D-5L. Inconsistencies from response redistribution was below 6% for all dimensions across languages. The measure of relative informativity was comparatively higher in EQ-5D-5L than in EQ-5D-3L in both language versions, with the exception of dimensions mobility and pain/discomfort in the English version. Convergent validity in terms of correlation with EQ-VAS was relatively better for EQ-5D-5L dimensions, with pain/discomfort of the Malay version having the strongest correlation (|r| = 0.37). Also, reliability testing revealed moderate to poor agreements on all 5L dimensions. CONCLUSIONS: EQ-5D-5L fared better in terms of psychometric performance compared to EQ-5D-3L for both language versions. This encourages the application of the EQ-5D-5L in health-related research in Malaysia.

Exploring strategies to overcome extra-organisational challenges faced by community pharmacies in Sarawak, Malaysia.

OBJECTIVES: The aims of this research were to determine extra-organisational challenges (e.g. market competition, governing policies) faced by community pharmacies in Sarawak, the coping strategies employed to deal with these challenges and explore potential legislative changes that can attenuate the intensity of these challenges. METHODS: Survey questionnaires (n = 184) were posted to all eligible community pharmacies in Sarawak, Malaysia. The questionnaire included sections on participants' demographic data, extra-organisational challenges faced, coping strategies employed and proposals to improve community pharmacy legislations. Items were constructed based on the findings of a prior qualitative research supplemented with relevant literature about these issues. KEY FINDINGS: High levels of homogeneity in responses were recorded on various extra-organisational challenges faced, particularly those economy-oriented. Strategic changes to counter these challenges were focused on pricing and product stocked, rather than services provision. Highly rated strategies included increasing discounts for customers (n = 54; 68%) and finding cheaper suppliers (n = 70; 88%). Legislative changes proposed that might increase their share of the pharmaceutical market were strongly supported by respondents, particularly about making it compulsory for general practitioners to provide patients the option to have their medicines dispensed in community pharmacies (n = 72; 90%). CONCLUSIONS: Current legislative conditions and Malaysian consumer mindset may have constrained the strategic choices of community pharmacies to deal with the strong extra-organisational challenges. A long-term multipronged approach to address these issues and increased involvement of community pharmacists themselves in this agenda are required to influence practice change.

An Interprofessional Evaluation of Health Literacy Communication Practices of Physicians, Pharmacists, and Nurses at Public Hospitals in Penang, Malaysia.

BACKGROUND: Health care practitioners carry a tremendous responsibility to differentiate the varying need of information and customized communication according to a patient's health literacy (HL) level. OBJECTIVES: To assess and compare the HL communication practices among physicians, pharmacists, and nurses serving at public hospitals in Penang, Malaysia. METHODS: A pretested, self-administered questionnaire was used to collect data from study participants of 6 public hospitals using stratified sampling. Descriptive and inferential statistics used to analyze the data with level of significance was set at P < 0.05. RESULTS: Of 600 distributed questionnaires, 526 (87.6%) were adequately filled and returned. Almost 19.0% (n = 98) of the respondents admitted that they did not frequently use simple language and avoid medical jargon during communication with patients. Only about half of the respondents reported frequently using other HL communication practices that include handing out education material to patients (52.2%, n = 275), asking the patient to repeat information (58.9%, n = 310), and asking patients' caregivers to be present during explanation (57.4%, n = 302). Comparatively, drawing pictures to ease patients' understanding (40.1%, n = 211) was the less-frequently practiced HL communication techniques. Health practitioners in the age group >41 years ( P = 0.046), serving 10 years and more ( P = 0.03) and those who have heard the term or concept of HL ( P = 0.004) have statistically significantly higher mean score of HL communication practices than other groups. CONCLUSIONS: The gap in the HL communication practices among physicians, pharmacists, and nurses warrants educational intervention, and standardized HL communication techniques guidelines are needed in the near future.

Health Literacy-Related Knowledge, Attitude, and Perceived Barriers: A Cross-sectional Study among Physicians, Pharmacists, and Nurses in Public Hospitals of Penang, Malaysia.

INTRODUCTION: Patients' health literacy (HL) has emerged as a critical determinant of health outcomes and becoming one of the core competencies of health-care providers. Therefore, this study aimed to assess among Malaysian physicians, pharmacists, and nurses, their HL-related knowledge, attitude, and perceived barriers, and also to determine the associated factors. METHODS: A cross-sectional study design was used to enroll 600 eligible respondents using stratified sampling from 6 public hospitals in Penang, Malaysia. A validated self-administered questionnaire was used for data collection. Descriptive and inferential analysis was performed with statistical significance defined as p < 0.05. RESULTS: The response rate was 87.6% with 526 questionnaires completed. Of these, 34.2% had poor knowledge, and more than half had negative attitude (51.9%) toward HL with no significant differences among physicians, pharmacists, and nurses. The majority of the respondents perceived time constraints and lack of human resources as major HL barriers. Respondents who had heard the term or concept of HL had significantly higher level of knowledge (p < 0.001) and more positive attitude (p < 0.001). While longer service years (≥11 years) significantly contribute to the higher level of HL knowledge among health-care providers (p = 0.028). CONCLUSION: The study findings supported the concern on inadequate knowledge and substantially negative attitude toward HL among study health-care providers with highest cited barriers were time constraint and human resources. Thus, efforts to improve their perspective about HL to be effective patient educators are highly advocated.

Improving pediatric liquid medication labeling of the hospital information system in Malaysia: qualitative analysis of pharmacists' perceptions.

BACKGROUND: Inadequacies of drug labeling have been frequently reported among Malaysian healthcare institutes, in which the Hospital Information System (HIS) is used. OBJECTIVE: To identify potential areas to improve the existing labels used for pediatric liquid medications. METHODS: This study was qualitative in nature, whereby focus group discussions (FGDs), face-to-face interviews (FTFIs), and onsite observation were used for data collection. Pharmacists stationed at three units (outpatient, inpatient and clinical pharmacy) of a tertiary hospital were targeted. Both FGDs and FTFIs were facilitated using a semi-structured interview guide, video-recorded and transcribed verbatim. All transcripts were thematically analyzed using content analysis approach. RESULTS: Thirteen pharmacists participated in FGDs, while five were approached for FTFIs. Data analysis resulted in four major themes: format of labels, presentation of medication instructions, insufficiency of information, and the need for external aids and education. Participants unanimously agreed on the need for enlarging font sizes of key information. Suggestions were made to use more specific instructions for administration times and pictograms to illustrate important directions. The absence of information about storage, stability and handling of liquid medications was also highlighted. While discussion mainly focused on improving drug labeling, participants consistently stressed the need for an instruction sheet and pharmacist-based, one-to-one education regarding medication instructions. CONCLUSION: This study provides important insights into critical shortcomings in current labeling practice, underlying the need for developing a new label that incorporates a new format, additional information and pictograms for pediatric liquid medications.

Improving pediatric liquid medication labeling of the hospital information system in Malaysia: qualitative analysis of pharmacists' perceptions

Background: Inadequacies of drug labeling have been frequently reported among Malaysian healthcare institutes, in which the Hospital Information System (HIS) is used. Objective: To identify potential areas to improve the existing labels used for pediatric liquid medications. Methods: This study was qualitative in nature, whereby focus group discussions (FGDs), face-to-face interviews (FTFIs), and onsite observation were used for data collection. Pharmacists stationed at three units (outpatient, inpatient and clinical pharmacy) of a tertiary hospital were targeted. Both FGDs and FTFIs were facilitated using a semi-structured interview guide, video-recorded and transcribed verbatim. All transcripts were thematically analyzed using content analysis approach. Results: Thirteen pharmacists participated in FGDs, while five were approached for FTFIs. Data analysis resulted in four major themes: format of labels, presentation of medication instructions, insufficiency of information, and the need for external aids and education. Participants unanimously agreed on the need for enlarging font sizes of key information. Suggestions were made to use more specific instructions for administration times and pictograms to illustrate important directions. The absence of information about storage, stability and handling of liquid medications was also highlighted. While discussion mainly focused on improving drug labeling, participants consistently stressed the need for an instruction sheet and pharmacist-based, one-to-one education regarding medication instructions. Conclusion: This study provides important insights into critical shortcomings in current labeling practice, underlying the need for developing a new label that incorporates a new format, additional information and pictograms for pediatric liquid medications (AU)

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Antibiotic use in residential aged care facilities.

BACKGROUND: High infection burden among the residential aged care facility (RACF) population has long been recognised; however, existing infection prevention effort is often limited to infection surveillance activity. There is a scarcity of evidence to guide antimicrobial stewardship in the Australian RACF setting. OBJECTIVE: This review summarises the current trends in antibiotic use and multi-drug resistant (MDR) organisms, challenges related to antibiotic prescribing and areas of suboptimal antibiotic prescribing for further improvement, particularly in the Australian RACF setting. DISCUSSION: There is widespread antibiotic prescribing in RACF, which may lead to the emergence of antibiotic resistance. Accordingly, there is an immediate need for judicious antibiotic use in this high-risk population to curb the rapid emergence of MDR organisms and other adverse consequences associated with inappropriate antibiotic use, as well as to reduce healthcare costs.

Antibiotic prescribing practice in residential aged care facilities--health care providers' perspectives.

OBJECTIVE: To explore organisational workflow and workplace culture influencing antibiotic prescribing behaviour from the perspective of key health care providers working in residential aged care facilities (RACFs). DESIGN, SETTING AND PARTICIPANTS: Qualitative approach using semistructured interviews, focus groups and onsite observation between 8 January 2013 and 2 July 2013. Nursing staff, general practitioners and pharmacists servicing residents at 12 high-level care RACFs in Victoria were recruited. MAIN OUTCOME MEASURES: Emergent themes on antibiotic prescribing practices in RACFs. RESULTS: Sixty-one participants (40 nurses, 15 GPs and six pharmacists) participated. Factors influencing antibiotic prescribing practice have been divided into workflow-related and culture-related factors. Five major themes emerged among workflow-related factors: logistical challenges with provision of medical care, pharmacy support, nurse-driven infection management, institutional policies and guidelines, and external expertise and diagnostic facilities. Lack of onsite medical and pharmacy staff led to nursing staff adopting significant roles in infection management. However, numerous barriers hindered optimal antibiotic prescribing, especially inexperienced staff, lack of training of nurses in antibiotic use and lack of institutional infection management guidelines. With regard to culture-related factors, pressure from family to prescribe and institutional use of advance care directives were identified as important influences on antibiotic prescribing practices. CONCLUSIONS: Workflow- and culture-related barriers to optimal antibiotic prescribing were identified. This study has provided important insights to guide antimicrobial stewardship interventions in the RACF setting, particularly highlighting the role of nurses.

Antimicrobial stewardship in residential aged care facilities: need and readiness assessment.

BACKGROUND: Information about the feasibility, barriers and facilitators of antimicrobial stewardship (AMS) in residential aged care facilities (RACFs) has been scant. Exploring the prevailing perceptions and attitudes of key healthcare providers towards antibiotic prescribing behaviour, antibiotic resistance and AMS in the RACF setting is imperative to guide AMS interventions. METHODS: Semi-structured interviews and focus groups were conducted with key RACF healthcare providers until saturation of themes occurred. Participants were recruited using purposive and snowball sampling. The framework approach was applied for data analysis. RESULTS: A total of 40 nurses, 15 general practitioners (GPs) and 6 pharmacists from 12 RACFs were recruited. Five major themes emerged; perceptions of current antibiotic prescribing behaviour, perceptions of antibiotic resistance, attitude towards and understanding of AMS, perceived barriers to and facilitators of AMS implementation, and feasible AMS interventions. A higher proportion of GPs and pharmacists compared with nurses felt there was over-prescribing of antibiotics in the RACF setting. Antibiotic resistance was generally perceived as an issue for infection control rather than impacting clinical decisions. All key stakeholders were supportive of AMS implementation in RACFs; however, they recognized barriers related to workload and logistical issues. A range of practical AMS interventions were identified, with nursing-based education, aged-care specific antibiotic guidelines and regular antibiotic surveillance deemed most useful and feasible. CONCLUSIONS: Areas of antibiotic over-prescribing have been identified from different healthcare providers' perspectives. However, concern about the clinical impact of antibiotic resistance was generally lacking. Importantly, information gathered about feasibility, barriers and facilitators of various AMS interventions will provide important insights to guide development of AMS programs in the RACF setting.

Prevalence of multidrug-resistant organisms and risk factors for carriage in long-term care facilities: a nested case-control study.

BACKGROUND: Long-term care facilities (LTCFs) are a potentially important reservoir of multidrug-resistant (MDR) organisms; however, limited data exist. METHODS: A point-prevalence study was conducted in four co-located LTCFs in Australia. Nasal and rectal swabs were cultured for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and MDR Gram-negative bacilli (GNB). Molecular typing and resistance detection were performed. Risk factors for colonization with an MDR organism were determined using a nested case-control study. RESULTS: Consent was obtained from 115 (85%) of 136 eligible participants. Forty-one (36%) residents carried at least one type of MDR organism. The prevalence was 16% MRSA (n = 18), 6% VRE (n = 7) and 21% MDR GNB [n = 24; including extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli (n = 12) and Acinetobacter baumannii (n = 6)]. The majority of ESBL-producing E. coli and A. baumannii were clonal. Current wound management [adjusted OR (AOR) 8.81 (95% CI 2.78-27.94), P < 0.001], medical device in situ [AOR 5.58 (95% CI 1.34-23.32), P = 0.018] and pressure ulcer [AOR 3.69 (95% CI 1.06-12.86), P = 0.04] were independent risk factors for MDR organism colonization. Advanced dementia [AOR 3.54 (95% CI 1.23-10.23), P = 0.02] and prolonged antibiotic use [AOR 2.95 (95% CI 1.01-8.60), P = 0.047] were independently associated with MRSA colonization, whilst current wound management [AOR 15.59 (95% CI 4.85-50.10), P < 0.001] and fluoroquinolone use [AOR 4.27 (95% CI 1.20-15.25), P = 0.025] were risk factors for MDR GNB colonization. CONCLUSIONS: LTCFs are an important reservoir of MDR organisms, with person-to-person transmissions being a potential issue. We have identified several predictors of colonization with MDR organisms, allowing a more targeted management of high-risk residents.

Community-onset bloodstream infection with multidrug-resistant organisms: a matched case-control study.

BACKGROUND: Multidrug-resistant (MDR) organisms have been increasingly reported at hospital admission. Recognising the magnitude, trend and predictors for MDR organisms in community-onset bloodstream infections (COBSI) is crucial for guiding empiric antibiotic prescribing. METHODS: Positive blood culture isolates recovered from patients presenting to the emergency department during a ten-year period (1st Jan 2002-31st Dec 2011) were assessed. Trend analyses of MDR organisms were performed. Risk factors for COBSI caused by an MDR organism and predictors for 30-day mortality were also determined. RESULTS: A total of 1721 positive blood culture isolates were identified during the study period with a yearly incidence of 30-43 isolates/10 000 ED presentations. The proportion of MDR Escherichia coli causing COBSI increased from 9%-26% (P < 0.001), whilst methicillin-resistant Staphylococcus aureus remained at high levels (20%-30%). A total of 360 patients were included in a matched case-control (1:1) study, and residents in long-term care facilities (adjusted odds ratio [AOR], 4.9 [95% CI, 2.1-11.6]), home wound care (AOR, 5.5 [95% CI, 1.6-18.7]), underlying immunosuppression (AOR, 3.5 [95% CI, 1.6-7.7]), recent surgery (AOR, 3.5 [95% CI, 1.1-11.6]), and exposure to antibiotics within 3 months (AOR, 5.5 [95% CI, 2.8-10.6]) were independently associated with MDR COBSI. High risk source of COBSI, age and Pitt bacteraemia score were independent predictors for 30-day mortality. CONCLUSIONS: A concerning trend in MDR organisms causing bloodstream infection from the community is occurring. Risk factors for MDR organisms have been identified to assist in empiric antibiotic prescribing for those presenting to hospital with sepsis.

Reducing inappropriate antibiotic prescribing in the residential care setting: current perspectives.

Residential aged care facilities are increasingly identified as having a high burden of infection, resulting in subsequent antibiotic use, compounded by the complexity of patient demographics and medical care. Of particular concern is the recent emergence of multidrug-resistant organisms among this vulnerable population. Accordingly, antimicrobial stewardship (AMS) programs have started to be introduced into the residential aged care facilities setting to promote judicious antimicrobial use. However, to successfully implement AMS programs, there are unique challenges pertaining to this resource-limited setting that need to be addressed. In this review, we summarize the epidemiology of infections in this population and review studies that explore antibiotic use and prescribing patterns. Specific attention is paid to issues relating to inappropriate or suboptimal antibiotic prescribing to guide future AMS interventions.

Surveillance of infection burden in residential aged care facilities.

OBJECTIVES: To explore the burden of illness associated with infectious syndromes and to measure the associated use of antimicrobials in residential aged care facilities (RACFs). DESIGN, SETTING AND SUBJECTS: Retrospective analysis of data for January 2006 to December 2010 from an infection surveillance system covering residents of four co-located RACFs, with a total of 150 residential care beds, in Melbourne, Victoria. MAIN OUTCOME MEASURES: Number of episodes and incidence of health care-associated infection (HCAI); rate of antimicrobial use; prescribing concordance with McGeer criteria for infection; frequency of clinical specimen collection. RESULTS: There were 1114 episodes of an infectious syndrome over 267, 684 occuppied bed-days (OBD), affording an average HCAI rate of 4.16 episodes/1000 OBD annually over 5 years (95% CI, 3.92-4.41). The mean rate of antimicrobial use was 7.07 courses/1000 OBD (range, 6.71-7.84). Around 40% of antimicrobial prescribing was for episodes that did not fulfil the McGeer criteria for clinical infection; this included about half of suspected urinary tract and upper respiratory tract infections (URTI), and about one-third of suspected lower respiratory tract and skin infections. Antimicrobials were routinely prescribed for URTI and bronchitis. Of all episodes treated with antimicrobials, 36% had documentation that a clinical specimen was obtained. CONCLUSIONS: The HCAI rate remained relatively stable over time. Routine surveillance and feedback of infection rates to the facilities did not result in a noticeable decrease of infection burden over time. It is of immediate concern that antimicrobials were being prescribed for a large proportion of suspected infections that did not meet criteria for clinical infection. Opportunities exist to further improve the use of antimicrobials in the RACF setting.

Accumulation of transferrin in Caco-2 cells: a possible mechanism of intestinal transferrin absorption.

Transferrin receptor (TfR)-mediated endocytosis and transcytosis in enterocyte-like Caco-2 cells was investigated in order to elucidate the transport mechanism of orally administered Tf-fusion proteins. Cellular uptake and pulse chase studies were performed in Caco-2, MCF-7 and bladder carcinoma (5637) cells using 125I-labeled Tf (125I-Tf). Co-localization studies of Rab 11 and FITC-Tf endocytosed at either the apical or basolateral membrane were performed in polarized Caco-2 cells grown on Transwells, using confocal laser scanning microscopy (LSM510, Zeiss). Unlike in MCF-7 or 5637 cells, where rapid recycling of Tf was observed, a significant amount of endocytosed 125I-Tf accumulated in Caco-2 cells. This accumulation was especially noticeable with the internalization of 125I-Tf from the apical membrane of polarized Caco-2 cells. Confocal microscopy studies showed that apically, but not basolaterally, endocytosed FITC-Tf was delivered to a Rab11-positive compartment. Our results suggest that a significant amount of apically endocytosed Tf in intestinal epithelial cells is transported to a Rab11-positive compartment, possibly a late endosomal and slow recycling compartment. The Rab11-positive compartment may control the release of apically internalized Tf for either slow recycling to apical membrane or processing to transcytotic compartments.

Comparison of monomeric and oligomeric transferrin as potential carrier in oral delivery of protein drugs.

Oligomeric transferrin (Tf) was used to investigate the effect that cross-linking of transferrin receptors (TfR) has on intracellular trafficking of the Tf-TfR complex and to determine whether or not the Tf-oligomer would be a better carrier than monomeric Tf for the oral delivery of protein drugs. The intracellular retention and transcytosis of the Tf-oligomer was determined by performing pulse chase studies on enterocyte-like Caco-2 cells. The intracellular retention of the Tf-oligomer was 2-fold higher than that of monomeric Tf while there was no significant difference in transcytosis. However, in vivo studies in CF-1 mice showed that the plasma concentrations of Tf from the orally administered Tf-oligomer were approximately 2-, 3- and 60-fold higher than that of orally administered monomeric Tf at 24, 48 and 72 h post-administration, respectively. In addition, the retention of the Tf-oligomer in the intestine was higher than that of monomeric Tf, which was consistent with in vitro studies. Insulin (In), when conjugated to the Tf-oligomer (Agg-Tf-S-S-In), was more effective than monomeric Tf-In conjugate (Mono-Tf-S-S-In) in reducing blood glucose levels when orally administered to streptozotocin (STZ)-induced diabetic rats. Post-oral administration of Agg-Tf-In, a delayed onset and prolonged hypoglycemic effect was observed. These results demonstrate that the cross-linking of TfR induced by the binding of the oligomeric Tf alters the intracellular trafficking and increases the intracellular retention of Tf-TfR complexes in polarized Caco-2 cells. The alteration of TfR trafficking could conceivably have caused the increase of insulin transport across the intestinal barrier when Agg-Tf-S-S-In was administered orally to STZ-induced diabetic rats. The delayed onset and prolonged effect of Agg-Tf-S-S-In in hypoglycemia strongly suggests that the Tf-oligomer can act as a sustained release carrier in the oral delivery of protein and peptide drugs.

Transferrin-oligomers as potential carriers in anticancer drug delivery.

PURPOSE: To investigate if the cross-linking of transferrin receptor (TfR) induced by Tf-oligomers alters the endocytosis of receptor-ligand complexes in cultured tumor cells and hence increases intracellular drug release. METHODS: An average of 3.5 Tf molecules per aggregate were cross-linked either by using homobifunctional linker (1, 11-bis-maleimidotetraethyleneglycol) [Tf(3.5-BM(PEO)4)] or heterobifunction linker [succinimidyl 4-(-p-maleimidophenyl)-butyrate] (Tf(3.5-SMPB)). Cell surface binding and competition experiments with 125I-Tf for TfR binding were studied to demonstrate that Tf-oligomers maintain specificity of the TfR-binding. To determine the degradation of Tf-oligomers in TfR-mediated endocytosis, cultured tumor cells were pulsed for 15 min with 125I-Tf-oligomers and chased for 2 h at 37 degrees C in the presence of excess unlabeled Tf. The chase medium was subjected to TCA precipitation to separate the intact and degraded Tf. To investigate if the alteration of TfR-trafficking facilitates the intracellular release of the drug from the Tf-conjugated form, methotrexate (MTX) was conjugated to Tf-oligomer (Agg-Tf-MTX) and its antiproliferative activity was compared with monomeric-Tf-MTX (Mono-Tf-MTX) in human colon carcinoma (Caco-2) cells, human breast adenocarcinoma (MCF-7) cells, wild-type Chinese hamster ovary (CHO) cells, and MTX-resistant CHO (CHO-MTX-RII) cells. RESULTS: TfR-mediated degradation of Tf-oligomers was higher than that of monomeric Tf in both Caco-2 and MCF-7 cells. The IC50 of Agg-Tf-MTX was lower than that of Mono-Tf-MTX in both tumor cell lines. The IC50 of MTX and Mono-Tf-MTX in CHO-MTX-RII cells was higher than that in wild-type CHO cells, whereas the Agg-Tf-MTX was almost identical in both the resistant and wild-type cells. CONCLUSIONS: Cross-linking of TfR induced by oligomeric Tf binding alters the intracellular trafficking of Tf-TfR complexes, redirects them out of the recycling pathway, and targets them to intracellular degradation in cultured tumor cells. The alteration of TfR-trafficking facilitates the intracellular release of the drug from the Tf-conjugated form. Consequently, Agg-Tf-MTX is more effective than Mono-Tf-MTX as a TfR-mediated antiproliferative agent in tumor cells, as well as in MTX-resistant transport deficient cells. Therefore, Tf-oligomers are potentially effective TfR-targeting carriers for intracellular delivery of anticancer drugs.